S.-K. Cho

Genetic associations of LYN with systemic lupus erythematosus.

We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case–control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 × 10−4, odds ratio (OR)=0.81 (95% confidence interval: 0.73–0.90)). This single nucleotide polymorphism (SNP) is located in the 5′ untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 × 10−3, OR=0.75 (95% CI: 0.62−0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.

Histiocytic necrotizing lymphadenitis in the context of systemic lupus erythematosus (SLE): Is histiocytic necrotizing lymphadenitis in SLE associated with skin lesions?:

Histiocytic necrotizing lymphadenitis (HNL), or Kikuchi’s disease, is a benign and self-limiting lymphadenopathy that typically affects young Asian females. It presents with lymphadenopathy, usually cervical, accompanied by fever, chills and leukopenia. Although the association between systemic lupus erythematosus (SLE) and HNL is rare, the number of reports of HNL in SLE patients is increasing. We present nine cases of HNL in patients with SLE. Among the seven patients with diverse skin manifestations, three had skin manifestations that were histologically compatible with SLE. A review of previous reports in the literature showed that cutaneous involvement was commonly found in HNL in association with SLE. In the patients who had simultaneous onset of both diseases, lupus flare-ups were commonly observed. We suggest that HNL in SLE patients is associated with cutaneous manifestations. This report contributes to our understanding of the relationship between these diseases.

A redundant epistatic interaction between IRF5 and STAT4 of the type I interferon pathway in susceptibility to lupus and rheumatoid arthritis

Objective K. K. and S.-K. C. are co-first authors, and C. K. and S.-C. B. are co-senior authors. Two transcription factors in the type I interferon pathway, IRF5 and STAT4, have been genetically associated with susceptibility to both systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study aimed to determine whether these two genes interact with each other to affect the disease susceptibilities. Methods The genetic interactions between IRF5 and STAT4 polymorphisms in SLE and RA susceptibility were examined using the epistasis options in PLINK software. This study analyzes the genetic data from 2558 unrelated Korean participants including 589 SLE patients, 987 RA patients, and 982 controls. Results All 12 polymorphisms were individually associated with SLE susceptibility (p = 2.49 × 10−8 to 0.00360). Among the three SLE-associated polymorphisms of IRF5, rs77571059, alternatively called CGGGG(3–4) indel, exhibited the lowest p value (4.60 × 10−5) and accounted for the observed associations of the other two single-nucleotide polymorphisms (SNPs). Among the nine SLE-associated SNPs of STAT4, rs16833215 exhibited the lowest p value (2.49 × 10−8) and accounted for all the other associations. These two polymorphisms, rs77571059 of IRF5 and rs16833215 of STAT4, interacted with each other for SLE susceptibility in a redundant manner (ORinteraction = 0.77, Pepistasis = 0.040). Furthermore, these two polymorphisms, which had been individually associated with RA susceptibility, also interacted for RA susceptibility in the same manner (ORinteraction = 0.75, Pepistasis = 0.014). Conclusions A redundant interaction between IRF5 and STAT4 polymorphisms was found in susceptibility to the type I interferon pathway-associated rheumatic autoimmune diseases, SLE and RA, calling for further studies on confirmation of these findings.

AB0014 Genetic influence of different measure for tumour necrosis factor inhibitors response in rheumatoid arthritis

Background The 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. Objectives We aimed to select the most optimal phenotype for TNFi response using heritability estimates using genome-wide association studies (GWAS) in the Korean population. Methods Disease 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 simultaneously Results The 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). Conclusions Our 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 Interest None declared

AB0966 Cross-cultural adaptation and validation of the korean version of the functional index for hand osteoarthritis (FIHOA)

