H.M. Kwon

FRI0487 Association between Fever Pattern and Clinical Manifestations in Adult Onset of Still's Disease: Unbiased Analysis of Fever Pattern Using Hierarchical Clustering

Background Adult onset of Stills disease (AOSD) is a systemic inflammatory disease characterized by fever, arthritis, salmon pink rash and elevated serum inflammatory markers. The classical fever of AOSD is intermittent with a quotidian or double-quotidian pattern. However, a significant subset of AOSD exhibits persistently high fever with little temperature fluctuation. It remains unclear as to whether the certain fever pattern is associated with specific clinical manifestations. Objectives To investigate the association between fever pattern and clinical characteristics in patients with AOSD. Methods A total of 70 patients with AOSD who were treated as inpatient at Seoul National University Hospital from 2004 through 2015 were enrolled. Patients were grouped based on the fever curves on days 2, 3 and 4 using hierarchical clustering. The clinical and laboratory characteristics of the groups were compared. Results 70 patients were divided into 2 groups based on the fever curves. The group 1 with 14 patients had a higher mean temperature (38.1±0.4°C vs. 37.2±0.5°C, p<0.001) with wider daily variation (2.7±0.9°C vs. 1.9±0.7°C, p<0.001) as compared to 56 patients in the group 2. Group 1 tended to be younger (38.4 ± 14.7 years vs. 46.1 ± 17.6 years, p=0.141) (Figure). Fever, arthritis, arthralgia and rash did not differ between them. However, group 1 tended to have more pericardial and lung involvement (42.9% v.s 23.2%, p=0.181). Group 1 had significantly lower platelet count (198,900 ± 68,000/μl vs. 312,900 ± 156,900/μl, p=0.0001), higher LDH (816.6 ± 376.4 IU/L vs. 477.5 ± 327.1 IU/L, p=0.002), higher mean ferritin level (27,004.1 ± 48,891.5 ug/mL vs. 6,852 ± 10,628.2 ug/mL, p=0.072) and d-dimer (9.5 ±7.9 ug/mL vs 3.3 ± 3.4 ug/mL) as compared to group 2, whereas white blood cell count, hemoglobin levels, CRP levels did note differ between the both groups. Group 1 tended to require longer time to a clinical remission (455.5 ± 850 days vs. 9.4 ± 115.7 days, p=0.137). Conclusions The unbiased analysis of fever reveals the presence of at least 2 distinctive fever patterns in AOSD. Spiking fever with higher daily variation was more often associated with higher inflammatory markers and coagulopathy and required longer treatment. Thus, fever pattern might be a prognostic factor in AOSD and AOSD patients with spiking fever might need more intensified treatment. Disclosure of Interest None declared

OP0094 Survival Benefit of Early Use of Cyclosporine in Dermatomyositis-Associated Interstitial Lung Disease

Background Interstitial lung disease (ILD) is the most common cause of mortality in patients with dermatomyositis (DM). Cyclosporine has been reported to improve clinical outcome in some patients with DM-associated ILD. Objectives To investigate the benefit of early introduction of cyclosporine on the survival of patients with DM-associated ILD. Methods All the patients with DM-associated ILD, who were treated with cyclosporine at Seoul National University Hospital (SNUH) and Seoul National University Bundang Hospital (SNUBH) between 1990 and 2013, were enrolled. Enrolled patients were diagnosed with DM according to Bohan-Peters classification criteria (n=28) or with clinically amyopathic dermatomyositis (CADM) according to Sontheimers classification criteria (n=19). ILD was diagnosed based on the typical findings on computed tomography (CT) and relevant respiratory symptoms or signs. Kaplan-Meier survival analysis was applied to compare overall mortality rates between patients who took cyclosporine as the initial treatment and those as the delayed treatment. Cox regression analysis was used to estimate the benefit of early treatment with cyclosporine after adjusting confounding characteristics. Results Among the 47 patients who were diagnosed with DM-associated ILD, 16 patients (34.04%) received cyclosprorine initially after diagnosis and 31 patients (65.96%) received cyclosporine after the trial of other immunosuppressants such as corticosteroids, cyclophosphamide or azathioprine. The mean time of follow-up was 43.57 person-years in initial treatment group and 76.23 person-years in delayed treatment group. The mortality rate was significantly lower in the initial treatment group than the delayed treatment group (0.02 person-years vs 0.18 person-years, p=0.0092 by log-rank test). The two groups did not differ in regard to age, sex, duration of disease, presence of autoantibodies, degree of dyspnea at initial visit, initial requirement of oxygen supplement, functional vital capacity (FVC) and diffusion capacity (DLCO) on pulmonary function test (PFT) and the presence of malignancy. Only the proportion of patients with CADM was higher in the initial treatment group than in the delayed treatment group (62.53% vs 29.03%, p=0.027). Survival benefit in the initial cyclosporine treatment remained significant even after adjusting for the CADM status (HR 0.075, 95% CI 0.009 - 0.603, p=0.015 by Cox-regression analysis). Figure 1. Survival curve in initial and delayed use of cyclosporin in patients with dermatomyositis-associated interstitial lung disease. Conclusions This study showed significant survival benefit of initial cyclosporine treatment in patients with DM-associated ILD. A randomized controlled study is warranted to clearly demonstrate the therapeutic benefit of early use of cyclosporine in this potentially fatal disease. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3718

