Search

Systemic lupus erythematosus (SLE) is characterized by the presence of various autoantibodies and the deposition of immune complex, which is cleared by Fcγ receptors. Genotype analysis was done to investigate whether the FcγRIIIA-176F/V polymorphism is a risk factor for SLE in Koreans. We genotyped 145 Korean SLE patients and 75 control subjects for FcγRIIIA-176F/V. After amplifying a 1.7-kb fragment containing the FcγRIIIA-176F/V polymorphic site using two FcγRIIIA gene-specific primers, we performed a nested polymerase chain reaction (PCR) for allele-specific genotyping at position 559 in FcγRIIIA. FcγRIIIA genotype or allele distribution was not significantly different between lupus patients and controls, and also between lupus nephritis patients and healthy controls. Neither creatinine clearance, 24 h urine proteinuria, number of American College of Rheumatology (ACR) criteria, nor the Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index was different according to the genotype. In conclusion, FcγRIIIA-176F/V polymorphism is not associated with SLE in Koreans. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by immune cell infiltration of the synovium, leading to the loss of cartilage, bone, and joint function. Although regulatory T (Treg) cells are thought to modulate the initiation and progression of RA, a consensus has yet to be reached regarding the function and composition of Treg cells in RA patients. To address these discrepancies, we analyzed not only the total Treg frequency but also that of Treg subpopulations in the peripheral blood of RA patients and healthy controls by flow cytometry. We found that the total Treg population was not significantly different between RA and control subjects. However, the effector Treg cell subgroup, defined as CD45RA−CD25hi, showed markedly decreased frequency in RA patients. In addition, the total Treg population from RA patients showed a significant decline in the expression of CD25. Both the naïve and effector Treg subgroups also showed marked reduction of CD25 expression in RA patients compared to controls. These data suggest that the decreased frequency of effector Treg cells and overall reduction of CD25 expression in Treg cells in the peripheral blood may be evidence of altered Treg homeostasis associated with RA pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Th17 cells produce IL-17 that plays an important role in host defense. However, little is known about whether aging affects human Th17 cells. Here we demonstrated that healthy elderly people (age≥65) had a decreased frequency of IL-17-producing cells in memory CD4+ T cells compared to healthy young people (age≤40) while both groups had similar frequencies of IFN-γ-producing cells in the same memory cell subset as measured by flow cytometry. In contrast, the healthy elderly had increased differentiation of IL-17-producing effector cells but not IFN-γ-producing cells from naive CD4+ T cells compared to the healthy young. The results of ELISA also showed similar findings with increased IL-17 production from naive CD4+ T cells and decreased IL-17 production from memory CD4+ T cells in the elderly compared to the young. These findings indicate that aging differentially affects naive and memory Th17 cell responses in humans. [Copyright &y& Elsevier]

This study aimed to examine the role of CD70, which is highly expressed on fibroblast-like synoviocytes (FLS), in rheumatoid arthritis (RA) patients. FLS isolated from RA (n = 14) and osteoarthritis (OA, n = 4) patients were stimulated with recombinant interleukin-17 (IL-17; 5 ng/mL) and tumor necrosis factor alpha (TNF-α; 5 ng/mL) for 24 h. Expression of CD70, CD27/soluble CD27 (sCD27), and hypoxia-inducible factor-2 alpha (HIF-2α) was analyzed by RT-qPCR, flow cytometry, and ELISA assays, respectively. Reactive oxygen species (ROS) expression and cell migration were also examined. The HIF-2α inhibitor PT-2385 and CD70 inhibitor BU69 were used to specifically suppress these pathways. Stimulation with IL-17 and TNF-α significantly induced CD70 expression in RA FLS. Although the synovial fluids from patients with RA contained high levels of sCD27, surface expression of CD27, a ligand of CD70, was rarely detected in RA FLS. Cytokine-induced CD70 expression was significantly decreased following antioxidant treatment. Following HIF-2α inhibition, RA FLS had decreased expression of CD70 and ROS levels. Migration of RA FLS was also inhibited by inhibition of CD70 or HIF-2α. The surface expression of CD70 is regulated by HIF-2α and ROS levels and is a key contributor to cytokine-enhanced migration in RA FLS. [ABSTRACT FROM AUTHOR]

