T.-H. Kim

Clinical importance of inflammatory facet joints of the spine in ankylosing spondylitis: a magnetic resonance imaging study

Objectives: The aims of this study were to assess the reliability of a novel magnetic resonance imaging (MRI) scoring system for inflammatory lesions of facet joints and to clarify the clinical significance of facet joint inflammation in ankylosing spondylitis (AS). Method: A total of 53 AS patients (45 males, 84.9%) were assessed for active inflammatory lesions involving the facet joints, as indicated by bone marrow oedema, at 23 discovertebral units (DVUs) between C2 and S1 using a novel scale, the AS Activity of the Facet joint (ASAFacet). The reliability of the ASAFacet was evaluated using intraclass correlation coefficients (ICCs) and Bland–Altman plots. Results: ICC values for the ASAFacet scores were 0.857 [95% confidence interval (CI) 0.741–0.919] for inter-observer and 0.941 (95% CI 0.873–0.969) for intra-observer reliability. Inflammatory activity scores in facet joints were evenly distributed at all spine levels (p = 0.294 for ASAFacet), whereas vertebral body inflammation was more prominent in the thoracic spine than in the cervical and lumbar spine [p < 0.001 for the AS spine MRI activity (ASspiMRI-a) score, p = 0.002 for the Berlin method, and p < 0.001 for the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index]. ASAFacet scores were closely associated with erythrocyte sediment rate (ESR) and C-reactive protein (CRP) levels (p < 0.05, respectively). Patients with peripheral arthritis had fewer lesions involving the vertebral bodies or facet joints than patients without peripheral arthritis (p < 0.001 for the four different MRI activity indexes). Conclusions: This study suggests that recognition of facet joint inflammation has the potential to contribute to our understanding of clinical outcomes in AS.

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 (2.5u2009million 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

OP0027 Characteristics of cytokines and changes in interleukin-17 levels in the synovial fluid of patients with ankylosing spondylitis on treatment with biologics

Background Biologic drugs targeting the inflammatory cytokines have been recommended in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Yet, some patients require a change in treatment because an adequate response is not achieved. Objectives The current study aimed to evaluate the levels of tumour necrosis factor alpha (TNF-α), interleukin (IL)−17, IL-23, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the joint fluid in patients with AS and RA and identify the important cytokines related with treatment-response. Methods Synovial fluid was obtained from 18 patients with AS and 19 with RA who suffered from arthritis of the knee; and the levels of the cytokines were measured. The differences in their levels between patients with AS and RA, and between patients treated with and without biologics (biologics group and non-biologics group) were analysed. Results TNF-α and GM-CSF levels in patients with AS were significantly lower than those in patients with RA (figure 1A, both p<0.01); however, IL-17 and IL-23 levels were not significantly different between the two groups. Furthermore, levels of IL-17 were markedly elevated in the biologics group compared with the non-biologics group in AS (figure 1B, p=0.04). However, in RA, there were no significant differences between the non-biologics and biologics group (figure 1C). Conclusions In AS, IL-17 in synovial fluid is a good marker of non-response to biologics and may be a good target for non-responders to TNF inhibitor. Disclosure of Interest None declared

AB0336 Magnetic resonance imaging-assessed synovial and bone changes in hand and wrist joints of rheumatoid arthritis patients