AB0622 Clinical Characteristics of Systemic Sclerosis Patients with Interstitial Lung Disease Who do not Require Immunosuppressive Treatment

Background Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs. Although interstitial lung disease (ILD) is a major cause of death in this disease, pulmonary function remains stable in a subset of SSc patients with ILD without any treatment. However, clinical characteristics in this subset of patients are not well characterized. Objectives To investigate clinical characteristics of SSc patients with ILD who do not require additional immunosuppressive treatment for ILD. Methods A total of 151 SSc patients with ILD who received medical care at Seoul National University Hospital between 1978 and 2013 were enrolled in this study. ILD was diagnosed based on chest computed tomography (CT) and the extent of ILD was semi-quantitatively graded into 1-4 (grade 1, <25%; grade 2, 25–50%; grade 3, 50–75%; grade 4, >75% of lung involvement). Detailed baseline clinical characteristics were obtained from medical record review. Mortality was ascertained from medical record review and data from the Statistics Korea. After confirming survival benefit of untreated group versus treated group with Kaplan Meier analysis, clinical characteristics of untreated group were defined by comparison with treated group (chi-square test or Student t-test). Sensitivity test was performed by proving survival benefit of patients with the defined characteristics in the untreated group (log-rank test). Results The mean (standard deviation) age at diagnosis of 151 patients was 48.7 (12.9) years and 88.7% were women. Eighty (52.9%) patients did not receive immunosuppressive treatment for ILD, while 71 (47.0%) patients required immunosuppressive treatment, which includes cyclophosphamide (n=46), azathioprine (n=8), glucocorticoids (n=14) and others (n=3). Interestingly, median survival of non-treatment group was significantly better than treatment group during the follow-up of 1300.80 person-years (p=0.029 by log-rank test). Compared with treatment group, non-treatment group had higher baseline predicted % of forced vital capacity (FVC, 79.2±16.8% vs. 68.0±18.2, p<0.001), predicted % of diffusion capacity of carbon monoxide (DLCO, 66.4±20.5 vs. 52.0±17.9, p<0.001), lower CT grade (Grade 1: 89.6% vs. 54.7%, p<0.001), absence of pulmonary arterial hypertension (83.8% vs. 64.8%, p=0.013) and absence of gastrointestinal involvement (60.0% vs. 39.0%). Other baseline characteristics were not different, which include age at diagnosis, duration of disease, skin subset, profile of autoantibodies, involvement of heart or kidney and subtypes of ILD on CT. Among the non-treatment group, patients with the defined characteristics showed significant survival benefit than those without the characteristics (p=0.0047 by log-rank test). Conclusions Watch and wait approach may be applied to patients with SSc-associated ILD with minimal pulmonary infiltrates on CT scan and absence of pulmonary arterial hypertension at ILD diagnosis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3686

SAT0014 Association of Hla Genes in Systemic Sclerosis with Interstitial Lung Disease