Purpose Our aim was to investigate the efficacy of monthly oral ibandronate in Korean women with rheumatoid arthritis and reduced bone mineral density (BMD) receiving long-term glucocorticoids. Methods Patients (n = 167 women) were randomly assigned (1:1) to receive ibandronate 150 mg or placebo every 4 weeks. Patients had taken glucocorticoid (equivalent of daily prednisolone ≥5 mg) for 3 or more consecutive months before enrollment, and had a lumbar spine 1 to 4 (L1–L4) T-score of < −1.0 and ≥ −2.5. Both groups were provided with daily calcium carbonate and cholecalciferol. The primary end point was the L1 to L4 BMD percent changes at 48 weeks compared with baseline. Findings Baseline characteristics were comparable between the 2 groups. BMD percent changes in L1 to L4 at 48 weeks were significantly different between the ibandronate versus the placebo group (+3.7% [5.1%] vs −1.9% [4.4%], respectively; P < 0.0001). BMD percent changes at 48 weeks in femur neck and total hip also had similar results ( P = 0.0073 and P = 0.0031, respectively). Decrease of serum type 1 collagen C-terminal telopeptide was significant at both 24 and 48 weeks in the ibandronate group. There was no incident of fragility fracture in both groups during the study period. Safety profiles, including adverse events, were comparable between the 2 groups. Implications Monthly oral ibandronate for 48 weeks is well tolerated and effective in reducing bone mineral loss in women with rheumatoid arthritis on long-term glucocorticoid therapy. Longer follow-up studies are needed to investigate the benefit of ibandronate on fracture rate reduction in this subset of patients. ClinicalTrials.gov identifier: NCT01287533. [ABSTRACT FROM AUTHOR]

Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) patients have increased reactive oxygen species (ROS) levels and an impaired redox balance compared with FLS from control patients. Liver kinase B1 (LKB1) plays a key role in ROS scavenging and cellular metabolism in various cancers. Here, we aimed to determine the specific mechanism of LKB1 in RA pathogenesis. FLS were obtained from RA patients (n = 10). siRNA-induced LKB1 deficiency in RA FLS increased ROS levels via NADPH oxidase 4 (NOX4) upregulation. RA FLS migration and expression of inflammatory factors, including interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF), were enhanced by LKB1 deficiency. LKB1-deficient RA FLS showed increased sensitivity to oxidative stress damage caused by hydrogen peroxidase exposure. siRNA-induced solute carrier family 7 member 11 (SLC7A11) deficiency in RA FLS enhanced NOX4 and ROS expression and increased cell migration. When LKB1-deficient RA FLS were stimulated with an AMP-activated protein kinase (AMPK) activator, the LKB1-inhibition-induced cell migration significantly decreased through the restoration of SLC7A11/NOX4 expression. LKB1 regulates the AMPK-mediated SLC7A11-NOX4-ROS pathway to control cell migration and inflammation. Our data indicate that LKB1 is a key regulator of redox homeostasis in RA FLS.

Background/aims: The aim of this study was to investigate long-term post-discontinuation outcomes in patients with rheumatoid arthritis (RA) who had been treated with tumor necrosis factor-α inhibitors (TNF-αi) which was then discontinued., Methods: Sixty Korean patients with RA who participated in a 5-year GO-BEFORE and GO-FORWARD extension trials were included in this retrospective study. Golimumab was deliberately discontinued after the extension study (baseline). Patients were then followed by their rheumatologists. We reviewed their medical records for 2 years (max 28 months) following golimumab discontinuation. Patients were divided into a maintained benefit (MB) group and a loss-of-benefit (LB) group based on treatment pattern after golimumab discontinuation. The LB group included patients whose conventional disease-modifying antirheumatic drug(s) were stepped-up or added/switched (SC) and those who restarted biologic therapy (RB)., Results: The mean age of patients at baseline was 56.5 years and 55 (91.7%) were females. At the end of follow-up, 23 (38.3%) patients remained in the MB group. In the LB group, 75.7% and 24.3% were assigned into SC and RB subgroups, respectively. Fifty percent of patients lost MB after 23.3 months. Demographics and clinical variables at baseline were comparable between MB and LB groups except for age, C-reactive protein level, and corticosteroid use. Restarting biologic therapy was associated with swollen joint count (adjusted hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.01 to 3.55) and disease duration (adjusted HR, 1.12; 95% CI, 1.02 to 1.23) at baseline., Conclusion: Treatment strategies after discontinuing TNF-αi are needed to better maintain disease control and quality of life of patients with RA.

