Kichul Shin

Adiponectin is a potential catabolic mediator in osteoarthritis cartilage

IntroductionAdiponectin has been implicated in the pathogenesis of osteoarthritis (OA). We studied the effects of adiponectin on the OA cartilage homeostasis.MethodsImmunohistochemical analysis was performed to evaluate differential expression of adiponectin receptors (AdipoRs) in nonlesional and lesional areas of OA cartilage. Cartilage and chondrocytes from the knee joints of primary OA patients were cultured in the presence of adiponectin (0~30 μg/ml). The levels of total nitric oxide (NO), matrix metalloproteinase (MMP)-1, -3, and -13, and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in the conditioned media. The levels of inducible NO synthase (iNOS) and MMPs were determined with the quantitative real-time reverse transcription-polymerase chain reaction. The concentrations of collagenase-cleaved type II collagen neoepitope (C1-2C) were determined in the supernatant of adiponectin-stimulated OA cartilage explants. The effects of kinase and NOS inhibitors were evaluated in the adiponectin-stimulated chondrocytes.ResultsThe expression levels of both AdipoR1 and AdipoR2 were significantly higher in lesional than in nonlesional areas of OA cartilage. The increased rate of AdipoR1-positive chondrocytes was twice that of AdipoR2-positive chondrocytes when compared between nonlesional and lesional areas. Adiponectin-stimulated OA chondrocytes showed increased total NO and MMP-1, -3, and -13 levels compared with nonstimulated cells. The TIMP-1 level was not affected. The C1-2C levels were increased by adiponectin in OA cartilage explant culture. AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) inhibitors (compound C and SP600125) significantly suppressed adiponectin-induced production of total NO and MMP-1, -3, and -13. Inducible NOS inhibitors enhanced the expression of the adiponectin-induced MMPs.ConclusionsAdiponectin causes matrix degradation in OA cartilage and increases MMPs and iNOS expression via the AMPK and JNK pathways in human OA chondrocytes. The catabolic effects of adiponectin may be counteracted by NO.

Hepatitis B virus reactivation in rheumatoid arthritis and ankylosing spondylitis patients treated with anti-TNFα agents: A retrospective analysis of 49 cases

Clinical guidelines regarding anti-viral prophylaxis for HBV surface antigen (HBsAg) carriers starting anti-TNFα agents are not yet fully established, even in endemic regions of HBV infection. We retrospectively collected the clinical data of 52 HBsAg carriers with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) that had been administered anti-TNFα treatment at seven medical centers in South Korea. Periodic data of liver function tests and serum HBV DNA were both utilized to assess HBV reactivation. The YMDD motif mutation of HBV DNA polymerase was tested in lamivudine-treated patients with elevated HBV DNA. Three of the 52 patients were excluded from the analysis. Of the 49 analyzed patients, 20 patients received anti-viral prophylaxis (15 lamivudine, five entecavir) with anti-TNFα treatment. The remaining 29 patients were treated with anti-viral agents if needed at the discretion of the clinician and did not receive prophylaxis. Of the 29 patients who did not receive primary prophylaxis, two (6.9%) developed viral reactivation within a year of anti-TNFα treatment. In the prophylaxis group, one patient developed viral reactivation at week 64 of anti-TNFα therapy attributed to YMDD mutation caused by lamivudine. Patients with HBV reactivation all responded well to anti-viral therapy. In summary, anti-viral prophylaxis helped preventing HBV reactivation in HBsAg carriers with RA or AS starting anti-TNFα, yet mutation in the YMDD motif of HBV DNA polymerase could be detrimental to some patients under long-term lamivudine prophylaxis.

Associations between the HLA-A polymorphism and the clinical manifestations of Behcet's disease.