Background Osteoarthritis (OA) is one of the most common type of arthritis and it most frequently involves joints of the hands. Measuring functional ability of hand OA patients is important in terms of assessment of treatment response, patient management and improvement of quality of life. The functional index for hand osteoarthritis (FIHOA) is one of the most frequently utilised questionnaire to assess the physical function of hand OA patients. The FIHOA has been translated into 17 languages, however, no Korean version of FIHOA is yet available. Objectives To translate the FIHOA into Korean, and establish the reliability and validity of the cross-culturally adapted Korean version of FIHOA (K-FIHOA) in patients with hand OA. Methods The FIHOA was translated into Korean following cross-cultural adaptation guidelines. The K-FIHOA was pretested in 40 hand OA patients (defined by ACR classification criteria). The adapted K-FIHOA was then administered to 100 consecutive hand OA patients together with the modified Health Assessment Questionnaire (mHAQ) and visual analogue scale (VAS) for hand pain. The test-retest reliability of each item and total scores were assessed using Spearman’s correlation coefficient and intraclass correlation coefficient (ICC). The internal consistency reliability was evaluated as the Cronbach’s alpha. The external construct validity was assessed using correlation between K-FIHOA and mHAQ and hand pain VAS. ResultsAbstract AB0966 – Table 1 K-FIHOA items Test-retest reliability Internal consistency Test Retest Spearman’s correlation coefficient ICC Adjusted item-totalCorrelation Item-item correlation Cronbach’s alpha if item is deleted Item 1 0.19±0.54 0.20±0.55 0.63 0.58 0.37 0.20–0.36 0.88 Item 2 0.25±0.59 0.25±0.59 0.58 0.54 0.51 0.26–0.48 0.88 Item 3 0.22±0.60 0.25±0.61 0.73 0.74 0.52 0.31–0.60 0.87 Item 4 0.35±0.66 0.30±0.59 0.62 0.58 0.59 0.33–0.52 0.87 Item 5 0.83±1.06 0.74±1.04 0.76 0.74 0.70 0.33–0.62 0.87 Item 6 0.40±0.85 0.40±0.88 0.66 0.75 0.63 0.22–0.73 0.86 Item 7 0.43±0.88 0.32±0.74 0.70 0.71 0.70 0.32–0.73 0.86 Item 8 0.19±0.53 0.13±0.37 0.62 0.56 0.47 0.25–0.60 0.87 Item 9 1.10±1.16 1.07±1.16 0.81 0.79 0.74 0.28–0.62 0.88 Item 10 0.43±0.79 0.39±0.69 0.85 0.80 0.44 0.20–0.52 0.88 Values are given as mean ±standard deviation. Abbreviations: K-FIHOA, the Korean version of functional index of hand osteoarthritis; ICC, intra-class correlation coefficient. The mean total score of the K-FIHOA was 4.39 [Standard deviation (SD=5.56)] in the first assessment and 4.04 (SD=5.22) in the second assessment. The test-retest reliability for the total score was strong (r=0.87 and ICC=0.75). Spearman’s rho for single item correlation ranged from 0.58 to 0.85 and ICC between single items were good or excellent (0.54–0.80). Cronbach’s alpha was high (0.88) suggesting a strong internal coherence in the items of the questionnaire. We identified significant correlations between K-FIHOA and hand pain VAS (r=0.53, p<0.01), mHAQ (r=0.52, p<0.01), and mHAQ hand function score (r=0.57, p<0.01).Abstract AB0966 – Figure 1 External construct validity of K-FIHOA with hand pain VAS, mHAQ, mHAQ hand function. Conclusions The K-FIHOA is a reliable and valid instrument for evaluating functional disability in Korean hand OA patients. Disclosure of Interest None declared

SAT0714 Increased risk of opportunistic infection in the early stage of rheumatoid arthritis