In osteoarthritis (OA), chondrocytes in cartilage undergo phenotypic changes and senescence, restricting cartilage regeneration and favoring disease progression. Although senescence biomarker p16INK4a expression is known to induce aging by halting the cell cycle, therapeutic applications for p16INK4a targeting are limited. Here, we aimed to reduce cartilage damage and alleviate pain using p16INK4a nanoparticles in OA. The p16INK4a expression of human OA chondrocytes and synoviocytes from patients with knee OA was measured and the levels of p16INK4a, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and matrix metalloproteinase (MMP) 13 were examined. p16INK4a siRNA was encapsulated into poly (lactic- co -glycolic acid) (PLGA) nanoparticles and characterized. The partial medial meniscectomy (pMMx) model was performed for the OA model which was investigated by molecular analysis and behavioral tests. The expression of p16INK4a was increased in the synovium and articular cartilage from OA patients. p16INK4a siRNA-loaded PLGA nanoparticles (p16 si&#95;NP) reduced the levels of TNF-α, IL-1β, and IL-6 especially in fibroblast-like synoviocytes (FLSs), and MMP13 in chondrocytes. Rhodamine-tagged NPs injected into the mouse knee joints were found mainly in the synovium. p16 si&#95;NP injection in the pMMx model alleviated pain-associated behavior, and reduced cartilage damage and p16INK4a in the synovium, and MMP13, collagen X, and NITEGE in cartilage. The preferential reduction of p16INK4a in FLSs by the application of RNAi nanomedicine could contribute to the recovery of osteoarthritic cartilage and relieve pain, suggesting that p16INK4a may be a viable future therapeutic candidate.

The essential micronutrient zinc regulates immune responses by affecting signaling pathways. In activated monocytes and macrophages, signaling networks mediate the metabolic reprogramming that meets the demands of participation in immune responses. Here, we demonstrated that cytoplasmic, bioavailable zinc was essential for promoting IL-1β production in activated human monocytes and macrophages downstream of glycolysis induced by the kinase-containing multiprotein complex mTORC1. The concentration of cytoplasmic zinc was determined by that of extracellular zinc, which was brought into cells through the zinc-specific importer Zip8. The abundance of Zip8 was increased in monocytes from patients with rheumatoid arthritis (RA), as well as in LPS-stimulated monocytes and macrophages from healthy individuals. The mTORC1-mediated phosphorylation of S6 kinase (S6K) was enhanced by zinc-mediated inhibition of PP2A, a phosphatase that targets S6K. As a result, IL-1β production was increased due to the activation of mTORC1-induced glycolysis. In monocytes of patients with RA, the expression of Zip8 and the zinc-inducible metallothionein isoform MT2A and the phosphorylation of S6K were enhanced compared with those of healthy controls. Furthermore, Zip8 expression correlated with more severe RA clinical parameters, suggesting that Zip8-mediated zinc influx is related to inflammatory conditions. These results provide insight into the role of cytoplasmic, bioavailable zinc in the metabolic reprogramming of human monocytes and macrophages in inflammatory responses.

Background: Patient-centered management is becoming increasingly important in gout, but there are limited studies exploring patients' perspectives and preferences. We aimed to investigate patients' perspectives and preferences regarding gout and gout management, and their impacts on adherence to urate lowering therapy (ULT)., Methods: A paper-based survey was performed in patients with gout seen at the rheumatology outpatient clinics of 16 tertiary hospitals. The survey included questions regarding demographics, comorbidities, gout attacks, current treatment and adherence, and patients' perspectives and preferences regarding gout and gout management. Multivariate regression analysis was performed to determine the factors associated with ULT adherence., Results: Of 809 surveyed patients with gout, 755 (94.5%) were using ULT. Among those using ULT, 89.1% had ≥ 80% adherence to ULT. Majority of the patients knew management strategies to some extent (94.8%), perceived gout as a life-long disease (91.2%), and were making efforts toward practicing at least one lifestyle modification (89.2%). Most patients (71.9%) obtained information about gout management during their clinic visits. Approximately half of the patients (53.6%) preferred managing their disease with both ULT and lifestyle modification, 28.4% preferred ULT only, and 17.4% preferred lifestyle modification only. Adherence was better in patients with older age (odds ratio [OR], 1.03), those with better knowledge of gout management strategies (OR, 3.56), and those who had preference for ULT (OR, 2.07)., Conclusion: Patients' perspectives and management preferences had high impacts on adherence to ULT in gout. Consideration of patients' perspectives and preferences is important for achieving the desired clinical outcome in gout., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Monocytes are important cellular effectors of innate immune defense. Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression. The expansion of intermediate CD14 + CD16 + monocytes has been reported in chronic inflammatory diseases including rheumatoid arthritis (RA). However, the mechanism underlying induction of CD16 and its role in monocytes remains poorly understood. Here, we demonstrate that activated platelets are important for induction of CD16 on classical CD14 + CD16 - monocytes by soluble factors such as cytokines. Cytokine neutralization and signaling inhibition assays reveal that sequential involvement of platelet - derived TGF-β and monocyte-derived IL-6 contribute to CD16 induction on CD14 + CD16 - monocytes. Activated platelet-induced CD16 on monocytes participates in antibody-dependent cellular phagocytosis (ADCP) and its level is positively correlated with phagocytic activity. CD14 + CD16 - monocytes treated with activated platelets preferentially differentiate into M2 macrophages, likely the M2c subset expressing CD163 and MerTK. Lastly, the amount of sCD62P, a marker of activated platelets, is significantly elevated in plasma of RA patients and positively correlates with clinical parameters of RA. Our findings suggest an important role of activated platelets in modulating phenotypical and functional features of human monocytes. This knowledge increases understanding of the immunological role of CD14 + CD16 + cells in chronic inflammatory diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Yoon, Kim, Yoo, Kang and Lee.)

