Background Previous genome wide association studies (GWASs) have demonstrated the association between IL-10 region and Behcet’s disease (BD) in Turkish and Japanese populations. However, our recent GWAS result obtained from a Korean population [1] did not replicate this finding, suggesting a significant ethnic difference in genetic susceptibility for BD. Objectives To fully examine the relationship between IL-10 and BD, the associations between BD and single nucleotide polymorphisms (SNPs) in IL-10 mediated signaling pathways were examined in Korean BD patients. Methods DNA samples were obtained from 181 patients who met the international study group criteria for BD and 181 age- and sex-matched healthy controls. Eighteen tag SNPs in JAK1 (rs17127024, rs310245, rs2991269, rs2230587, rs2780898, rs2274948, rs310222, rs2256298, rs3818753, rs2780831, rs10889502, rs12563017, rs11208537, rs11208538, rs1353595, rs17127171, rs7553101, and rs4244165), five in TYK2 (rs34536443, rs12720356, rs2304256, rs280523, and rs12720217), and five in STAT3 (rs3744483, rs2293152, rs6503695, rs744166, and rs12948909) selected using the Japanese panel of international HapMap data with a minor allele frequency of more than 5% and with r2 > 0.8 were genotyped using PCR and RFLP method. Results The mean (± standard deviation) age of BD patients was 43.4 ± 10.3 years. Eighty five (47.0%) patients were male. The mean age and gender distribution of controls were similar. Genetic loci with a deviation from Hardy-Weinberg equilibrium in controls (rs11208538 in JAK1), or without any polymorphism in study subjects (rs34536443 and rs12720356 in TYK2) were not included in the analysis. The frequency of C allele at rs12948909 in STAT3 was higher in BD patients than in controls (odds ratio = 1.54, 95% confidence interval [1.00-2.38], p = 0.047), which, however, lost statistical significance after permutation-based correction for multiple testing. No significant associations were found between alleles of the rest 24 SNPs and BD. In addition, there was no genotype found to have a significant association with BD. In linkage disequilibrium (LD) analysis, eight haplotypes from two LD blocks in JAK1 and three haplotype from one LD block in STAT3 were identified but showed no association with BD. Conclusions Together with our GWAS finding, the result of this study further suggests that genetic dysregulation of IL-10 or IL-10 mediated intracellular signaling is not a predominant pathogenic mechanism for BD in Koreans. References Lee YJ, Horie Y, Wallace GR, Choi YS, Park JA, Song R, Kang YM, Kang SW, Baek HJ, Kitaichi N, Meguro A, Mizuki N, Namba K, Ishida S, Kim J, Niemczek E, Lee EY, Song YW, Ohno S, Lee EB. Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet’s disease. Ann Rheum Dis. 2012 Oct 6. [Epub ahead of print] Disclosure of Interest None Declared
BackgroundHigh transmissibility and immune evasion of SARS-CoV-2 Omicron variant made it dominant variant worldwide since January 2022. Before Omicron era, several studies demonstrated that autoimmune inflammatory rheumatic disease (AIIRD) patients were vulnerable to COVID-19 infection compared to general population. However, there is a lack of epidemiologic data regarding COVID-19 outbreak in patients with AIIRD in Omicron era.ObjectivesTo identify incidence rate, hospitalization rate and potential risk factors for COVID-19 outcomes in AIIRD patients during Omicron outbreak.MethodsThis study was a prospective longitudinal study from January 1 to October 31, 2022. We included patients who visited rheumatology outpatient clinic in a nationwide, tertiary referral center in South Korea. Included patients were classified into two groups (AIIRD and non-AIIRD groups) based on underlying disease. Vaccination and infection history of COVID-19 were obtained through self-report via questionnaire and data from Korea Disease Control and Prevention Agency (KDCA). Main outcome of this study was an incidence of COVID-19 infection during the observation period. Clinical factors associated with the incidence of COVID-19 infection were investigated using Cox proportional hazard model. In the final multivariable model, clinical factors that showed a relevant association (P < 0.1) with the outcome in the univariable analysis were included as covariates.ResultsA total of 1,814 patients were analyzed (AIIRD group: 1,535, non-AIIRD group: 279). The COVID-19 incidence in AIIRD group (47.6%) was higher than that reported in general population of South Korea (43.9%) and this trend was prominent in those aged < 70 years. Longitudinal change in COVID-19 