Background Magnetic resonance imaging (MRI) is a sensitive and useful method for the detection of synovitis and joint destruction in rheumatoid arthritis (RA) patients. However, the patterns of MRI-detected bone erosion, bone marrow edema (BME), synovitis, and tenosynovitis have received insufficient attention. Objectives Therefore, this study evaluated the patterns of bone erosion, BME, synovitis, and tenosynovitis, and calculated the RA-MRI score (RAMRIS) of patients with RA at the carpal and metacarpophalangeal (MCP) joints using MRI. Methods MRI datasets from 43 RA patients were analyzed. All patients had undergone MRI of one wrist. In addition, 36 patients had MCP joint images taken, and 3 had also received MRI of the contralateral wrist and MCP joints. The MR images were evaluated for bone erosion, BME, and synovitis in consensus by 2 blinded readers according to the OMERACT RA-MRI score (RAMRIS). The MRI-detected tenosynovitis was evaluated based on Haavardsholms tenosynovitis score. Results The capitate, lunate, triquetrum, and hamate bones were the most common sites of erosion and BME and showed the highest RAMRIS erosion and BME scores. Moreover, MRI-detected tenosynovitis was present in 78.3% of all patients with RA, and the extensor compartment 4 and flexor digitorum profundus and superficialis were frequently affected. Conclusions This study identified the distribution and prevalence of MRI-detected bone erosion, BME, synovitis, and tenosynovitis of the wrist and MCP joints in RA patients. The patterns of the MRI-detected abnormalities may help to select sites for the application of MRI protocols in clinical trials and practice. References Ejbjerg B, McQueen F, Lassere M, Haavardsholm E, Conaghan P, OConnor P, et al. The EULAR-OMERACT rheumatoid arthritis MRI reference image atlas: the wrist joint. Annals of the rheumatic diseases. 2005;64 Suppl 1:i23–47. Ostergaard M, Edmonds J, McQueen F, Peterfy C, Lassere M, Ejbjerg B, et al. An introduction to the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas. Annals of the rheumatic diseases. 2005;64 Suppl 1:i3–7. Conaghan P, Bird P, Ejbjerg B, OConnor P, Peterfy C, McQueen F, et al. The EULAR-OMERACT rheumatoid arthritis MRI reference image atlas: the metacarpophalangeal joints. Annals of the rheumatic diseases. 2005;64 Suppl 1:i11–21. Haavardsholm EA, Ostergaard M, Ejbjerg BJ, Kvan NP, Kvien TK. Introduction of a novel magnetic resonance imaging tenosynovitis score for rheumatoid arthritis: reliability in a multireader longitudinal study. Annals of the rheumatic diseases. 2007;66(9):1216–20. Acknowledgements The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Disclosure of Interest None declared

SAT0154 Effectiveness and safety of CT-P13 in patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis: observational study in republic of korea