Background: Reactive oxygen species (ROS) regulate the migration and invasion of fibroblast-like synoviocytes (FLS), which are key effector cells in rheumatoid arthritis (RA) pathogenesis. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) induces ROS generation and, consequently, enhances cell migration. Despite the important interrelationship between RA, FLS, and ROS, the effect of NOX4 on RA pathogenesis remains unclear., Methods: FLS isolated from RA (n = 5) and osteoarthritis (OA, n = 5) patients were stimulated with recombinant interleukin 17 (IL-17; 10 ng/ml) and tumor necrosis factor alpha (TNF-α; 10 ng/ml) for 1 h. Cell migration, invasion, adhesion molecule expression, vascular endothelial growth factor (VEGF) secretion, and ROS expression were examined. The mRNA and protein levels of NOX4 were analyzed by RT-qPCR and western blotting, respectively. The NOX4 inhibitor GLX351322 and NOX4 siRNA were used to inhibit NOX4 to probe the effect of NOX4 on these cellular processes., Results: Migration of RA FLS was increased 2.48-fold after stimulation with IL-17 and TNF-α, while no difference was observed for OA FLS. ROS expression increased in parallel with invasiveness of FLS following cytokine stimulation. When the expression of NOX was examined, NOX4 was significantly increased by 9.73-fold in RA FLS compared to unstimulated FLS. Following NOX4 inhibition, cytokine-induced vascular cell adhesion molecule 1 (VCAM1), VEGF, and migration and invasion capacity of RA FLS were markedly decreased to unstimulated levels., Conclusion: NOX4 is a key contributor to cytokine-enhanced migration and invasion via modulation of ROS, VCAM1, and VEGF in RA FLS.