Background Interstitial lung disease (ILD) is associated with a significant morbidity and mortality in systemic sclerosis (SSc). Many studies have reported the association between human leukocyte antigen (HLA) alleles and increased risk of SSc, but the associated between ILD in SSc and HLA alleles remains unclear. Objectives The aim of this study was to investigate the association of HLA class I and HLA class II with ILD in Korean SSc cohort. Methods A total of 170 SSc patient (105 SSc patients with ILD and 65 SSc patients without ILD) were enrolled at Seoul National University Hospital from 1988 to 2014. Two hundred one healthy participants from Korean Marrow Donor Program (KMDP) were recruited as controls. Demographic information, clinical skin subset (limited vs. diffuse), SSc-specific autoantibodies (anti-topoisomerase I (ATA), anti-centromere (ACA), anti-ribonucleoprotein (RNP)), and internal organ involvement (ILD, pulmonary arterial hypertension, gastrointestinal, renal involvement) of the enrolled patients were characterized. ILD were diagnosed based on the findings of the chest computed tomography. HLA-A, -B, -C,-DQB1,-DRB1, and -DPB1 typing were performed PCR amplification with directly sequencing from extracted genomic DNA. Results HLA-B*52:01, C*12:02, DRB1*15:02, DPB1*09:01, and DPB1*13:01 alleles were more frequent in SSc patients with ILD than healthy controls. However, the frequencies of these genes did not differ between SSc patients with and without ILD (Table). ATA positive SSc was associated with HLA-B*52:01, C*12:02, DRB1*15:02, DPB1*09:01, and DPB1*13:01 alleles compared to ATA negative SSc and DPB1*09:01 showed the highest odds ratio for ATA (OR =23.08).Table 1. HLA frequencies in patient with systemic sclerosis with ILD and without ILD compared to healthy controls HLA alleles SSc_Total ILD(+)SSc ILD(−)SSc Control SSc Total vs. Control ILD(+)SSc vs. Control ILD(−)SSc vs. Control (N=170) (n=105) (n=65) (N=201) Pc Pc Pc B*52:01 23 (13.5) 20 (19.0) 3 (4.6) 9 (4.5) 0.076 <0.001 1.000 C*12:02 23 (13.5) 20 (19.0) 3 (4.6) 9 (4.5) 0.046 <0.001 1.000 DRB1* 15:02 29 (17.1) 24 (22.9) 5 (7.7) 14 (7.0) 0.074 <0.001 1.000 DPB1* 09:01 22 (12.9) 18 (17.1) 4 (6.2) 9 (4.5) 0.045 <0.001 1.000 DPB1* 13:01 52 (30.6) 38 (36.2) 14 (21.5) 25 (12.4) <0.001 <0.001 1.000 Abbreviation: HLA, human leukocyte antigen; SSc, systemic sclerosis; ILD, interstitial lung disease; OR, odds ratio; Pc, corrected P by Bonferroni correction. Pc of ILD(+)SSc vs. ILD(−)SSc: HLA-B*52:01 (Pc=0.304), C*12:02 (Pc=0.184), DRB1*15:02 (Pc=0.407), DPB1*09:01 (Pc=0.570), DPB1*13:01 (Pc=0.660). Conclusions SSc patients with ILD have several specific HLA genes compared with healthy controls and the frequencies of these HLA genes were significantly higher in ATA-positive SSc as well. Therefore, ATA positivity and ILD are associated with ceratin HLA class I and II in SSc patients. References Zhou X, Lee JE, Arnett FC, Xiong M, Park MY, Yoo YK, et al. HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans. Arthritis Rheum 2009;60:3807–14. Disclosure of Interest None declared