Background CT-P13 is approved as a biosimilar of innovator infliximab for marketing in 79 countries around the world. After approval, observational study has been conducted in Republic of Korea in patients with Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS), Psoriatic Arthritis (PsA) and Plaque Psoriasis (PS). Objectives To evaluate the effectiveness and safety of CT-P13 under routine care in Republic of Korea. Methods This observational study included both biologic naïve patients (Naïve group) and patients who switched from other anti-tumor necrosis factor (TNF)s to CT-P13 (Switch group). Effectiveness were evaluated based on remission (DAS28≤2.6 in RA, BASDAI<3 in AS and absence of swollen and tender joint counts in PsA), and response (BASDAI 20/50/70 in AS and PASI 50/75 in PS). Adverse events (AEs) were collected over 6 month period. Results Total 940 patients (400 with RA, 531 with AS, 3 with PsA and 6 with PS) were registered and 338 (36.0%) patients (108 with RA, 228 with AS, 2 with PS) who switched to CT-P13 were included. The proportion of patients achieving remission was similar between Naïve and Switch groups in both RA and AS during post-baseline visits (Table 1). In RA, the proportion of patients achieving each disease activity category by DAS28 was similar between Naïve and Switch groups (Figure 1). The proportion of patients who achieved BASDAI 20/50/70 response gradually increased from week 6 to week 24 or 30 in Naïve group with AS (Figure 1). Fifty percent of naïve patients with PsA achieved clinical remission. The proportions of both PASI 50 and 75 responses were 50% at Week 22 in Naïve group and were 100% and 50% in Switch group, respectively during post-baseline visits in PS patients. Throughout this study, treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events (TESAE) were reported as Table 2. Only 11% of patients experienced infection.Table 1. Clinical remission in RA and AS Naïve Switch Baseline Post-baseline Baseline Post-baseline RA DAS28 (ESR) 0/181 (0.0%) 24/182 (13.1%) 0/25 (0.0%) 5/25 (20.0%) DAS28 (CRP) 0/180 (0.0%) 43/179 (24.0%) 2/25 (8.0%) 6/24 (25.0%) AS BASDAI 2/292 (0.7%) 199/292 (68.2%) 112/209 (53.6%) 150/210 (71.4%)Table 2. Summary of safety results n/N (%) RA AS PsA PS TEAE 198/400 (49.5) 183/531 (34.5) 1/3 (33.3) 3/6 (50.0) TEAE related with CT-P13 73/400 (18.3) 64/531 (12.1) 0/3 (0.0) 2/6 (33.3) TESAE 52/400 (13.0) 14/531 (2.6) 0/3 (0.0) 1/6 (16.7) TESAE related with CT-P13 15/400 (3.8) 6/531 (1.1) 0/3 (0.0) 0/6 (0.0) Infusion-related reactions 28/400 (7.0) 11/531 (2.1) 0/3 (0.0) 0/6 (0.0) Conclusions CT-P13 is efficacious and well-tolerated in RA/AS/PsA/PS patients. Efficacy and safety results in patients treated with CT-P13 were clinically consistent to historical data [1,2,3]. Especially, Switch group results showed that CT-P13 provides a useful alternative to other anti-TNFs. References Kobayashi et al (2016). Hetland et al (2005). Hetland et al (2010). Disclosure of Interest D.-W. Kim: None declared, T.-H. Kim: None declared, S. R. Kwon: None declared, E. Y. Lee: None declared, C.-N. Son: None declared, Y. S. Kim: None declared, S. H. Kim: None declared, Y.-B. Park: None declared, J.-W. Hur: None declared, H.-S. Lee: None declared, S. J. Lee Employee of: CELLTRION,Inc., S. H. Lee Employee of: CELLTRION,Inc.

AB0120 Accelerated osteogenic differentiation of human bone-derived cells in ankylosing spondylitis

Background Ankylosing spondylitis (AS) is characterized by excessive bone formation with syndesmophytes, leading to bony ankylosis. The contribution of osteoblasts to the pathogenesis of ankylosis is poorly understood. Objectives The aim of this study was to determine molecular differences between disease controls (Ct) and AS bone-derived cells (BdCs) during osteogenic differentiation. Methods We confirmed osteoblastic differentiation of Ct and AS BdCs under osteogenic medium by observing morphological changes and measuring osteoblastic differentiation markers. Osteoblast differentiation was detected by alkaline phosphatase (ALP) staining and activity, and alizarin red S and hydroxyapatite staining. Osteoblast-specific markers were analyzed by qRT-PCR, immunoblotting, and immunostaining. To examine the effects of inflammation, we added AS and healthy control serum to Ct and AS BdCs, and then analyzed osteoblast-specific markers. Results AS BdCs showed elevated basal intercellular and extracellular ALP activity compared to Ct. When osteoblast differentiation was induced, AS BdCs exhibited higher expression of osteoblast-specific marker genes and faster mineralization than Ct BdCs, indicating that these cells differentiated more rapidly into osteoblasts. ALP activity and mineralization accelerated when serum from AS patients was added to Ct and AS BdCs. Conclusions Our results revealed that AS BdCs showed significantly increased osteoblastic activity and differentiation capacity by regulating osteoblast-specific transcription factors and proteins compared to Ct BdCs. Active inflammation caused by adding AS serum accelerated bony ankylosis. Our study could provide useful basic data for understanding the molecular mechanism of ankyloses in AS. Disclosure of Interest None declared

AB0713 Spectrum of Atlantoaxial Ankylosis (AAA) in The Ankylosing Spondylitis (AS): Is It Really Chronological Changes That Occur with Disease Progression or Are There Two Completely Different Pathways?