incidence during the observation period showed two peaks in March and August in both groups, which was the same trend with general population. There were 30 cases of hospitalization due to COVID-19 infection, with the rate was comparable between AIIRD and non-AIIRD groups (1.7% vs. 1.5%, P = 0.970). The incidence rate of COVID-19 in the AIIRD group was comparable to that in the non-AIIRD group (47.6% vs. 44.8%, P = 0.386). In the AIIRD group, COVID-19 infection occurred less frequently in patients with old age (≥70 years) and those receiving glucocorticoid treatment. Other clinical factors such as use of DMARDs and biologics, and underlying diseases were not associated with COVID-19 incidence in the multivariable analysis. Of note, at least one COVID-19 vaccination did not lower its incidence (unadjusted HR 1.06 [95% CI 0.82-1.38]). Although patients who received booster vaccination were less likely to be infected with COVID-19 (unadjusted HR 0.79 [0.68-0.92]), this protective effect was significant only in patient younger than 70 years (Figure 1).ConclusionDuring the Omicron outbreak in South Korea, incidence of COVID-19 infection in patients with AIIRD and non-AIIRD was comparable. Immunomodulatory agents and specific rheumatic diseases did not increase the COVID-19 incidence, and booster vaccination against COVID-19 decreased the infection only in patients younger than 70 years.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
BackgroundTumor necrosis factor inhibitors (TNFi) have become a mainstay of management for axial spondyloarthritis (axSpA). However, it remains unclear whether patients with axSpA should continue the standard-dose TNFi after achieving stable disease activity. Although complete discontinuation of TNFi is followed by early relapse in most cases, several studies documented that reduced doses of TNFi in patients with prolonged low disease activity showed similar effects on disease control and drug survival compared to standard dose of TNFi. One of the main problem in the dose-tapering strategies for TNFi is a selection of the appropriate patient. However, there has been a lack of robust evidence regarding clinical factors predicting the flare after tapering of TNFi in patients with axSpA.ObjectivesThis study aims to develop and validate the prediction model to select the patients in whom tapering of TNFi does not lead to flare.MethodsWe used the data from Korean College of Rheumatology Biologics registry, which included a total of 1,730 patients receiving biologic DMARD from 2017 to 2019 in South Korea. In this study, a total of 526 patients who were initially treated with the standard-dose TNFi and tapered the dose after at least 1 year of the treatment were analyzed. Dose quotient (DQ, 0-1) was applied to quantified TNFi used during interval. The main outcome was an occurrence of flare defined as ASDAS-CRP score of ≥2.1 after 1 year of tapering TNFi. To develop the prediction model, clinical factors having relevant association (p < 0.1) with the outcome were first selected as candidate predictors. Logistic regression using a stepwise approach through backward elimination was used for the final model.ResultsPatients’ mean (SD) age was 37.5 (11.9) years, 418 (79.5%) were men, and 474 (90.1%) were HLA-B27 positive. Mean disease duration was 5.0 (6.1) years and 433 (82.3%) were TNF naïve. The mean BASFI and ASDAS-CRP at baseline were 3.4 (2.6) and 3.7 (1.0), respectively. Approximately two-thirds of the patients (65.8%) were initiated TNFi tapering at the first 1 or 2 years from baseline. At the time of TNFi tapering, the mean DQ was 0.67 (0.15) and 381 (72.4%) were prescribed concurrently with NSAIDs, and the mean BASFI and ASDAS-CRP were 1.3 (1.8) and 1.6 (0.9), respectively. During 12 months of follow up starting from the TNFi tapering, 127 (24.1%) experienced the flare. The multivariable analysis revealed that HLA-B27 positivity (OR 0.337; 95% CI 0.161-0.705; p=0.004), inflammatory back pain (OR 2.920; 95% CI 1.283-6.648; p=0.011), ASDAS-CRP at tapering (OR 2.798; 95% CI 2.030-3.856; p<0.001), and BASFI at tapering (OR 1.214; 95% CI 1.051-1.402; p=0.008) were significantly associated with flare. Based on the results of the logistic regression analysis, the predicted probability was calculated by the following formula: P=1/[1+ exp{-(1.088 x HLA-B27 negativity + 1.072 x inflammatory back pain + 1.567 x psoriasis + 0.623 x family history of axSpA + 1.092 x diabetes mellitus + 0.435 x DQ at TNFi tapering + 1.029 x ASDAS-CRP at TNFi tapering + 0.194 x BASFI at TNFi tapering)}]. The best cut-off value of the model