SAT0451 The HLA Class II Profile in Korean Patients with Inflammatory Myositis

Background Polymyositis (PM) and dermatomyositis (DM) is known to be associated with certain HLA alleles in several ethnic groups including Caucasians, African-Americans, and the Japanese. Objectives To investigate the profile of HLA class II alleles in Korean patients with PM and DM Methods Sequencing based genotyping for HLA-DRB1 and -DPB1 was performed in 140 Korean patients with DM (n=104) or PM (n=36) and in 207 healthy controls. Associations of each HLA-DR or -DP allele with myositis or clinical subsets of myositis were examined. Results HLA-DRB1*14:54 (odds ratio [95% confidence interval] 1.05 [1.01-1.09]), -DRB1*15:02 (2.44 [1.03-5.81]), -DRB1*16:02 (1.04 [1.00-1.07], and -DPB1*09:01 (2.44 [1.03-5.81]) were found to be susceptibility alleles while HLA-DRB1*14:01 (0.93 [0.90-0.97]) and -DRB1*15:01 (0.38 [0.18-0.79]) to be protective alleles for inflammatory myositis (Table 1). In DM, HLA-DRB1*15:02 (3.14 [1.30-7.62]) and -DPB1*09:01 (2.87 [1.17-7.05]) carriers were more frequent while HLA-DRB1*14:01 (0.93 [0.90-0.97]), -DRB1*15:01 (0.30 [0.12-0.74]), and -DPB1*04:02 (0.44 [0.20-0.94]) carriers were less frequent than controls. In PM, HLA-DRB1*14:03 (6.52 [1.78-23.81]), and -DRB1*14:54 (1.13 [1.00-1.23]) carriers were more frequently observed. When PM and DM were compared, HLA-DRB1*14:03 carriers were more frequently observed in PM (5.43 [1.23-24.02]). When the association between each allele and clinical subsets was examined, patients with interstitial lung disease (ILD) carried HLA-DRβ1*04:03 (6.34 [1.35-29.76]), -DRβ1*07:01 (0.22 [0.08-0.64]), -DRβ1*09:01 (0.16 [0.05-0.60]) -DRβ1*12:02 (2.91 [1.16-8.01]) DRβ1*15:01 (0.10 [0.01-0.80]), -DPβ1*14:01 (8.90 [1.08-73.21]), and -DPβ1*17:01 (0.11 [0.01-0.92]) more frequently than patients without. DM patients with ILD showed higher frequency of HLA-DRβ1*04:05 than DM patients without ILD (4.68 [1.24-17.74]). Other associations included dysphagia with HLA-DRβ1*08:02 (6.73 [1.51-30.00]), -DRβ1*14:54 (5.19 [1.09-24.57]), and -DPβ1*03:01 (5.19 [1.09-24.57]), arthralgia with HLA-DRβ1*03:01 (4.79 [1.21-18.98]) and -DPβ1*02:01 (2.30 [1.10-4.82]), and mechanics hand with HLA-DRB1*08:03 (3.25 [1.12-9.45]) and -DRB1*12:02 (5.04 [1.66-15.29]). Regarding skin rashes, heliotrope rash was associated with HLA-DRβ1*09:01 (2.98 [1.05-8.46]) and -DPβ1*05:01 (0.41 [0.18-0.87]), Gottrons papules with HLA-DRβ1*14:05 (8.77 [1.07-72.17]), -DPβ1*02:01 (2.29 [1.11-4.73]), -DPB1*02:02 (0.086 [0.01-0.67]), and -DPB1*05:01 (0.41 [0.20-0.85]), and shawl sign with HLA-DRB1*14:05 (4.67 [1.15-18.99]) and -DPB1*14:01 (4.67 [1.15-18.99]). Cancer development was associated with HLA-DRB1*12:01 (7.25 [1.65-31.89]) and -DRB1*13:02 (0.81 [0.74-0.88]). No HLA-DRB1 or -DPB1 allele was found to be associated with anti-Jo1 antibody. Conclusions Korean patients with inflammatory myositis showed a unique profile of HLA-DR and -DP alleles compared with other ethnic groups. Alleles associated with disease susceptibility were different between PM and DM. Clinical subsets, particularly ILD, showed different immunogenetic backgrounds. Disclosure of Interest None declared

THU0297 Serum CXCL8, 10 and 12 are Increased in Patients with Behcet's Disease and CXCL10 Levels are Correlated with Number of Erythematous Nodosum

Background Chemokines are multifunctional mediators that control leukocyte recruitment into the inflammatory sites and enhance immune responses. It remains to be investigated which chemokines are important in Behcets disease (BD). Objectives The objective of this study was to investigate serum levels of neutrophil and lymphocyte chemoattractants in BD patients and its association with disease activity and symptoms. Methods We collected sera from patients with BD (n=64) and age-, sex matched healthy controls (n=21). Serum levels of chemokines were assayed for the neutrophil chemoattractants (CXCL1 and CXCL8) and lymphocyte chemoattractants (CXCL9, CXCL10, CXCL12, CXCL13 and CXCL16) by using a multiplex assay. Behcets disease current activity form (BDCAF) and symptoms were evaluated at the time of blood collection. Results Serum levels of CXCL8, CXCL10 and CXCL12 were significantly higher in the BD patients than in healthy controls (p<0.001, p=0.050 and p=0.002, respectively). Serum chemokine levels were not associated with BDCAF in BD patients. But CXCL10 levels were significantly higher in patients with erythematous nodosum (EN) than in patients without EN (p=0.008). AdditionaIly, CXCL10 levels were significantly correlated with number of EN (r=0.338, p=0.006). There was no difference of serum level of CXCL1, CXCL9, CXCL13 and CXCL16 between BD and healthy controls Conclusions Serum levels of CXCL8, CXCL10 and CXCL12 were significantly higher in the BD patients than in healthy controls. CXCL10 levels were correlated with number of EN in BD patients. Disclosure of Interest None declared