Background The morphologic characteristics of atlantoaxial ankylosis in AS patient and suggests different pathways of involvement resulting in atlantoaxial subluxation in AS patients Objectives To evaluate morphologic characteristics of AAA in AS patient and classify them into categories which reflects the end-stage manifestations of two differents disease pathways. Methods Plain radiographs of cervical spine in 62 AS patients with AAA were reviewed. We classified AAA in AS patients into three subtypes: loss of atlantodental interval (type I), ankylosis of facet joint (type II) and ankylosis of anterior longitudinal ligament or anterior atlantooccipital membrane with cervical spine (type III). And then, we categorized 62 AS patients with AAA into two subgroups: group A (21 patients) with only synovial joint involvement of AS (type I or type II or both) and group B (41 patients) with enthesis involvement of AS with additional synovial joint involvement (type III plus type I or type II or both). We compared the results of mSASSS and disease duration between group A and B. Results The mean cervical mSASSS of patients in group A and B were 27.3 and 16.0 each (p value, 0.196). The mean duration of AS patients in group A and B were 23.7 and 23.6 years each. There was no siginificant differences in cervical, lumbar and total mSASSS or disease duration between the two groups. Conclusions We propose that atlantoaxial joint involvement in the AS patients is not chronological changes that occur with disease progression, but rather it is end-stage manifestation of two different pathways: one only involving synovial joint and the other one involving both synovial joint and enthesis. References Martel W. The occipito-atlanto-axial joints in rheumatoid arthritis and ankylosing spondylitis. Am J Roentgenol Radium Ther Nucl Med 1961;86:223–240 Meijers KA, van Voss SF, Francois RJ. Radiological changes in the cervical spine in ankylosing spondylitis. Ann Rheum Dis1968;27:333–338 Lee HS, Kim TH, Yun HR, Park YW, Jung SS, Bae SC, et al. Radiologic changes of cervical spine in ankylosing spondylitis.Clin Rheumatol 2001;20:262–266 Laiho K, Kauppi M. The cervical spine in patients with ankylosing spondylitis. Clin Exp Rheumatol 2002;20:738 Disclosure of Interest None declared

OP0270 Targeting IL-23 Can Attenuate Progression of Spinal Ankylosis in Ankylosing Spondylitis

Background IL-23 has been implicated in the development of ankylosing spondylitis (AS). The role of IL- 23 in AS pathogenesis has emerged as a therapeutic target. This study aimed to clarify that anti IL-23 blockade can prevent progression of bony ankylosing in AS patients. Objectives We investigated endoplasmic reticulum (ER) stress and IL-23 cytokine could play a role in human bone-derived osteoblast cells and blocking it leads to regulation of bone-related genes and/or preventing bone ankylosis in AS. Methods Primary human osteoblast cells were isolated from diced bones of facet joints which were taken from surgical operation of 8 AS patients and 8 healthy controls (HC). The tissues of facet joints in AS were stained and compared with those of HC. Osteoblast differentiation- and ER stress-related genes were determined by quantitative RT-PCR, immunoblotting, immunofluorescence, and immunohistochemistry. Osteoblast activity of all bones-derived osteoblast cells was confirmed by Alkaline Phosphatase activity (ALP) and Alizarin Red (ARS) staining. The ER stress by BIX, selective BIP inducer X, in the regulation of IL-23 expression and secretion was evaluated by quantitative RT-PCR and ELISA. Results We found that elevated RUNX2, BIP, and IL-23 protein expressions were observed at osteoblast cells in human AS compared to HC. In addition, mRNA levels of bone differentiation (ALP, BMP2, COL1A, RUNX2, C/EBPβ, OPG, and OCN) and ER stress (BIP and CHOP)-related genes were highly expressed in human AS. In particular, IL-23 and RUNX2 expressions were significantly increased in AS. BIX-mediated ER stress stimulated induction of osteoblast activity and IL-23 secretion via modulating RUNX2 and C/EBPβ genes. Intriguingly, RUNX2 Knockdown by shRNA impeded ER stress-induced effects. Moreover, osteoblast activity and RUNX2 expression in AS were significantly reduced by IL-23 blockers, but not TNFα blockers. Conclusions This is the first report to show that ER stress, osteoblastic activity, and IL-23 expression in AS were increased compared to HC, suggesting that sustained ER stress induces osteoblast activity and IL-23 expression. Notably, these effects in AS were reduced by IL-23 blockade. Taken together, our results supported that blocking IL-23 may represent a promising therapeutic target to assist and prevent bony progression in AS. Disclosure of Interest None declared

