BackgroundThe genetic studies of tumour necrosis factor inhibitors (TNFi) response in patients with rheumatoid arthritis (RA) have largely relied on the changes in complex disease scores as a measure of treatment response. It is expected that genetic architecture of such complex score is heterogeneous and not very suitable for pharmacogenetic studies.ObjectivesWe aimed to select the most optimal phenotype for TNFi response using heritability estimates using genome-wide association studies (GWAS) in the Korean population.MethodsDisease Activity Scores based on 28 joint counts (DAS28) and Clinical Disease Activity Index (CDAI) were assessed at baseline, and after 6 months in 370 Korean RA patients who started TNFi due to moderate or high disease activity. Genotypes were generated on the Illumina HumanOmni2.5Exome array (2.5 million variants) in TNFi-treated Korean patients with RA. We estimated heritability using a linear mixed-modelling approach (GCTA) for the TNFi drug-response phenotype ΔDAS28, ΔCDAI and its separate components, such as Δ swollen joint count (SJC), Δ tender joint count (TJC), Δ erythrocyte sedimentation rate (ESR), Δ visual-analogue scale of general health (VAS-GH) and Δ provider global assessment of disease activity (PrGA). Furthermore, a multivariate GWAS approach was implemented, analysing separate DAS28 and CDAI components simultaneouslyResultsThe highest heritability estimates were found for ΔPrGA (h2=0.76) and ΔTJC (h2=0.73); lower heritability was found for ΔDAS28 (h2=0.32) with estimates for ΔESR (h2=0.66), ΔSJC (h2=0.62), ΔCDAI (h2=0.60) and ΔVAS-GH (h2=0.53) (all p-value<0.005).ConclusionsOur results indicate that multiple SNPs together explain a substantial portion of the variation in change in provider global assessment of disease activity in TNFi-treated patients with RA. In conclusion, optimal phenotype based on heritability suggests the use of changes in clinical disease activity index (CDAI) including provider global assessment than DAS28 in pharmacogenetic study.Disclosure of InterestNone declared
Background Patients with rheumatoid arthritis (RA) have an increased risk of fracture caused by loss of joint function, medication and decreased bone mineral density (BMD). Objectives This study aimed to identify the incidence rate of fractures in RA patients and to explore the possible risk factors for fractures in RA patients. Methods A total of 3,557 RA patients in the KORean Observational study Network for Arthritis (KORONA) were included in this study. The information of new fractures was obtained through annual patient self-reported questionnaires. Their demographic profile, disease-specific outcomes, history of prior fracture, medications, and available BMD data were collected. The standardized incidence ratio (SIR) for fractures in RA patients was calculated and possible risk factors for fractures were explored using the logistic regression analysis. To identify the effect of bisphosphonate in RA patients with osteoporosis, we further performed logistic regression analysis. Results A total of 3,557 RA patients were included in this study and the 194 patients with 215 fractures were observed over a mean follow-up of 18 months. Vertebral fractures (n=36) were the most common fractures, followed by wrist (n=33) and rib fractures (n=21). Total fracture crude incidence rates were 41, 34.5 and 42.1 per 100,000 person year for total, male, and female patients, respectively. The SIRs of all types and major osteoporotic fractures were 3.11[95% confidence interval (CI) 2.69-3.53], and 1.41 (CI 1.05-1.86), respectively. Patients who have experienced any fracture had older age (p<0.01), longer disease duration (p=0.02), having osteoporosis (p<0.01), history of prior fracture (p<0.01) and were currently using corticosteroid (p=0.03) and bisphosphonates (p<0.01). Since BMD is most strong predictor for future fracture, logistic regression to identify the risk factors for fractures was performed for patients who had BMD data at baseline (n=866), and only having osteoporosis [Odds ratio (OR) 2.69, CI 1.17-6.18, p=0.02] was independently related to incident fracture in RA patients. In addition, older age (OR 1.03, CI 1.00-1.06, p=0.05) tend to increase the fracture incidence. Subgroup analysis for osteoporosis patients (T score <-2.5, n=210), higher functional disability with HAQ increased fracture risk (OR 2.06, CI 1.07-3.96, p=0.03) and the use of bisphosphonate showed a protective effect for future fracture (OR 0.33, CI 0.13-0.83, p=0.02) in RA patients. Conclusions Rheumatoid arthritis patients had a 3-fold increased risk of fractures as compared to those of general population. Classical risk factors for fracture such as osteoporosis with BMD and old age were associated with fractures in RA patients. In RA patients with osteoporosis, higher functional disability was a risk factor for fracture, while the use of bisphosphonate showed protective effect on their future fracture. Acknowledgements This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfar...