Background The increased risk of opportunistic infections (OIs) in rheumatoid arthritis (RA) patients who started biologic disease modifying anti-rheumatic drugs (DMARDs) has been well known. However, it has not been studied regarding the increased risk of OIs in the early stage of RA. Objectives To study the increased risk of incidence rate (IR) of OIs in early RA patients compared with established RA patients, and to evaluate the risk factors for developing the OIs in the early stage of RA. Methods Retrospective cohorts of early and established RA patients were conducted independently using the Korean National Healthcare claims database. Early RA patients (n=14,081) were identified in 2010 having disease free period for 1 year before index date, and receiving continuous treatment for over three years. Established RA patients (n=226,838) were recruited between 2010 and 2012 with using the ICD10 code of RA and any DMARD use. Follow-up started on the index date and ended on the data of the development of OIs, at 12 months, or at the time of death. The incidence rates of OIs were compared between two groups by calculating incidence rates ratio (IRR) and standardized incidence ratio (SIR) for overall or each OIs. The multivariable regression model was used to evaluate the risk factors for OIs in the early stage of RA. Results The IRs of overall OI in early and established RA patients were 3.81 (95% CI 3.52–4.11)/100PY and 3.67 (95% CI, 3.59–3.74)/100PY, respectively. The SIR for overall OIs in early RA patients was 1.14 (95% CI, 1.05–1.23). The herpes zoster (SIR 1.12, 95% CI 1.03–1.22) and candidiasis (SIR 2.40; 95% CI 1.55–3.54) were commonly affected in the early stage of RA patients. Older age more than 50 years old [50<age≤60 (OR 1.74, 95% CI 1.30–2.33), 60<age≤70 (OR 1.85, 95% CI 1.36–2.52), 70<age (OR 1.89, 95% CI 1.34–2.68)], more comorbidities [one comorbidities (OR 1.53, 95% CI 1.24–1.89), ≥2 of comorbidities (OR 1.84, 95% CI 1.47–2.29)], and corticosteroid ≥5mg per day (OR 1.38, 95% CI 1.13–1.69) were associated with increased risk of OIs in the early stage of RA patients.Table 1 Type of opportunistic infection Established RA Early RA SIR comparing early RA patients with established RA patients N=226,838 N=14,081 IR/100PY 95% CI IR/100PY 95% CI SIR 95% CI Total 3.67 3.59–3.74 3.81 3.52–4.11 1.14 1.05–1.23 Tuberculosis 0.71 0.67–0.75 0.70 0.54–0.87 1.06 0.82–1.33 Herpes zoster 2.79 2.72–2.85 2.89 2.64–3.13 1.12 1.03–1.22 Cytomegalovirus 0.02 0.02–0.03 0.03 0.00–0.06 0.98 0.20–2.86 Epstein–Barr virus 0.01 0.00–0.01 0.04 0.00–0.07 3.54 0.96–9.06 Pneumocystis jiroveci pneumonia (PJP) 0.01 0.01 - 0.02 0.02 -0.01–0.04 1.20 0.15–4.34 Candidiasis 0.10 0.08–0.11 0.11 0.07–0.16 2.40 1.55–3.54 Aspergillosis 0.02 0.02–0.03 0.02 0.00–0.05 0.84 0.17–2.47 Cryptococcosis 0.01 0.00–0.01 0.01 -0.01–0.02 1.15 0.03–6.39 RA = rheumatoid arthritis, SIR = standardized incidence ratio, PY = person year, N = number, IR = incidence rate, CI = confidence interval. Conclusions The incidence of OIs is increased in early stage of RA patients compared with established RA patients. Old age, comorbidities, high corticosteroid dose were related with the development of OI. Physicians should be aware of the possible occurrence of OIs in early stage of RA treatment. Disclosure of Interest None declared

AB1193 Developing the korean educational needs assessment tool (KOREAN-ENAT) in rheumatoid arthritis: a cross-cultural validation using rasch analysis

Background The Educational Needs Assessment Tool (ENAT) is a 39-item patient-completed questionnaire designed to help patients identify and prioritize their educational needs. It was originally developed in the UK and validated in 7 rheumatic diseases including rheumatoid arthritis (RA).1 Objectives This study aimed to undertake cross-cultural adaptation and validation of the ENAT in RA for use in Korea. Methods The study involved two main phases: (1) Cross-cultural adaptation of the ENAT from English into Korean and (2) validation of the Korean-ENAT. The first phase followed an established process of cross-cultural adaptation of self-report measures.2 For the second phase, patients with RA completed the Korean-ENAT at the outpatient clinic of a university hospital and Rasch measurement computer program, WINSTEPS, was used to analyze the data. Fit to the model was determined by the observed data Infit and Outfit statistics (≥0.50 and ≤1.50); where a value of 1.00 suggests a perfect fit to the model expectations. The unidimensionality of the scale was determined by item (and person) separation index ≥2.00 and reliability ≥0.80. Results An adequate conceptual equivalence was achieved following the adaptation process. A total of 123 patients completed the Korean-ENAT. Their mean ± SD age was 46.7±12.3, disease duration 53.7±71.2 months and the majority (81.3%) were female. Thirty-five of the 39 items displayed good fit to the model. The 4 items deviating from the model had Infit and Outfit >1.50. The item separation index (5.26) and item reliability index (0.97) provided evidence for good reliability of items. All the 7 domains of the Korean-ENAT were found to fit the Rasch model. The internal consistency of the Korean-ENAT was high and unidimensionality was confirmed (Person separation index =3.41 reliability index =0.92; item separation index =16.82 and reliability index =1.00).Table 1. Fit statistics for the Korean ENAT subscales Infit Outfit Point-biserical correlation Subscales MNSQ ZSTD MNSQ ZSTD PTMEA CORR. Pain 1.31 2.30 1.40 2.80 0.75 Movement 1.00 0.10 1.01 0.10 0.85 Feelings 0.77 -1.90 0.80 -1.60 0.84 Disease 1.27 2.00 1.15 1.00 0.84 Treatments 1.30 2.20 1.21 1.40 0.85 Self-help 1.05 0.50 1.08 0.70 0.84 Support 0.75 -2.10 0.75 -2.10 0.83 MNSQ = mean-square; ZSTD = z-standardized; MNSQ between ≥0.50 and ≤1.50 for model fit. Conclusions Using a standard process in cross-cultural adaptation, the ENAT was adapted into Korean and Rasch analysis confirmed that the construct validity, reliability, and unidimensionality of the Korean-ENAT. The Korean-ENAT provides valid and reliable estimates of educational needs of people with RA in Korea. References Ndosi M, et al. Validation of the educational needs assessment tool as a generic instrument for rheumatic diseases in seven European countries. Ann Rheum Dis 2014; 73: 2122–9. Beaton DE, et al. Guidelines for the process of cross-cultural adaptation of self-report measures. Spine 2000; 25: 3186–91. Disclosure of Interest None declared