AB0621 Efficacy and Safety of Long Term Cyclophosphamide Treatment for Interstitial Lung Disease in Systemic Sclerosis

Background Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc). Treatment with cyclophosphamide (CYC) for 1 year has been shown to preserve pulmonary function. However, long-term efficacy and safety of CYC treatment for more than 1 year remains to be known. Objectives To investigate efficacy and tolerability of long-term CYC treatment in SSc patients with ILD. Methods All of the SSc-associated ILD patients who have been treated with CYC for more than 1 year at Rheumatology clinic of Seoul National University Hospital between 1978 and 2013 were enrolled. The information on clinical characteristics and pulmonary function test results were obtained from medical record review. Chest computed tomography (CT) was reviewed by a radiologist and classified into 4 grades depending on the extent of lung involvement. Mortality data were obtained from medical record or mortality record from Statistics Korea. Results A total of 32 SSc patients with ILD were treated with CYC for more than 1 year with the mean treatment duration of 28.0 months (range: 12.0- 70.5 months). The mean age at diagnosis was 47.5±9.4 years and women were dominant at 84.4%. The mean functional vital capacity (FVC) at baseline was 66.0±16.0% of predicted. At baseline 18 (64.3%) patients had CT grade of 2 or more. After mean (standard deviation) follow up period of 4.1 (3.1) years, FVC remained stable with the mean increase of 2.3 (2.5) % (P=0.365, by paired t test). Furthermore, the degree of pulmonary involvement on CT did not progress. Six patients died during the follow-up; pneumonia (n=1), pulmonary hypertension (n=1), subdural hemorrhage (n=1), heart failure (n=2) and malignancy (n=1). Adverse events during CYC treatment included severe infection (n=4), cytopenia (n=4), hemorrhagic cystitis (n=1) and alopecia (n=3). Conclusions Prolonged treatment with CYC for more than 1 year is associated with stabilization of ILD in the respect of pulmonary function and extent of lung involvement on CT. Long-term maintenance treatment with CYC may be an option to treat severe ILD in SSc patients. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4302

AB0615 Elevated Erythrocyte Sedimentation Rate is Associated with Pulmonary Impairment and Poor Outcome in Patients with Dermatomyositis

Background Interstitial lung disease (ILD) is a common cause of death in patients with dermatomyositis (DM). Especially, patients with clinically amyopathic DM (CADM) have a worse outcome due to ILD which is often refractory to corticosteroids. Lung involvement as an additional target of inflammation increases the total inflammatory burden in patients with DM. Objectives To investigate whether erythrocyte sedimentation rate (ESR) elevation is associated with ILD and a worse prognosis in patients with DM. Methods All patients with DM including CADM receiving clinical care in our institution from January 2004 through June 2013 were enrolled. Patients who had shortness of breath or abnormal finding on chest radiograph underwent a high resolution computed tomography (HRCT) and pulmonary function test (PFT). ILD was diagnosed when HRCT showed typical findings compatible with ILD. Results A total of 114 DM patients were enrolled in this study. The mean age of patients at diagnosis was 49.4±12.3 years. 69.3% were female. The mean follow-up duration was 32.3±29.3 months. ILD was present in 53 (46.5%) patients. Among 28 patients with CADM, 14 (50%) had ILD. The levels of ESR were significantly higher in patients with ILD than those without ILD (49.9±23.3 vs. 34.4±24.1 mm/hr, p=0.001). The difference was more profound between the CADM patients with ILD and those without ILD (56.3±23.8 vs. 25.4±22.9 mm/hr, p=0.002). The ESR levels were inversely correlated with the forced vital capacity (r=−0.238, p=0.036) and diffusing capacity of carbon monoxide (r=−0.334, p=0.004). Further, the patents with baseline ESR ≥30mm/hr had a worse survival as compared to those with ESR <30mm/hr (p=0.002, by log rank test). Conclusions The ESR elevation at the time of DM diagnosis is associated with pulmonary impairment and a poor outcome in patients with DM. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3276