Background Early and aggressive treatment offers better outcomes in early rheumatoid arthritis (RA). The long-term effect of early treatment and effect of early treatment on functional disability have not been studied. Objectives To determine whether early diagnosis and treatment have long-term benefits for disease activity and functional disability in patients with RA enrolled in the KORean Observational study Network for Arthritis (KORONA). Methods A total of 4540 rheumatoid arthritis patients completed questionnaires to establish their demographic profile, medical history, disease-specific outcomes, and RA-related information. We defined early and delayed RA diagnoses as lag-times of shorter than and at least 1 year. Disease activity was measured with the DAS28–ESR, and it was dichotomized using a score of 2.6. Functional disability was measured with the Korean HAQ-DI, and was dichotomized using a score of 1. We used the chi-square test and t-test to identify differences between male and female patients, and crude and multiadjusted models to identify the impacts of early diagnosis on disease activity and functional disability. Results In crude and multiadjusted models, early diagnosis was not associated with a higher remission rate (OR 1.10, CI 0.94-1.28 in crude model, OR 1.05, CI 0.83-1.32 in multiadjusted model). We performed subgroup analysis according to disease duration; there was no association between early diagnosis and remission rate. Early diagnosis was associated with functional disability in crude model (OR 0.79, CI 0.68-0.91) but not in multiadjusted model (OR 0.85, CI 0.72-1.002). In subgroup analysis according to disease duration and disease activity, early diagnosis was independently associated with functional disability for a shorter disease duration (OR 0.78, CI 0.63-0.96 in disease duration <10 years) and the presence of moderate-to-severe disease activity (OR 0.83, CI 0.69-0.99 in DAS28-ESR ≥3.2). Image/graph Conclusions Early diagnosis is associated with functional disability especially with a disease duration of less than 10 years and the presence of moderate-to-severe disease activity. Disclosure of Interest None Declared
Background The importance of tight control is supported by solid clinical evidence. While treating RA with the aim of achieving remission or a low disease activity-as determined by disease activity score employing 28 joints count (DAS28) or the simplified and the clinical disease activity index (SDAI, CDAI) -is reasonable and important, this approach is not widely accepted in the clinical situation. Objectives To identify the effects of tight control of rheumatoid arthritis (RA) on various disease outcomes in a large observational study. Methods We selected 1900 RA patients with a baseline DAS28-ESR of more than 3.2 and who had 1 year of follow-up data. The patients were divided into two groups: (1) disease-modifying antirheumatic drugs (DMARDs)-changed group (patients who changed the types or amounts of their DMARDs) and (2) DMARDs-unchanged group (patients who maintained their DMARDs). We measured various disease outcomes, including the Health Assessment Questionnaire–Disability Index (HAQ-DI), DAS28-ESR, C-reactive protein (CRP), ESR, and global health assessments by both physicians and patients. The t-test was used to identify the effects of tight control of RA on various disease outcomes. Results Patients in the DMARDs-changed group were younger, had a shorter disease duration, used less leflunomide, used more biologic agents. At baseline, they had higher DAS28-ESR (4.62±0.96 in DMARDs-changed group versus 4.42±0.90 in DMARDs-unchanged group, p<0.001), CRP (1.15±1.62 versus 0.81±1.14, p<0.001), global health assessment by both physician (34.05±20.00 versus 26.94±18.16, p<0.001) and patient (48.96±25.34 versus 46.18±24.74, p=0.016). In the comparison between baseline and the 1-year follow-up, the DMARDs-changed group showed greater improvements in HAQ-DI (–0.76±1.43 versus –0.59±1.22, p=0.006), CRP (–0.39±1.71 versus –0.11±1.37 mg/dl, p=0.001), and the global health assessment by a physician (–11.21±24.18 versus –8.10±19.20, p=0.002). Image/graph Conclusions Immediate changes in DMARDs according to disease activity can improve disease outcomes, especially DAS28-ESR, CRP, and the global health assessment by a physician. Disclosure of Interest None Declared
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