IntroductionThe objective was to investigate associations between the HLA-A gene and Behcets disease (BD) and its clinical manifestations.MethodsGenotyping for the HLA-A locus was performed using the polymerase chain reaction-Luminex typing method in 223 BD patients and 1,398 healthy controls.ResultsThe phenotypic frequencies of HLA-A*02:07 (odds ratio (OR) = 2.03, P = 0.002), A*26:01 (OR = 1.85, P = 0.008), and A*30:04 (OR = 2.51, P = 0.006) tended to be higher in BD patients than in normal controls, but the frequency of A*33:03 (OR = 0.59, P = 0.003) tended to be lower in BD patients. A meta-analysis adopting our and the Japanese data confirmed the associations of HLA-A*02:07, A*26:01, and A*33:03 with BD. Furthermore, the frequencies of the HLA-A*02:07, A*26:01, and A*30:04 were significantly higher in patients with skin lesions (OR = 2.37, P < 0.0005, Pc < 0.012) and arthritis (OR = 2.32, P = 0.002, Pc = 0.048), with uveitis (OR = 3.01, P < 0.0005, Pc < 0.012), and with vascular lesions (OR = 9.80, P < 0.0005, Pc < 0.012) and a positive pathergy test (OR = 4.10, P = 0.002, Pc = 0.048), respectively, than in controls. In HLA-B*51 non-carriers, these associations were also significant, being much stronger between HLA-A*26:01 and uveitis (OR = 4.19, P < 0.0005, Pc < 0.012) and between HLA-A*30:04 and vascular lesions (OR = 13.97, P < 0.00005, Pc < 0.0012). In addition, HLA-A*30:04 was associated with genital ulcers in HLA-B*51 non-carriers (OR = 3.89, P = 0.002, Pc = 0.048).ConclusionsHLA-A*02:07, A*26:01, and A*30:04 were associated with increased risk for BD, while HLA-A*33:03 with decreased risk. HLA-A*02:07, A*26:01, and A*30:04 were associated with skin lesions and arthritis, with uveitis, and with vascular lesions, genital ulcers, and a positive pathergy test, respectively.

Head-to-head comparison of udenafil vs amlodipine in the treatment of secondary Raynaud’s phenomenon: a double-blind, randomized, cross-over study

OBJECTIVEnRP is a reversible vasoconstriction of digital arteries that causes pain and skin discoloration. This study compared the efficacy of the new phosphodiesterase type 5 inhibitor udenafil with that of the calcium channel blocker amlodipine in the treatment of secondary RP.nnnMETHODSnA total of 29 patients with secondary RP associated with connective tissue diseases were enrolled in this double-blind, randomized, cross-over study. The patients were randomized to receive udenafil 100 mg/day or amlodipine 10 mg/day for 4 weeks. After a washout period they were crossed over to the other drug for another 4 weeks. The primary outcome was RP frequency before and after treatment. The secondary outcomes were RP condition scores, RP duration, number of digital ulcers, HAQ, physician global assessment and digital artery flow before and after treatment.nnnRESULTSnAmlodipine and udenafil both decreased the rate of RP attack significantly. The drugs did not differ in terms of RP frequency or any of the secondary outcomes except for digital blood flow; udenafil improved it significantly better than amlodipine (P = 0.021). Udenafil was well tolerated without serious adverse effects.nnnCONCLUSIONnUdenafil and amlodipine have comparable efficacy in improving RP attacks. In addition, udenafil improves the blood flow in digital arteries compared with amlodipine.nnnTRIAL REGISTRATIONnwww.clinicaltrials.gov, protocol number NCT01280266.

The usefulness of bone SPECT/CT imaging with volume of interest analysis in early axial spondyloarthritis

