Y.-G. Kim

Effects of advanced glycation end products on the expression of COX-2, PGE2 and NO in human osteoarthritic chondrocytes

OBJECTIVE Advanced glycation end products (AGE) accumulate in articular cartilage with age. We investigated the effects of AGE in primary-cultured human OA chondrocytes. METHODS Chondrocytes were cultured with/or without AGE-bovine serum albumin (AGE-BSA) and the expression levels of inducible nitric oxide (iNOS), cyclooxygenase (COX)-2 microsomal prostaglandin E synthase-1 (mPGES-1) were evaluated using RT-PCR and western blot analysis. Prostaglandin E(2) (PGE(2)) was analysed by ELISA and nitric oxide (NO) was analysed by Griess reaction assay. Pharmacological studies to elucidate the involved pathway were executed using specific inhibitors of MAPK and receptor for AGE (RAGE). RESULTS We found that treatment of OA chondrocytes with AGE-BSA increased COX-2, mPGES-1 and iNOS mRNA and protein, as well as elevating production of PGE(2) and NO. Pre-treatment with the MAPK inhibitors SP600125 (JNK inhibitor), SB202190 (p38 inhibitor) or PD98059 (ERK inhibitor) significantly inhibited AGE-BSA induction of COX-2 expression and production of PGE(2). In contrast, SN50, a nuclear factor-kappaB (NF-kappaB) inhibitor, had no effect on levels of COX-2 and PGE(2). SB202190 and SN50, but not SP600125 and PD98059, decreased AGE-BSA-induced production of NO. Pre-treatment with soluble receptor for AGE (sRAGE) also reduced AGE-stimulated COX-2, iNOS and PGE(2), implicating the involvement of RAGE. CONCLUSIONS These results show that AGE may augment inflammatory responses in OA chondrocytes by increasing PGE(2) and NO levels, possibly via the MAPK pathway for PGE(2) and the NF-kappaB pathway for NO.

Behcet's disease associated with bone marrow failure in Korean patients: clinical characteristics and the association of intestinal ulceration and trisomy 8

OBJECTIVES The aim of this study was to determine the clinical characteristics of Behcets disease (BD) associated with bone marrow failure (BMF), classified as conditions such as myelodysplastic syndrome (MDS) or aplastic anaemia (AA), in Korea. METHODS A retrospective analysis was made of 13 patients with BD associated with BMF (MDS 8 cases, AA 5 cases) and 66 patients with BD not associated with BMF. These patients all fulfilled the diagnostic criteria of the international BD study group. RESULTS BD patients with BMF showed significantly lower leucocyte count, haemoglobin level and platelet count when compared with patients without BMF (P < 0.001). BD patients with BMF had significantly higher serum CRP level at the time of BD diagnosis compared with patients without BMF (P = 0.03). Intestinal lesions were more frequent in BD patients with BMF than those without BMF (61.5% vs 13.6%, P = 0.001). Cytogenetic abnormality was observed in 90.9% of BD patients with BMF. Of the cytogenetic abnormalities, trisomy 8 was most common, occurring in 70% of the patients. In four patients with refractory BD associated with BMF, successful treatment of BMF by haematopoietic stem cell transplantation resulted in clinical remission of BD. CONCLUSIONS Our study indicates that intestinal ulceration is a characteristic finding in BD associated with BMF. It also suggests that cytogenetic aberration, especially trisomy 8, may play an important role in the pathogenesis of BD associated with BMF.