Objectives: This study aims to examine the possible associations of mitochondrial single nucleotide polymorphisms (SNPs) and Behçet's disease (BD) in a larger patient group., Patients and Methods: Whole blood or buffy coat was collected from 98 BD patients (31 males, 67 females; mean age 48±2.8 years; range 20 to 60 years) from four university hospitals located in the Chung-Cheong district of the Republic of Korea, and 196 age- and sex-matched healthy controls (HCs) (62 males, 134 females; mean age 46.91±12.90 years; range 20 to 68 years) from Konyang University Hospital. Twenty targeted mitochondrial deoxyribonucleic acids (DNAs) were genotyped and compared using the revised Cambridge Reference Sequence. Chi square and Fisher's exact tests were used to analyze association of mitochondrial DNA SNPs with BD susceptibility and its clinical characteristics., Results: There were no differences for m.248A>G, m.304C>A, m.709G>A, m.3010G>A, m.3970C>T, m.4883C>T, m.5178C>A, m.6392T>C, m.6962G>A, m.10310G>A, m.10609T>C, m.12406G>A, m.12882C>T, m.13928G>C, m.14668C>T, m.16129G>A, and m16304T> between patient and HC groups. However, m.16182A>C and m.16183A>C were more frequently observed in the patient group than the HC group (22 [22.4%] vs. 24 [12.2%], p=0.061 and 32 [32.7%] vs. 42 [21.4%], p=0.092) but without statistical significance. m.4883C>T and m.5178C>A were associated with posterior location of oral ulcers (p=0.025 for each) and m.16183A>C was associated with deep oral ulcers (p=0.001), while m.16189T>C was associated with deep oral ulcers and thrombosis (p=0.042, 0.048, respectively)., Conclusion: m.16182A>C and m.16183A>C may be associated with BD in the Korean population., Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Objectives: Depression is more common in patients with systemic lupus erythematosus (SLE) compared to the general population. However, few studies have investigated risk factors of depression in SLE patients, and the results are inconsistent. This study evaluated the prevalence of, and risk factors for, depression in ethnically homogeneous Korean SLE patients., Methods: In this study, 505 consecutive SLE patients were enrolled from the Korean Lupus Network registry. Demographic variables, clinical manifestations, laboratory findings, physician global assessment, and SLEDAI-2000 and SLICC damage index were recorded at enrolment. Patients were identified as having depressive symptoms using the Korean version of the Beck Depression Inventory (BDI) with a cut-off ≥16, and categorised into four groups. Multivariable logistic regression analyses were performed to identify independent risk factors for depression defined as a BDI score ≥16., Results: Of the 505 patients, 97 (19.2%) were diagnosed with depression. Patients with a higher BDI score were older, more likely to be a current smoker, and had a SLICC score >1. Conversely, they had lower income and educational levels. Regarding the serologic findings, patients with a higher BDI score had lower anti-double-stranded DNA positivity and higher anticardiolipin (aCL) positivity. On multivariate analysis, the following factors were associated with depression: current smoking status (OR 2.533, p=0.049), aCL-positivity (OR 2.009, p=0.035), and a SLICC damage index score >1 (OR 2.781, p=0.039). On the other hand, high-level education (OR 0.253, p=0.024) and a high income (OR 0.228, p=0.008) were negatively associated with depression., Conclusions: Our results show that depression is prevalent in patients with SLE and multiple factors are associated with depression in SLE. These data could help guide target programmes for those at high risk of depression in SLE.

Purpose: This study assessed the relationships among the risk factors for and components of metabolic syndrome (MetS) and health-related quality of life (HRQOL) in a hypothesized causal model using structural equation modeling (SEM) in patients with systemic lupus erythematosus (SLE)., Methods: Of the 505 SLE patients enrolled in the Korean Lupus Network (KORNET registry), 244 had sufficient data to assess the components of MetS at enrollment. Education level, monthly income, corticosteroid dose, Systemic Lupus Erythematosus Disease Activity Index, Physicians' Global Assessment, Beck Depression Inventory, MetS components, and the Short Form-36 at the time of cohort entry were determined. SEM was used to test the causal relationship based on the Analysis of Moment Structure., Results: The average age of the 244 patients was 40.7 ± 11.8 years. The SEM results supported the good fit of the model (χ 2  = 71.629, p = 0.078, RMSEA 0.034, CFI 0.972). The final model showed a direct negative effect of higher socioeconomic status and a positive indirect effect of higher disease activity on MetS, the latter through corticosteroid dose. MetS did not directly impact HRQOL but had an indirect negative impact on it, through depression., Conclusions: In our causal model, MetS risk factors were related to MetS components. The latter had a negative indirect impact on HRQOL, through depression. Clinicians should consider socioeconomic status and medication and seek to modify disease activity, MetS, and depression to improve the HRQOL of SLE patients.