to define the flare was 0.2416 (95% CI 0.176, 0.301) with sensitivity 74.0% and with specificity 81.0%. AUC was 0.828 (95% CI 0.786-0.869) indicating a good predication (Figure 1). The internal validation with bootstrapping showed minimal overfitting (estimated AUC 0.794) and good calibration between observed and predicted values (calibration slope 1.110, 95% CI 0.903, 1.317; intercept 0.026, 95% CI -0.091, 0.039).Figure 1.Apparent performance of developed model for prediction of flare after 12 months of tumor necrosis factor inhibitors tapering.ConclusionWe developed the prediction model for the flare after 12 months of TNFi tapering in patients with axSpA. It might be applicable in real world setting, although external validation will be required in the future investigation.References[1]Zavada J, et al. Ann Rheum Dis. 2016;75(1):96-102.AcknowledgementsWe greatly thank to the the Clinical Research Committee of the Korean College of Rheumatology and all participating hospitals.Disclosure of InterestsNone declared
Background:Semaphorin 4D (SEMA4D) / CD100, known as a subfamily of axonal guidance proteins, has also been reported to act as an immunoregulator in several infectious and inflammatory diseases [1]. Sjögren’s syndrome (SS) is a systemic autoimmune disease that primarily affects the exocrine glands by infiltrated lymphocytes resulting in dryness of mouth and eyes. IL-17 was reported to impair the integrity of tight junction barrier and attenuate the expression of aquaporin 5 (AQP5), causing salivary gland dysfunction in SS [2].Objectives:This study was aimed to evaluate the role of SEMA4D in patients with SS and investigate the effect of SEMA4D on human salivary gland epithelial cell (SGEC) and T cell.Methods:Soluble SEMA4D levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA) from patients with SS, non-SS sicca and healthy controls. Immortalized human SGECs, originated from acini (NS-SV-AC) and duct (NS-SV-DC), were used to evaluate the effects of SEMA4D. CD4+T cells from human peripheral blood were isolated to determine the secretion of cytokines in response to SEMA4D. IFN-γ and IL-17 were used to determine the effects on AQP5 expression of SGEC.Results:The levels of soluble SEMA4D in plasma were increased in patients with SS (median [interquartile range]: 1221.3 [393.5] pg/mL) compared to non-SS sicca (940.2 [355.1] pg/mL,p= 0.006) or healthy controls (909.5 [108.0] pg/mL,p <0.0001). The levels of soluble SEMA4D in plasma were correlated with the levels of several autoantibodies including anti-SSA (Spearman’s rho = 0.358,p= 0.006), anti-SSB (rho = 0.350,p= 0.007), and anti-muscarinic receptor 3 (M3R) Ab (rho = 0.495,p< 0.001), and also correlated with total IgG (rho = 0.431,p= 0.002). SEMA4D-stimulated SGECs showed decreased expression of tight junctions such as occludin and Zo-1. CD4+T cells secreted IFN-γ (p= 0.025), IL-17 (p= 0.028), and IL-21 (p= 0.007) with SEMA4D stimulation. IFN-γ and IL-17 decreased AQP5 expression in SGECs.Conclusion:SEMA4D contributed to decreased expression of tight junction in SGECs. SEMA4D induced production of IFN-γ and IL-17 in CD4+T cells and these cytokine decreased AQP5 expression in SGECs.References:[1]Worzfeld T, Offermanns S. Nat Rev Drug Discov. 2014;13(8):603-21.[2]Bhattarai KR, Junjappa R, Handigund M, Kim HR, Chae HJ. Autoimmun Rev. 2018;17(4):376-90.Disclosure of Interests:None declared
BackgroundThe idiopathic inflammatory myopathies (IIM) are autoimmune connective tissue diseases affecting skeletal muscle, skin and other organ systems. IIM-related interstitial lung disease (IIM-ILD) is the most common extra-muscular manifestation, being the leading cause of morbidity and mortality. Several studies have suggested that ILD pattern based on chest high-resolution computed tomography (HRCT) can be related to disease course and treatment response, but the results vary considerably. Moreover, the clinical impact of the quantitative ILD (QILD) score, a validated computer-aided scoring system in assessing ILD severity from HRCT, and its longitudinal changes have not yet been evaluated in IIM-ILD.ObjectivesThis study aims to investigate ILD patterns and QILD scores in patients with IIM-ILD, to identify their clinical impact, and to delineate longitudinal changes of QILD measurement.MethodsA total of 80 patients with IIM (polymyositis 22, and dermatomyositis 58) who underwent at least 2 times of serial HRCT scans were included. Visual ILD patterns were assessed by multiple thoracic radiologists. Quantitative analysis of HRCT was presented as total extent of QILD scores (%) in whole lung