Successful treatment of recurrent lupus enteritis with rituximab

Sir, A 23-year-old Korean woman was admitted to our hospital in August 2007 with a 4-day history of abdominal pain associated with nausea and vomiting. Three years prior to admission she had been diagnosed with systemic lupus erythematosus (SLE) based on malar rash, lymphocytopenia, positive anti-nuclear antibody, anti-Ro antibody, and anti-double-stranded (ds)DNA antibody. Antiphospholipid antibodies including lupus anticoagulant, anti-cardiolipin antibodies (immunoglobulin [Ig]M and IgG), beta2-glycoprotein I antibodies (IgM and IgG) were all negative on two repeated tests. Prior to this admission, the patient had experienced six episodes of recurrent lupus enteritis from May 2005 to July 2007. With each episode of lupus enteritis, she complained of abdominal pain with or without vomiting and diarrhea, and enhanced computed tomography (CT) scans of the abdomen showed diffuse mucosal edema and bowel wall thickening involving the small and large intestine (target-like appearance) with variable amounts of ascites (Figure 1). Laboratory findings at each admission were unremarkable except for hypocomplementemia. On each occasion, she completely recovered after intravenous (IV) treatment with high-dose steroids (methylprednisolone 1mg/kg/day) and conservative treatments including bowel rest and IV fluids. After the third episode of recurrent lupus enteritis, she received mycophenolate mofetil (MMF) until the fourth episode, and was treated with oral cyclophosphamide (CYC) for 3 months, followed by azathioprine (AZA) for 4 months. However, she experienced two more episodes of recurrent lupus enteritis until July 2007. At the seventh admission for lupus enteritis in August 2007, we decided to administer rituximab 500mg per week IV for 2 consecutive weeks in addition to high-dose steroids. The patient’s absolute CD19 count was 36.7/mm at the time of the first infusion, which decreased to 17.4/mm at 2 weeks after the first rituximab infusion. In September 2007, 3 weeks after the first infusion, the lupus enteritis recurred and high-dose methylprednisolone (2mg/kg/day IV) was administered. At four weeks after the first rituximab infusion, the patient’s CD19 count decreased to 3.1/mm. Thereafter, with gradual tapering of oral corticosteroids, no further lupus enteritis relapse occurred. At 6 months after the first infusion, the patient’s CD19 count was increased to 47.3/mm. For fear of possible relapse of lupus enteritis, she wanted repeated infusion of rituximab rather than observation without rituximab therapy. She received a second cycle of rituximab with concomitant methylprednisolone 100mg/day IV. At 7 months after this second infusion, with a CD19 count of 52.3/mm, the patient received a third cycle of rituximab with concomitant methylprednisolone. In December 2008, 15 months after discharge, the oral methylprednisolone was tapered off and no subsequent symptoms and signs of lupus flare have been reported (Figure 2). Lupus enteritis is one of the most serious complications of SLE. High doses of steroids are required and surgical intervention is indicated if extensive bowel infarction or perforation occurs. Antiphospholipid antibody syndrome can induce intestinal ischemia or infarction and cause symptoms similar to those of mesenteric vasculitis. In our patient, there was no evidence of anti-phospholipid antibodies or thrombosis, and diffuse mucosal edema with bowel wall thickening (target-like appearance) and complete reversibility after immunosuppressive treatments were strongly indicative of intestinal ischemia secondary to mesenteric vasculitis. The recommended initial treatment for lupus enteritis is high-dose parenteral steroids together with complete bowel rest. However, relapse is not uncommon, even in patients who show a good initial response to this treatment. Recently, a case of severe relapsing lupus enteritis treated successfully with a combination of CYC and rituximab was reported. This patient remained free of relapse for 2 years after treatment with two cycles of intra-venous (IV) methylprednisolone 100mg rituximab 500mg IV and CYC 500mg IV. However, the use of single-agent rituximab in lupus enteritis has not been reported. Rituximab is a chimeric monoclonal antibody directed against the CD20 molecule present on B lymphocytes. Several reports have described the use of rituximab to successfully treat refractory lupus Correspondence to: Yong-Gil Kim, Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388–1 Pungnap-dong, Songpa-gu, Seoul 138–736, Korea. E-mail: bestmd2000@amc.seoul.kr Received 9 April 2009; accepted 4 June 2009

Systemic lupus erythematosus complicated by acquired von Willebrand’s syndrome

Haematological abnormalities are common in systemic lupus erythematosus (SLE). In some cases of acquired von Willebrand syndrome (AvWS), von Willebrand disease (vWD) is associated with autoimmune or lymphoproliferative disorders. In this study, we describe a 36-year-old woman with SLE and AvWS. The patient was referred to our hospital because of easy bruisability and recurrent vaginal bleeding. She had no history of bleeding tendency and no family history of bleeding diathesis, but she had a history of recurrent arthralgia, photosensitivity and sicca symptoms. Tests for antinuclear, anti–double stranded DNA, anticardiolipin and anti–β2-glycoprotein I antibodies were all positive. Analysis of haemostatic parameters showed complete absence of von Willebrand factor ristocetin cofactor (vWF:Rco), von Willebrand antigen (vWF:Ag) and ristocetin-induced platelet aggregation (RIPA). Electrophoretic analysis of plasma showed a complete absence of high–molecular weight vWF multimer. The presence of antibody to vWF was detected by enzyme linked immunosorbent assay (ELISA). Treatment with corticosteroids improved SLE symptoms and corrected bleeding diasthesis. Also, the multimeric patterns of vWF became normalised and anti–vWF antibody disappeared. These findings indicated that this patient had SLE associated with AvWS, which was ameliorated by corticosteroid treatment.