BackgroundThe role of conventional bone scintigraphy in diagnosing early axial spondyloarthritis (SpA) is yet controversial. Single positron emission computed tomography (SPECT) plus CT is an imaging modality that adds better anatomical information to scintigraphy of the sacroiliac (SI) joint. Our aim was to investigate the usefulness of bone SPECT/CT with volume of interest (VOI) analysis in early axial SpA patients.MethodsTwenty patients (male: female ratiou2009=u200912:8; age rangeu2009=u200917–65 years) presenting with inflammatory back pain meeting the Amor criteria of early axial SpA were recruited from a single center in South Korea. Bone scintigraphy was performed 180xa0min after intravenous injection of 1110xa0MBq of Tc-99xa0m-HDP, followed by bone SPECT/CT. The ratio between the entire SI joint and sacrum (SIS ratio) was measured by both bone SPECT/CT and bone scintigraphy. Data from 13 controls were also evaluated. Receiver operating characteristic (ROC) curve was plotted for further analysis, and the correlation between the SIS ratio and SI joint grade by plain radiography was assessed.ResultsThe SIS ratio of early axial SpA patients vs. control subjects was significantly increased in bone SPECT/CT (pu2009<u20090.001). However, no significant difference was detected in bone scintigraphy. ROC curve analysis showed a significant difference in the area under curve (AUC) of bone SPECT/CT vs. bone scintigraphy (0.862 vs. 0.523, respectively; pu2009<u20090.001). With a cut-off SIS ratio of 1.50, ROC curve analysis showed a sensitivity of 80.0% and specificity of 84.6% in bone SPECT/CT. The SIS ratio measured in SPECT/CT, but not that measured in bone scintigraphy, was significantly increased with a higher grade of SI joint changes in plain radiography (pu2009=u20090.014).ConclusionBone SPECT/CT is more useful than conventional bone scintigraphy in identifying sacroiliitis in early axial SpA patients, even with mild SI joint changes in plain radiography. By combining CT, we can accurately delineate the sacrum and SI joint uptake with our VOI method.

THU0179 Discontinuation of Nonsteroidal anti-Inflammatory Drugs in Rheumatoid Arthritis Patients with Low Disease Activity

Background Although nonsteroidal anti-inflammatory drug (NSAIDs) is effective in relieving joint pain in rheumatoid arthritis (RA) patients, long-term use of NSAIDs can cause adverse effects on gastrointestinal or cardiovascular organs. When patients discontinue daily use of NSAIDs, there is often a dichotomous clinical response in patient-reported outcomes (PRO). Objectives We aimed to examine the clinical outcome especially joint pain, and its associated factors in RA patients with low disease activity (LDA) after discontinuing NSAIDs. Methods This study was a 16-week, multi-center prospective open-label trial conducted at eight rheumatology clinics in Korea. RA patients who achieved LDA (DAS28 <3.2) who were on NSAIDs for more than 2 consecutive months, discontinued the NSAID. Acetaminophen (AAP) was used as the rescue medication. During the study period, changes of DAS28 and PRO including pain visual analogue scale (VAS) and Routine Assessment of Patient Index Data 3 (RAPID-3) score were assessed. NSAIDs were restarted when patients 1) pain was uncontrolled with AAP and 2) PRO were aggravated. The endpoint was to analyze the group of patients who continued to withdraw NSAIDs within the study period. Patients were further classified to have “sustained effectiveness” who met the following: 1) 16-week pain VAS ≤30 mm or increase less than 20% from baseline and 2) 16-week RAPID-3 score ≤6 or increase less than 20% from baseline. Results A total of 121 RA patients with LDA were enrolled in the study. Four patients were lost to follow-up. At the end of the study, 18 (15.3%) patients had restarted NSAIDs owing to uncontrolled pain. In general, there was a difference in pain VAS between baseline (median 15 mm (IQR 5–20)) and 16 weeks (median 17 mm (IQR 5–40)) (p=0.022). Changes of DAS28 and RAPID-3 were insignificant in patients taking on-demand AAP (n=99) (0 versus 16 weeks; DAS28, p=0.111; RAPID-3; p=0.339). Moreover, 60% of the total patients (73/117) ended up to show sustained effectiveness without restarting NSAIDs. By using a multivariate logistic regression model, we found out that joint swelling was the detrimental factor compromising sustained effectiveness (OR 0.312, 95% C.I. 0.125–0.777, p=0.012). Conclusions Discontinuation of NSAIDs can be attempted in RA patients with LDA, especially in those without swollen joints at the time point of its cessation. Disclosure of Interest None declared