and most severe zone. Individual time-estimated ΔQILD score between first 2 visits was derived using a linear approximation of yearly change, where the duration of median (IQR) was 1.0 (0.4-1.6) years in the first 2 HRCT scans.ResultsThe median (IQR) age of the patients was 52.0 (43.5-58.5) years and 60 (75.0%) were women. Baseline median score of whole lung-QILD and most severe zone-QILD were 28.1% (19.1-43.8) and 68.0% (45.5-81.8), respectively, and QILD score showed significant correlations with pulmonary function tests (r=-0.349, p=0.002 for % predicted forced vital capacity; and r=-0.381, p=0.001 for % predicted diffusing capacity for carbon monoxide). The individual time-estimated yearly ΔQILD score between first 2 visits presented that approximately half of the patients showed improvement or stability in QILD scores; however, when patients were sorted by visual assessment in ILD subtype on HRCT, approximately two-thirds of the patients with usual interstitial pneumonia (UIP) pattern were aggravated in QILD scores and less than half of subjects with nonspecific interstitial pneumonia and organizing pneumonia were aggravated (Figure 1, 80% for UIP vs. 44.4% for non-UIP, p=0.013). There was no immunosuppressive drugs related to meaningful improvement in QILD scores during first 2 visits. Notably, we observed significant aggravation of QILD scores in tacrolimus users (n=7, median time-estimated whole lung-yarly ΔQILD 20.3 (2.7-38.4)) compared with tacrolimus non-users (n=73, median time estimated whole lung-yearly ΔQILD -1.2 (-8.3-6.5)). Among 80 patients, 6 (7.5%) were died due to various lung complications. Higher baseline QILD scores were noted in deaths (median whole lung-QILD 45.4 (32.9-56.5)) than in survivors (median whole lung-QILD 26.9 (19.0-42.4)), albeit not significant (p=0.084). Poor survival rate was observed in patients with high grade of ground glass opacity by visual assessment in right upper lobe (log-rank test, p=0.042). Among subgroup of patients with 3 serial HRCT scans (n=41), dynamic changes of four distinct patterns (improving, worsening, convex, and concave) were observed.Figure 1.Cleveland dot plot of individual time-estimated yearly ΔQILD during fist 2 visits.ConclusionThe changes in QILD score in IIM-ILD are dynamic and present different by visual assessment. QILD score has the potential for evaluation of the severity changes, prognosis and medication response in patients with IIM-ILD.References[1]Tashkin DP, et al. Ann Rheum Dis 2016;75(2):374-81.7 truncated values in the graph A. NSIP: nonspecific interstitial pneumonia; OP: organizing pneumonia; UIP: usual interstitial pneumonia.Disclosure of InterestsNone declared
Background There are currently limited treatment options for rheumatoid arthritis (RA) patients with chronic hepatitis B (CHB). Numerous recommendations or consensus have been published for selecting conventional and biologic disease modifying anti-rheumatic agents (DMARDs) for these patients. However, there is limited data demonstrating what DMARDs are practically prescribed within the population of an endemic region of CHB. Objectives To study the prescription characteristics of conventional and biologic DMARDs, as well as the rate of combination of anti-viral agents in RA patients with CHB in Korea. Methods We analyzed the Korean National Health Insurance claims database (2007-2009) of RA patients through the co-work with Korean Health Insurance Review and Assessment Service. Patients with CHB were defined by an algorithm including prescription information, blood tests, and the ICD-10 code. Among biologic DMARDs, data of etanercept, adalimumab, infliximab, and rituximab data were only available during the study period. Results There were 8,677 CHB patients (3.8%) among 226,592 RA patients in the database. The age distribution or gender difference in CHB patients was comparable to the general RA population. Hydroxychloroquine was the most frequently (66.2%) prescribed DMARD. Thirty four percent of CHB patients had been prescribed with methotrexate (MTX) during the study period, only 7.6% with concomitant anti-viral treatment. About 3% of RA patients with CHB were prescribed with TNF inhibitors, which was significantly lower compared with the rate in the general RA population in Korea. Conclusions MTX is yet one of the DMARDs frequently prescribed to Korean RA patients with CHB. Our data also indicate that biologic DMARDs are indeed seldom prescribed in this particular subgroup of patients. Disclosure of Interest None Declared