Incidence of Atrial Tachyarrhythmias in Patients With Early Repolarization Syndrome Analysis of Patients With Implantable Cardioverter Defibrillators

Atrial tachyarrhythmias (ATAs) occur in a significant proportion of Brugada syndrome (BrS) patients and are often an important cause of inappropriate shocks. The aim of this retrospective study was to evaluate the incidence of ATAs and ATA-induced inappropriate shocks in early repolarization syndrome (ERS) patients as compared to BrS patients.We analyzed data from 20 consecutive patients who were diagnosed with ERS and compared them with patients diagnosed with BrS (n = 31). Clinical and ICD interrogation data were collected and analyzed for all events with ICD shocks.Three patients had a history of atrial fibrillation (AF) prior to ICD implantation. One patient had AV reentrant tachycardia and was successfully ablated before ICD implantation. ATAs were newly diagnosed in 4 patients with no prior history of AF. There were no significant differences in gender, age, or left atrial diameter between ATA development. Four (20%) of 20 consecutive patients received inappropriate ICD shocks for ATAs. One suffered from repeat inappropriate shocks triggered by paroxysmal AF and received catheter ablation for AF.ATAs were not infrequent in patients with ERS and seemed to be related to inappropriate ICD therapy. Careful ICD programming is required to reduce ATA-related inappropriate ICD shock in patients with ERS.

Lupus enteritis: clinical characteristics and predictive factors for recurrence.

Objectives To compare the clinical characteristics of lupus enteritis (LE) and non-enteric lupus (non-LE) patients and identify predictors of LE recurrence. Methods We retrospectively reviewed the medical records of 62 systemic lupus erythematosus (SLE) patients in a tertiary hospital who experienced enteric symptoms and underwent abdominal computed tomography scanning between January 1997 and December 2013. We compared the clinical characteristics between LE and non-LE patients and between recurrent LE and non-recurrent LE cases. Results Out of 62 SLE patients with enteric symptoms, 46 cases (74%) were compatible with LE based on computed tomography findings. The C4 level was decreased in the LE group compared with the non-LE group (9.0 ± 5.6 vs. 12.3 ± 6.2, p = 0.032). Recurrence of LE was observed in 14 patients (28%). Initial involvement at the colon (79% vs. 41%, p = 0.026) and bladder with/without the ureter was more common in the recurrent group (57% vs. 25%, p = 0.048). By multivariate analysis, the hazard ratios of variables associated with recurrence were 4.689 for colon involvement (95% confidence interval: 1.245–17.659, p = 0.0220] and 5.468 for cystitis with/without ureteritis (95% confidence interval: 1.629–18.360, p = 0.006). Conclusion Colon and urinary tract involvement in LE patients may be associated with the recurrence of LE.

Factors associated with acute gout attacks in normouricaemic gout patients receiving allopurinol: a retrospective study

Objective: To identify factors associated with acute gout attacks in normouricaemic gout patients receiving allopurinol. Methods: We reviewed the medical records of 860 patients with chronic gout who were treated with allopurinol at a single tertiary hospital between 2003 and 2009. Of these, 135 patients had serum urate concentrations ≤ 360 μmol/L (6 mg/dL). Patients whose serum urate concentrations exceeded 360 μmol/L (6 mg/dL) at least once during follow-up were excluded. Patients who experienced at least one acute attack during follow-up, despite normouricaemia [≤ 360 μmol/L (6 mg/dL)], were classified as the Attack group (n = 51). The others were classified as the Non-attack group (n = 84). Results: The gout disease duration was significantly longer in the Attack group than in the Non-attack group (p = 0.036). The presence of tophi and multiple joint involvement were associated with acute attacks in normouricaemic gout patients. Multivariate analysis showed that both the presence of tophi [odds ratio (OR) 4.16, 95% confidence interval (CI) 1.41–12.23, p = 0.010] and the number of involved joints (OR 1.51, 95% CI 1.05–2.17, p = 0.028) were independently associated with acute attacks in normouricaemic gout patients receiving allopurinol. Conclusion: The presence of tophi and multiple joint involvement were associated with acute attacks in normouricaemic gout patients receiving allopurinol.

Characteristics of early repolarization parameters and prognostic implications in the general ambulatory Korean population.

BACKGROUND We tested a hypothesis that the 2 fundamental components of early repolarization (ER), J wave and ST elevation (STE) might have different prevalence and prognostic implications. METHODS The study population comprised 26,345 general ambulatory Korean subjects (mean 48.0±10.2years old, 53.2% male) who underwent medical checkups from January 2002 to December 2002. ER was found in 2950 subjects (11.2%), who were divided into 3 groups (J [J wave only, n=1874, 7.1%], JST [both J wave and STE, n=489, 1.8%], and ST [STE only, n=587, 2.3%]). RESULTS The prevalence of STE decreased with age, whereas J waves remained at a constant level in all age groups. The most common pattern of ER was the J pattern, with a horizontal/descending ST segment in the inferior leads; in lateral precordial leads, ST or JST patterns with ascending ST segments were more common. During the mean follow-up of 126.0±11.1months, a total of 710 subjects died (2.7%). Subjects in the J group were at higher risk (Hazard ratio 1.60, 95% confidence interval 1.27-2.01, p<0.001), while those in the JST and ST groups showed similar survival outcomes compared to controls without J waves or STE. CONCLUSIONS J waves and STE showed different age and lead distributions and prognostic implications. The presence of the J wave itself was associated with a higher relative risk of mortality. However, due to the low event rate, its clinical significance appears to be limited.