Aim: There is growing evidence that cold-inducible RNA-binding protein (CIRP) promotes inflammatory responses. This study investigated the relationship between CIRP and rheumatoid arthritis (RA)., Methods: Peripheral blood and synovial fluid were collected from 15 patients with RA and from 16 patients with osteoarthritis (OA). The concentration of CIRP was measured with the sandwich enzyme-linked immunosorbent assay (ELISA)., Results: The concentration of serum CIRP was significantly elevated in the RA patient group (RA patients = 26.39 ± 10.48 pg/mL, OA patients = 17.14 ± 7.24 pg/mL, P = 0.009). Furthermore, the RA patient group had a significantly higher CIRP concentration than that of the OA patient group in synovial fluid (153.56 ± 108.93 pg/mL vs. 23.63 ± 16.18 pg/mL, P < 0.001). The mean synovial fluid concentration of CIRP was significantly higher than that of the serum concentration in the RA patient group (serum concentration = 26.39 ± 10.48 pg/mL, synovial fluid = 153.56 ± 108.93 pg/mL, P < 0.001). Disease Activity Score of 28 joints (DAS28)-ESR (erythrocyte sedimentation rate) and DAS28-CRP (C-reactive protein) were positively correlated with the synovial fluid concentration of CIRP (DAS28-ESR: r = 0.582, P = 0.023; DAS28-CRP: r = 0.541, P = 0.037)., Conclusion: The serum and synovial concentrations of CIRP in the RA patients were increased compared to the OA patients. Additionally, the synovial concentration of CIRP in RA patients correlated well with disease activity, that is, the DAS28-ESR/CRP. Based on these results, CIRP mediates inflammation and is a potential marker for synovial inflammation., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affect the joints and inflammatory cell migration into inflamed articular sites contribute to this disease. Among the inflammatory cells, human mucosal-associated invariant T (MAIT) cells were recently recognized as critical cellular component with a pathological role in RA. However, their migratory characteristics are poorly understood. The aim of this study was to determine whether human MAIT cells preferentially traffick to inflamed synovial sites in rheumatoid arthritis patients and to elucidate the underlying mechanism. First, we found that TNFα and IL-1β were elevated in synovial fluid (SF) of RA patients, which resulted in increased expression of E-selectin, ICAM-1 and V-CAM-1 on blood vessel endothelial cells. To understand whether TNFα and IL-1β in the SF facilitated MAIT cell migration, we analyzed CD161 + TCRα7.2 + MAIT and other CD3 + T cells for differences in migratory capacity. Collectively, our results demonstrate that TNFα and IL-1β in the SF facilitated MAIT cell migration dependent on expression of selectin ligand, sialyl Lewis X (sLe X ) and CCR6 on MAIT cells. We also showed that MAIT cells in the SF from RA patients equipped upregulated sLe X compared to the peripheral blood of RA patients and healthy persons, which suggest that TNFα and IL-1β mediated expression of E-selectin preferentially attract sLe X mediated MAIT cell migration into the SF of RA patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Despite improved quality of care for rheumatoid arthritis (RA) patients, many still experience treatment failure with a biologic agent and eventually switch to another biologic agent. We investigated patterns of biologic treatment and reasons for switching biologics in patients with RA. Patients with RA who had started on a biologic agent or had switched to another biologic agent were identified from the prospective observational Korean nationwide Biologics (KOBIO) registry. The KOBIO registry contained 1184 patients with RA at the time of initiation or switching of biologic agents. Patients were categorized according to the chronological order of the introduction of biologic agents, and reasons for switching biologics were also evaluated. Of the 1184 patients with RA, 801 started with their first biologic agent, 228 were first-time switchers, and 89 were second-time or more switchers. Second-time or more switchers had lower rheumatoid factor and anti-CCP positivity, and higher disease activity scores at the time of enrollment than the other groups. Among these patients, tocilizumab was the most commonly prescribed biologic agent, followed by adalimumab and etanercept. The most common reason for switching biologics was inefficacy, followed by adverse events, including infusion reactions, infections, and skin eruptions. Furthermore, the proportion of inefficacy, as a reason for switching, was significantly higher with respect to switching between biologics with different mechanisms of action than between biologics with similar mechanisms. In this registry, we showed diverse prescribing patterns and differing baseline profiles based on the chronological order of biologic agents.

Objective: Lung diseases (LD) are common extra-articular manifestations in rheumatoid arthritis (RA). However, little is known about factors associated with susceptibility to rheumatoid arthritis-related lung diseases (RA-LD). The aim of the present study was to investigate whether the single nucleotide polymorphisms (SNPs) of PADI4 and HLA-DRB1 alleles were associated with RA-LD., Methods: Blood samples and clinical data were collected from 116 consecutive RA patients who satisfied the 1987 American College of Rheumatology classification criteria. RA-LD was diagnosed using high-resolution computed tomography of the chest. All patients were genotyped for SNPs of PADI4 and HLA-DRB1 alleles and analyzed for full amino acid sequence of the HLA protein corresponding to a 4-digit HLA typing. Data were analyzed by independent t test (or Mann-Whitney test) for continuous variables, Chi-square test (or Fisher's exact test) and trend test for categorical variables, and logistic regression analysis., Results: Ninety-four (81.0 %) RA patients had LD, of which eight (6.9 %) had interstitial lung disease (ILD) and 92 (79.3 %) had airway abnormalities in which 64 (55.2 %) showed bronchiectasis and 47 (40.5 %) revealed bronchial wall thickening. The recessive genotype of padi4&#95;92 was susceptible to airway abnormalities (OR = 2.22, 95 % CI = 1.05-4.49, p = 0.034). Tryptophan at position 9 of HLA-DRB1 sequence was associated with the susceptibility to RA-ILD (OR = 22.89, 95 % CI = 1.20-432.56, p = 0.037)., Conclusion: PADI4 polymorphisms and HLA-DRB1 alleles could attribute differently to the development of airway abnormalities and ILD, respectively, in RA.