BackgroundRheumatoid arthritis (RA) is a chronic, inflammatory disease that leads to progressive cartilage and bone destruction. OX40 ligand (OX40L) is expressed predominantly on antigen-presenting cells and highly associated with joint inflammation in RA[1]. Yet, the role of OX40L in osteoclastogenesis is unclear.ObjectivesIn this study, we investigated the effects of dual blocking of TNF and OX40L by bispecific antibody (IMB-101) on RANKL-induced osteoclastogenesis.MethodsCD14+ monocytes were isolated from peripheral blood mononuclear cells (PBMCs) of healthy donors (n=6). CD14+ monocytes were cultured with M-CSF (20ng/ml) and RANKL (40ng/ml) for 6 to 7 days in the presence of TNF antibody, OX40L antibody, or bispecific antibody. TRAP-positive multinucleated giant cells (>3 nuclei/cell) were counted as osteoclast. PU.1, RANK and NFATc1, markers of osteoclast differentiation were assessed by the quantitative reverse transcription PCR (RT-qPCR). The expression of OX40L was analyzed in the presence of RANKL or TNF at the early and late stage of osteoclast differentiation.ResultsThe expression of OX40L was increased by RANKL and TNF at the early stage of osteoclast differentiation (day 3) in a TNF dose-dependent manner. IMB-101 decreased RANKL-induced osteoclastogenesis via downregulating NFATc1 expression (Figure 1). IMB-101 further reduced PU.1, RANK and NFATc1 expression during early stage of osteoclast differentiation (day 3) compared to TNF inhibitor or TNF inhibitor and OX40L inhibitor (n=3).ConclusionOur data suggested that IMB-101 might have a beneficial effect on imbalance of the bone resorption in RA especially by suppressing osteoclast differentiation.Figure 1.Reference[1]Yoshioka, Taro et al. “Contribution of OX40/OX40 ligand interaction to the pathogenesis of rheumatoid arthritis.”European Journal of Immunology30 (2000): n. pag.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
BackgroundIdiopathic inflammatory myopathy (IIM) is a rare autoimmune disease characterized by proximal muscle weakness, elevated muscle enzymes, inflammation in the muscle. If the muscle is already damaged in IIM, it may not regain full strength even after treatment. Also the mechanisms that contribute to muscle weakness in myositis are currently unknown. Nox is the main source of ROS production in various cells types, and is also the source of mitochondria ROS. Excessive expression of Nox4 is characteristic of sclerosis, fibrosis, and cardiac related diseases, and it had been reported that knock down of Nox4 lowers the production of superoxide and hydrogen peroxide. However, the effect of Nox4 in myositis has not been reported.ObjectivesWe investigated the expression and role of Nox4 in damaged myoblasts of myositis.MethodsMyoblasts were isolated from IIM patients who underwent muscle biopsy in Seoul National University Hospital between February 2019 and February 2021. Skeletal muscle cell(SMC) was purchased. Myoblasts and SMCs were treated with cytokine mixture {interferon gamma(IFN-γ), interleukin(IL)-6, IL-15} or PBS for 30 minutes. The expression of Nox4, MyoD and myosin heavy chain(MYH) in myoblast and myotube was analysed by Western blot. For inhibition of Nox4, GKT137831(inhibitor of Nox4) was treated before the cytokine stimulation.ResultsMyoblasts from IIM patients did not differentiate into myotubes like healthy myoblasts suggesting impaired muscle regeneration. Myoblasts from IIM patients express higher level of Nox4 compared to healthy myoblasts. When treated with cytokine mixture(IFN-r, IL-6, IL-15), healthy myoblasts or SMC mimicked inflammatory myositis and showed increased expression of Nox4 and decreased expression of MYH similar to myositis phenotype. Nox4 inhibitor suppressed Nox4 expression and MyoD overexpression in inflammatory myoblasts.ConclusionWe showed that Nox4 expression is increased in myoblasts from IIM patients and is associated with impaired muscle regeneration. Nox4 inhibition attenuated Nox4 and MyoD overexpression in inflamed myoblasts.References[1]Bi Y, Lei X, Chai N,et al.NOX4: a potential therapeutic target for pancreatic cancer and its mechanism.J Transl Med19, 515 (2021)[2]Rayavarapu S, Coley W, Kinder T.B.,et al.Idiopathic inflammatory myopathies: pathogenic mechanisms of muscle weakness.Skeletal Muscle3, 13 (2013)[3]Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis.Lancet. 2003 Sep 20;362(9388):971-82.[4]Piera-Velazquez S, Makul A, Jiménez SA. Increased expression of NAPDH oxidase 4 in systemic sclerosis dermal fibroblasts: regulation by transforming growth factor β.Arthritis Rheumatol. 2015 Oct;67(10):2749-58.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.