THU0381 The Incidence of Herpes Zoster Infection in Patients with Ankylosing Spondylitis: Analysis from Korean National Health Insurance Service–Cohort Sample Database: Table 1.

Background Herpes zoster (HZ) infection occurs more commonly in patients with underlying autoimmune disease, partially due to immunosuppressive treatment. However, little is known about the incidence of HZ in patients with ankylosing spondylitis (AS), especially who were treated with conventional disease modifying anti-rheumatic drugs (cDMARDs) or TNF inhibitors. Objectives The aims of our study were to investigate the incidence of HZ in AS patients and to determine whether use of cDMARDs or TNF inhibitors could increase the risk of HZ infection in AS patients. Methods We used database of the Korean National Health Insurance Service–Cohort Sample (1,025,340 individuals) from 2002 to 2013, which was age-, gender-, district- and income stratified random sample. We evaluated HZ incidence among three groups (non-DMARD users, cDMARDs [sulfasalazine, methotrexate] users and TNF inhibitor users) based on drug exposure episodes. Cox proportional hazard analysis was performed to investigate the association between treatment group and HZ infection. Results Among 1,079 patients with AS, we identified 54 HZ infections. Crude incidence rates were 11.0 per 1000 patient-years (95% CI, 8.2–14.3) in all AS patients; 9.1 (95% CI, 6.2–12.8) in non-DMARD users, 16.7 (95% CI, 9.1–28.0) in cDMARDs users and 14.1 (95% CI, 6.1–27.8) in TNF inhibitor users, respectively. Adjusted hazard ratio (HR) of HZ infection was higher in cDMARDs users and TNF inhibitor users than in non-DMARD users (Table). In subgroup analysis, TNF inhibitor increased the risk of HZ infection more significantly in female (adjusted HR =8.01; 95% CI, 1.97–32.54) and patients older than 50-yr (adjusted HR =7.29; 95% CI, 1.88–28.21), but not in patients exposed to baseline corticosteroid (95% CI, 0.53–32.84) compared to non-DMARD users.Table 1. Hazard ratio of herpes zoster in ankylosing spondylitis patients according to the treatment regimens Exposures Crude hazard ratio (95% CI) Adjusted hazard ratio (95% CI)a Non-DMARD 1.00 [Reference] 1.00 [Reference] Conventional DMARD 3.11 (1.47–6.58) 3.70 (1.68–8.14) TNF inhibitors 2.60 (1.09–6.19) 3.52 (1.37–9.01) Etanercept 2.57 (0.84–7.91) 3.93 (1.21–12.76) Infliximab 1.71 (0.23–12.75) 2.00 (0.27–15.04) Adalimumab 2.53 (0.56–11.39) 3.40 (0.66–17.53) Switching 6.43 (0.82–50.40) 6.27 (0.72–54.77) aAdjusted for gender, age and baseline corticosteroid use. Conclusions The incidence of HZ in AS patients was 11.0 per 1000 patient-years which is similar to the previously reported incidence in general Korean population. cDMARDs or TNF inhibitors increased the risk of HZ infection in AS patients, especially in female and older patients, which can be considered as target of HZ vaccination in AS population. 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