AB0124 Inhibitory Effects of A Novel Bispecific Antibody against Tnf-Alpha and CXCL10 in Animal Model of Rheumatoid Arthritis

Background Tumor necrosis factor-α (TNF-α) plays a crucial role in the pathogenesis of rheumatoid arthritis (RA) and monoclonal antibodies targeting TNF-α are used as a popular therapeutic interventions in RA patients. CXCL10 is a chemokine that potentially plays a role in the immunopathogenesis of RA. The development of bispecific antibody (BiAb) as a therapeutic agent for RA may have great clinical potential. We constructed a single-chain BiAb against both TNF-α and CXCL10 (IgG-based format). Objectives We investigated the inhibitory effects of BiAb targeting TNF-α and CXCL10 on in vitro and in vivo model of RA. Methods We performed TNF-α neutralization assay using WEHI cell and tube formation assay of HUVEC cell to investigate TNF-α antagonistic effect of BiAb. Then we performed T cell migration assay induced by CXCL10 using transwell system and inhibitory assay of osteoclastogenesis. The effects of BiAb were determined by arthritis severity score, histological damage in Tg197 human TNF transgenic mice. Results BiAb suppressed TNF-α comparatively with adalimumab in TNF-α neutralization assay, tube formation assay and osteoclast differentiation. Cell migration induced by CXCL10 was inhibited by BiAb dose dependently. Treatment with BiAb resulted in beneficial effects on clinical and histological parameters of Tg197 human TNF transgenic mice model. Conclusions Our results demonstrate the novel BiAb effectively neutralized TNF-α and CXCL10 in vitro and in vivo model of rheumatoid arthritis. We suggest that BiAb could be a promising biologic agent for the treatment of RA. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3074

AB0544 The usefulness of bone spect-ct imaging with volume of interest analysis in early axial spondyloarthritis

Background Imaging is an important tool in diagnosing axial spondylo-arthritis (SpA). In contrast to magnetic resonance imaging, conventional bone scintigraphy has not been so helpful for early detection of axial SpA. However, SPECT (single positron emission computed tomography)/CT has the advantage of better delineating the changes of the sacroiliac (SI) joints as well as the underlying structure. Objectives To investigate the usefulness of bone SPECT-CT with volume of interest (VOI) analysis in early axial SpA. Methods Fifteen patients presenting with inflammatory back pain meeting the Amor criteria of SpA were recruited from a single center in South Korea. Bone scintigraphy was performed 180 min after intravenous injection of 1110 MBq of Tc-99m-HDP, followed by bone SPECT-CT. The ratio between the entire SI joint and sacrum (SIS ratio) was measured by both bone SPECT-CT and bone scintigraphy. Data from 13 controls were also evaluated. The ROC curve was plotted for further analysis, and the correlation between the SIS ratio and SI joint grade by plain radiography was assessed. Results Figure A, B are bone SPECT-CT images of a representative early axial SpA patient, whereas Figure C, D are those of a control subject. The SIS ratio of early axial SpA patients vs. control subjects was significantly increased (p = 0.000) in bone SPECT-CT. However, no significant difference was detected in bone scintigraphy. ROC curve analysis showed a significant difference in the AUC of bone SPECT-CT vs. bone scintigraphy (0.873 vs. 0.560, respectively; p = 0.000). With a cutoff SIS ratio of 1.5, ROC curve analysis showed a sensitivity of 83.3% and specificity of 76.9% in bone SPECT-CT. The SIS ratio measured in SPECT-CT, but not that measured in bone scintigraphy, was significantly increased with a higher grade of SI joint changes in plain radiography (p = 0.000). Image/graph Conclusions Bone SPECT-CT is more useful than conventional bone scintigraphy in identifying sacroiliitis in axial SpA patients, even with mild SI joint changes in plain radiography. Disclosure of Interest None Declared