AB1121 Trabecular bone score combined with clinical risk factors can predict incident fracture in rheumatoid arthritis patients

Background Fracture is one of the most common and important comorbidities in rheumatoid arthritis (RA) patients, especially patients who use glucocorticoids (GC). However, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) which is the gold standard of diagnosing and monitoring osteoporosis is not a useful tool for predicting new fracture in RA patients. Previous studies suggested the possibility of trabecular bone score (TBS) as a useful predictor for incident fracture. Objectives We aimed to evaluate the accuracy of TBS combined with clinical risk factors or BMD for prediction of new fracture in patients with RA. Methods A total of 100 female RA patients were enrolled with assessment of TBS, BMD, and clinical risk factors for fracture. During follow-up period, we calculated the incident rate of all fractures. After dividing the patients according to the use of GCs, we compared baseline characteristics and fracture-free survival between two groups. We compared accuracies of TBS, BMD, clinical risk factors for fracture and their combinations for predicting new fractures using areas under the receiver operator characteristic (ROC) curve (AUC). Results A total of 14 fractures in 12 patients were occurred among 100 patients during follow-up (428.8 person-years): 9 among the 44 in GC users and 5 in 56 GC non-users. Incidence of fracture was not different between two groups (log-rank test, p=0.27). AUC for incident fracture prediction of TBS alone [AUC 0.54, 95% confidence interval (CI) 0.35–0.72] was comparable with TBS combined with L-spine BMD (AUC 0.54, 95% CI 0.36–0.71) or with hip BMD (AUC 0.55, 95% CI 0.37–0.73). Accuracy for prediction of new fracture is increased when TBS was combined with age and history of previous fracture (AUC 0.74, 95% CI 0.62–0.85). In GC users, history of previous fracture alone (AUC 0.79, 95% CI 0.62–0.97) showed the best accuracy for predicting new fracture among TBS, BMD, clinical risk factors for fracture and their combinations. Conclusions TBS combined with age and previous history of fracture showed the highest accuracy for predicting new fracture compared to TBS or BMD alone or their combinations in RA patients. In GC users, history of previous fracture alone showed the highest accuracy for predicting new fracture. References Briot K, Paternotte S, Kolta S, Eastell R, Reid DM, Felsenberg D, et al. Added value of trabecular bone score to bone mineral density for prediction of osteoporotic fractures in postmenopausal women: the OPUS study. Bone 2013;57:232–6. McCloskey EV, Oden A, Harvey NC, Leslie WD, Hans D, Johansson H, et al. A Meta-Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX. J Bone Miner Res 2016;31:940–8. Disclosure of Interest None declared

AB0107 Association Heterogeneity Mapping Identifies An Asian-Specific Association of The GTF2I Locus with Rheumatoid Arthritis