Autoimmune rheumatoid arthritis is characterized by chronic inflammation and hyperplasia in the synovial joints. Although the cause of rheumatoid arthritis is largely unknown, substantial evidence has supported the importance of immune cells and inflammatory cytokines in the initiation and progression of this disease. Herein, we demonstrated that the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) alleviated type II collagen-induced arthritis in a mouse model. The levels of pro-inflammatory cytokines are elevated in both human patients with rheumatoid arthritis and mice with collagen-induced arthritis. BOT-4-one treatment reduced the levels of pro-inflammatory cytokines in mice and endotoxin-stimulated macrophages. BOT-4-one treatment suppressed the polarization of Th1- and Th17-cell subsets by inhibiting the expression and production of their lineage-specific master transcription factors and cytokines, as well as activation of signal transducer and activator of transcription proteins. In addition, BOT-4-one inhibited mitogen-activated protein kinase and NF-kappaB signaling as well as the transcriptional activities and DNA-binding of transcription factors, including activator protein-1, cAMP response element-binding protein and NF-kappaB. Our results suggest that BOT-4-one may have therapeutic potential for the treatment of chronic inflammation associated with autoimmune rheumatoid arthritis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

B7-H3, a newly identified B7 family member, has functional duality as a co-stimulator and co-inhibitor that fine-tunes T cell-mediated immune responses. Given that B7-H3 expression on human monocytes and dendritic cells is enhanced by inflammatory cytokines, its potential inmmunoregulatory role at sites of inflammation has been suggested. Further, monocytes play crucial roles in the pathophysiology of various inflammatory disorders including autoimmune diseases; however, the immunological role of B7-H3 in rheumatoid arthritis (RA) has not been defined. Thus, we aimed to investigate the possible roles of monocyte B7-H3 in the pathogenesis of RA. Synovial monocytes, but not peripheral monocytes, in RA patients predominantly express surface B7-H3. The 4Ig isoform of B7-H3 is exclusively induced on the cell surface, whereas the 2Ig B7-H3 isoform is constitutively expressed in the intracytoplasmic region of both peripheral and synovial monocytes. B7-H3 knockdown experiments reveal that surface B7-H3 has an inhibitory effect on IFN-γ production in CD4 memory cells. Moreover, surface B7-H3 expression on synovial monocytes inversely correlates with RA clinical parameters. Our findings demonstrate that activation-induced B7-H3 expression on synovial monocytes has the potential to inhibit Th1-mediated immune responses and immunomodulatory roles affecting RA pathogenesis., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Nucleobase adenine is produced by dividing human lymphoblasts mainly from polyamine synthesis and inhibits immunological functions of lymphocytes. We investigated the anti-allergic effect of adenine on IgE-mediated mast cell activation in vitro and passive cutaneous anaphylaxis (PCA) in mice. Intraperitoneal injection of adenine to IgE-sensitized mice attenuated IgE-mediated PCA reaction in a dose dependent manner, resulting in a median effective concentration of 4.21 mg/kg. In mast cell cultures, only adenine among cytosine, adenine, adenosine, ADP and ATP dose-dependently suppressed FcɛRI (a high affinity receptor for IgE)-mediated degranulation with a median inhibitory concentration of 1.6mM. It also blocked the production of LTB4, an inflammatory lipid mediator, and inflammatory cytokines TNF-α and IL-4. In addition, adenine blocked thapsigargin-induced degranulation which is FcɛRI-independent but shares FcɛRI-dependent signaling events. Adenine inhibited the phosphorylation of signaling molecules important to FcɛRI-mediated allergic reactions such as Syk, PLCγ2, Gab2, Akt, and mitogen activated protein kinases ERK and JNK. From this result, we report for the first time that adenine inhibits PCA in mice and allergic reaction by inhibiting FcɛRI-mediated signaling events in mast cells. Therefore, adenine may be useful for the treatment of mast cell-mediated allergic diseases. Also, the upregulation of adenine production may provide another mechanism for suppressing mast cell activity especially at inflammatory sites., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The objectives of the study are to demonstrate the non-inferiority of PG201 (Layla(®)) 600 mg in comparison with celecoxib 200 mg for the treatment of symptomatic knee osteoarthritis (OA). In total, 309 patients were randomly assigned to receive either the test drug, PG201 600 mg (n = 154) or celecoxib 200 mg (n = 155). The primary efficacy variable was improvement in mean 100-mm pain VAS score from baseline to the final visit (week 8), and this value was compared between the 2 treatment groups. Secondary outcome variables included changes from baseline in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain VAS score and subscale score, patient's global assessment of disease status quality of life (short form-36) and responder index at weeks 4 and 8. For safety assessment, adverse events were recorded at each clinical visit. At weeks 8, the 100-mm pain VAS scores were significantly decreased in patients receiving both PG201 600 mg (p < 0.0001) and celecoxib 200 mg (p < 0.0001) as compared to the baseline scores; however, no statistically significant differences in these values were noted between the groups (p = 0.312). These results met pre-specified criteria for non-inferiority for both the intent-to-treat and per-protocol populations. PG201 600 mg and celecoxib 200 mg were both well tolerated and no statistically significant differences in the tolerability profile between the groups. PG201 600 mg was as effective and safe as celecoxib 200 mg in the treatment of symptomatic knee OA and might be a useful new medication for the treatment of symptomatic knee OA.