AB0689 Extravascular manifestations of takayasu arteritis: historical cohort study in korea

Background Takayasu arteritis (TAK) is systemic disease characterised by large vessel involvement. Although the vascular characteristics of TAK are well characterised, there is no well-organised study demonstrating the extravascular manifestations of TAK. Objectives To evaluate the characteristics of extravascular manifestations of TAK, and to identify the association between vascular and extravascular manifestations of TAK. Methods TAK patients from two independent cohorts who fulfilled the 1990 ACR classification and encoded M314 according to ICD-10 code between January 2012 and October 2017 were included in the study. Characteristics of the patients were retrospectively collected from the electronic dataset. A radiologist reviewed CT scans of all included patients to evaluate the pattern of vascular involvement and presence of sacroiliitis. Clinical findings including uveitis, skin lesion, oral ulcer, arthritis, and inflammatory bowel disease (IBD) were reviewed. Logistic regression analysis was performed to evaluate the association between vascular and extravascular manifestation. Results A total of 268 TAK patients were included. Mean age at diagnosis was 41.2±14.2 years and 236 (88.1%) were female. The most commonly involved vessel was common carotid artery (176 [65.7%]), and the most common type of vascular involvement was type V (120 [44.8%]). Extravascular manifestation of TAK was observed in 51 (19.0%) patients (table 1). The most common extravascular manifestation was arthritis (axial arthritis [sacroiliitis] [7.1%] and/or peripheral arthritis [6.0%]) (11.9%) followed by recurrent aphthous stomatitis (8.6%) and IBD (2.6%). In multivariable logistic regression analysis, the following factors were significantly associated with presence of arthritis (axial and/or peripheral arthritis): type IIB vascular involvement (adjusted OR 2.956, 95% CI 1.337–6.537, p=0.007) and erythrocyte sedimentation rate (ESR) (adjusted OR 1.014 95% CI 1.003–1.025, p=0.012).Abstract AB0689 – Table 1 Extravascular manifestations of Takayasu arteritis n=268 Any extravascular manifestation 51 (19.0%) Arthritis (axial arthritis [sacroiliitis] and/or peripheral arthritis) 32 (11.9%) Recurrent aphthous stomatitis 23 (8.6%) Inflammatory bowel disease 7 (2.6%) Erythema nodosum 4 (1.5%) Uveitis 2 (0.7%) Conclusions Extravascular manifestations of TAK are not rare and observed in up to one-fifth of patients. The most common extravascular manifestation was arthritis including sacroiliitis (11.9%). Type IIb vascular involvement pattern and high ESR were significantly associated with arthritis in TAK. Acknowledgements None Disclosure of Interest None declared

96 Urinary biomarker related with tubular inflammation in lupus nephritis

Background and aims Severe tubulointerstitial damage represents a poor prognosis of lupus nephritis (LN). Immunoglobulin binding protein 1 (IGBP1) was known as a phosphoprotein associated with the immunoglobulin receptor in B cells. Our study determined urinary IGBP1 levels in LN patients and addressed correlations between urinary IGBP1 levels and clinical variables. Methods The levels of IGBP1 were measured in urine of SLE patients with or without nephritis, and healthy subjects. Correlation analyses between urinary IGBP1 levels and the disease-related variables including C3/4, anti-dsDNA, and SLE Disease Activity Index (SLEDAI) were examined. We performed correlation analyses of urinary IGBP1 levels with activity index score or chronicity index score in renal tissues. To define IGBP1 expression in renal pathologies, immunohistochemical staining were performed. In addition, to identify genetic relationship with IGBP1, microarray was performed in HK2 tubular cells treated with IGBP1-siRNA. Results Urinary levels of IGBP1 were significantly higher in LN patients than in SLE patients without nephritis and healthy individuals. Among the disease-related variables, SLEDAI scores, anti-dsDNA, and C3 were correlated with the levels of urinary IGBP1. Further, urinary IGBP1 levels represented a positive association with activity index score in renal pathology. IGBP1 was stained mainly in tubules, especially in class III, IV and V. In microarray analysis, IL-7 receptor was closely related with IGBP1 down-regulation. Conclusions This study demonstrates that the levels of urinary IGBP1 were higher in LN patients and correlated with disease activity and activity index score of renal pathology. Therefore, urinary IGBP1 might be a valuable marker for determining the activity of LN.