Background Genetic association studies using multiple ancestral cohorts have revealed a large overlap of rheumatoid arthritis (RA)-risk alleles among different ancestries, but there are some exceptional loci showing heterogenic association among populations. Objectives Here we investigated genetic variants with distinct effects on the development of RA in Asian and European populations. Methods Ancestry-related association heterogeneity was examined using the association data from large Korean (n=9,299) and European (n=45,790) rheumatoid arthritis cohorts with Immunochip and genome-wide SNP array data. Novel disease associations detected in Koreans were validated using two independent Asian cohorts (n=5,166) and a meta-analysis. Results We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus and showed that this heterogeneity is due to an Asian-specific association effect (PHeterogeneity =9.6×10-9 at rs73366469 [ORMeta =1.37 and PMeta =4.2×10–13 in Asians; ORMeta =1.00 and PMeta =1.00 in Europeans]) in RA. Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal SNP (rs117026326; linked to rs73366469), whose minor allele is common in Asians but rare in Europeans. Conclusions We identified the largest effect on Asian RA across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant. References Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–81 (2014). Kim, K. et al. High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. Ann Rheum Dis 74, e13 (2015). Acknowledgement This study was supported by the Korea Healthcare Technology R&D Project of the Ministry for Health & Welfare (HI13C2124), the Japanese Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid for Scientific Research (15H04965) and the US National Institutes of Health (R01MD007909 and R01AR060366). *Drs. Kwangwoo Kim and So-Young Bang contributed equally to this work. Disclosure of Interest None declared

SAT0366 The Comparison of Effectiveness in Second-Line Biologic Therapy for Patients with Rheumatoid Arthritis who Failed one TNF Inhibitor: Results from the National Korean Registry

Background RA treatment has improved significantly with the introduction of TNF inhibitor, but it has little or no effect in about 30% of treated patients. According to EULAR recommendation, patients who failed to TNF inhibitor should switch to a different TNF inhibitor or other biologics including abatacept (ABT), rituximab, or tocilizuamb. However, no consensus has been reached on the strategy of switching. Objectives To compare the effectiveness of second-line biologic therapy in RA patients who failed to their fist TNF inhibitor. Methods We recruited 161 patients who switched biologics after failure of one TNF inhibitor from BIOlogics Pharmacoepidemiologic StudY (BIOPSY), a prospective, national biologics registry in Korea. They were divided into two groups according to the first TNF inhibitor: 101 patients with anti-TNF monoclonal antibodies (MABs: infliximab, adalimumab, golimumab) and 60 patients with etanercept (ETN). The patients who failed with the previous MABs were categorized by MABs→MABs (n=21), MABs→ETN (n=41) and MABs→ABT (n=39). The patients who failed with ETN were divided by two groups of ETN→MABs (n=32) and ETN→ABT (n=28). Drug retention rates were compared across the three or two groups according to the first TNF inhibitor using Kaplan-Meier analysis and log-rank test. The Cox regression model was used to compare risk of drug for discontinuation between groups. Results Among three groups from patients treated with MABs, the demographic and clinical characteristics were comparable with age (p=0.99), gender (p=0.35), their disease duration (p=0.24). Concomitant medication with corticosteroid (p=0.86) and methotrexate (p=0.79) were not different, but duration of previous MABs treatment showed statistical significance (10.2±8.3 in MABs→MABs vs. 6.0±6.9 in MABs→ETN vs. 11.4±12.0 in MABs→ABT, months, p=0.03). At starting time of second biologics, disease activity (DAS28ESR 6.4±1.4 vs. 6.0±1.1 vs. 6.4±1.0, p=0.19) and functional disability (HAQ-DI 1.3±0.7 vs. 1.4±0.7 vs. 1.5±0.7, p=0.51) had no statistical significance between three groups. The drug retention rates during 20 months were comparable (53.2% in MABs→MABs vs. 55.9% in MABs→ETN, 66.0% in MABs→ABT, p=0.39). After adjusting confounding factors, the groups of MABs→ABT (HR 0.32, 95% CI 0.11-0.92) and MABs→ETN (HR 0.34, 95% CI 0.12-0.96) showed lower rate of discontinuation of second biologics compared to MABs→MABs as reference. For patients who failed to ENT, demographic and clinical characteristics were comparable between two groups. At starting time of second biologics, disease activity was higher in ETN→ABT than that of ENT→MABs (6.2±1.2 vs. 5.5±1.2, p=0.02), but the drug retention rates during 20months were not statistical different between two groups (29.8% in ENT→MABs vs. 45.7% in ENT→ABT, p=0.14). Conclusions In the clinical practice, switching to ETN or ABT in patients who failed to MABs showed more favorable drug continuation. For patients with previous ETN, both MABs and ABT had similar drug continuation rate. References Emery P, et al. Ann Rheum Dis. 2014 Jan 29. doi: 10.1136/annrheumdis-2013-203993. Disclosure of Interest None declared