The ligation of interleukin-1 receptor (IL-1R) or tumor necrosis factor receptor 1 (TNFR1) induces the recruitment of adaptor proteins and their concomitant ubiquitination to the proximal receptor signaling complex, respectively. Such are upstream signaling events of IKK that play essential roles in NF-κB activation. Thus, the discovery of a substance that would modulate the recruitment of key proximal signaling elements at the upstream level of IKK has been impending in this field of study. Here, we propose that brazilin, an active compound of Caesalpinia sappan L. (Leguminosae), is a potent NF-κB inhibitor that selectively disrupts the formation of the upstream IL-1R signaling complex. Analysis of upstream signaling events revealed that brazilin markedly abolished the IL-1β-induced polyubiquitination of IRAK1 and its interaction with IKK-γ counterpart. Notably, pretreatment of brazilin drastically interfered the recruitment of the receptor-proximal signaling components including IRAK1/4 and TRAF6 onto MyD88 in IL-1R-triggerd NF-κB activation. Interestingly, brazilin did not affect the TNF-induced RIP1 ubiquitination and the recruitment of RIP1 and TRAF2 to TNFR1, suggesting that brazilin is effective in selectively suppressing the proximal signaling complex formation of IL-1R, but not that of TNFR1. Moreover, our findings suggest that such a disruption of IL-1R-proximal complex formation by brazilin is not mediated by affecting the heterodimerization of IL-1R and IL-1RAcP. Taken together, the results suggest that the anti-IKK activity of brazilin is induced by targeting IKK upstream signaling components and subsequently disrupting proximal IL-1 receptor signaling complex formation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In the turkey, exogenous serotonin (5-hydroxytryptamine, 5-HT) increases prolactin (PRL) secretion by acting through the dopaminergic (DAergic) system. In the present study, infusion of the 5-HT(2C) receptor agonist, (R)(-)-DOI hydrochloride (DOI), into the third ventricle stimulates PRL secretion, whereas the 5-HT(1A) receptor agonist, (+/-)-8-OH-DPAT hydrobromide (DPAT), inhibits PRL secretion. Using the immediate-early gene, c-fos, as an indicator of neuronal activity, in situ hybridization histochemistry showed preferential c-fos co-localization within tyrosine hydroxylase immunoreactive neurons (the rate limiting enzyme in DA synthesis) in the areas of the nucleus preopticus medialis (POM) and the nucleus premammillaris (PMM), in response to DPAT and DOI, respectively. To clarify the involvement of 5-HT(1A) and 5-HT(2C) receptors in PRL regulation, their mRNA expression was determined on hypothalamic tissue sections from birds in different reproductive stages. A significant difference in 5-HT1A receptor was observed, with the POM of hypoprolactinemic short day and photorefractory birds showing the highest expression. 5-HT2C receptors mRNA did not change during the reproductive cycle. The data presented support the notion that DA neurons in the PMM and POM mediate the stimulatory and inhibitory effects of 5-HT, respectively, on PRL secretion and the 5-HTergic system can both stimulate and inhibit PRL secretion., (Copyright © 2013. Published by Elsevier GmbH.)