Jung-Yoon Choe

A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy

Objectives To compare the efficacy, safety, immunogenicity and pharmacokinetics (PK) of SB2 to the infliximab reference product (INF) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate therapy. Methods This is a phase III, randomised, double-blind, multinational, multicentre parallel group study. Patients with moderate to severe RA despite methotrexate therapy were randomised in a 1:1 ratio to receive either SB2 or INF of 3 mg/kg. The primary end point was the American College of Rheumatology 20% (ACR20) response at week 30. Inclusion of the 95% CI of the ACR20 response difference within a ±15% margin was required for equivalence. Results 584 subjects were randomised into SB2 (N=291; 290 analysed) or INF (N=293). The ACR20 response at week 30 in the per-protocol set was 64.1% in SB2 versus 66.0% in INF. The adjusted rate difference was −1.88% (95% CI −10.26% to 6.51%), which was within the predefined equivalence margin. Other efficacy outcomes such as ACR50/70, disease activity score measured by 28 joints and European League against Rheumatism response were similar between SB2 and INF. The incidence of treatment-emergent adverse events was comparable (57.6% in SB2 vs 58.0% in INF) as well as the incidence of antidrug antibodies (ADA) to infliximab up to week 30 (55.1% in SB2 vs 49.7% in INF). The PK profile was similar between SB2 and INF. Efficacy, safety and PK by ADA subgroup were comparable between SB2 and INF. Conclusions SB2 was equivalent to INF in terms of ACR20 response at week 30. SB2 was well tolerated with a comparable safety profile, immunogenicity and PK to INF. Trial registration number NCT01936181.

No differences of carotid intima-media thickness between young patients with ankylosing spondylitis and healthy controls.

OBJECTIVE Accelerated atherosclerosis in inflammatory rheumatic diseases such as ankylosing spondylitis (AS) stands out among the leading causes of morbidity and mortality. We assessed the correlation between subclinical carotid atherosclerosis and its related clinical parameters in AS patients. METHODS Twenty-eight patients (23 males, 5 females) with AS and 27 sex- and age-matched controls were consecutively recruited to this study. We estimated the carotid intima-media thickness (IMT) and parameters related to arterial elastic properties, including the distensibility coefficient (DC), stiffness index (beta), and incremental elastic modulus (E(inc)) using high-resolution ultrasonography. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS Carotid IMT values and arterial elastic parameters in AS patients showed no statistical significance compared to those of controls (0.57+/-0.07 vs 0.55+/-0.05, p=0.387 for IMT, 28.45+/-9.23 vs 31.93+/-9.52, p=0.175 for DC, 2.32+/-0.18 vs 2.29+/-0.15, p=0.559 for stiffness index (beta), and 0.14+/-0.05 vs 0.12+/-0.03, p=0.116 for E(inc)). The serum level of IL-6 in AS patients was significantly different compared with controls (p=0.001), but not in serum levels of TNF-alpha and MCP-1 (p=0.162, p=0.087, respectively). Carotid IMT and all arterial elastic parameters calculated in this study were not found to be associated with serum levels of TNF-alpha, IL-6, and MCP-1. CONCLUSION This cross-sectional study showed that carotid IMT and parameters related with arterial elastic properties in young AS patients without clinically evident cardiovascular risk factors were not different from those of sex- and age-matched healthy controls. Serum levels of TNF-alpha, IL-6, and MCP-1 did not reflect the degree of carotid subclinical atherosclerosis. However, these findings should be confirmed further in a larger population.

Melittin suppresses EGF-induced cell motility and invasion by inhibiting PI3K/Akt/mTOR signaling pathway in breast cancer cells.

Bee venom is a natural compound produced by the honey bee (Apis mellifera), and has been reported as having the biological and pharmacological activities, including anti-bacterial, anti-viral and anti-inflammation. In the present study, the inhibitory effects of bee venom and its major peptide components on the tumor invasion were demonstrated. It was confirmed the inhibitory effects of bee venom, melittin, and apamin on the EGF-induced invasion of breast cancer cells. Transwell invasion and wound-healing assays showed that bee venom and melittin significantly inhibits the EGF-induced invasion and migration of breast cancer cells. Also, bee venom and melittin reduced the EGF-stimulated F-actin reorganization at the leading edge, but apamin did not affect. Particularly, melittin inhibited the EGF-induced MMP-9 expression via blocking the NF-κB and PI3K/Akt/mTOR pathway. In addition, melittin significantly suppressed the EGF-induced FAK phosphorylation through inhibition of mTOR/p70S6K/4E-BP1 pathway. These results suggest that inhibitory effects of melittin on breast cancer cell motility and migration may be related to the inhibition of mTOR pathway.

Bee venom suppresses LPS-mediated NO/iNOS induction through inhibition of PKC-α expression.

ETHNOPHARMACOLOGICAL RELEVANCE Bee venom (BV) is a traditional Korean medicine that has been widely used with satisfactory results in the treatment of some immune-related diseases, especially rheumatoid arthritis. AIM OF THE STUDY The purpose of this study is to elucidate the molecular mechanism underlying the anti-inflammatory effects of BV, which is used in the treatment of various inflammatory diseases in traditional Korean medicine. We evaluated the anti-inflammatory effect of BV on NO generation and iNOS expression by LPS in rat C6 glioma cells. MATERIAL AND METHODS BV was obtained from the National Institute of Agricultural Science and Technology (NIAST) of Korea. Nitrite measurement, Immuno blot analysis, Reverse transcriptase-PCR and Electrophoretic mobility shift assay (EMSA) were used for assessment. RESULTS BV suppressed the LPS-induced NO generation and iNOS expression, and it also inhibited the expressions of LPS-induced pro-inflammatory molecules including Cox-2 and IL-1 beta in rat C6 glioma cells. Then, BV inhibited LPS-induced expression of PKC-alpha and MEK/ERK, not p38 and JNK. Moreover, inhibition of LPS-induced iNOS expression by BV was dependent on transcriptional activities of AP-1/NF-kappaB through MEK/ERK pathway. CONCLUSION These results indicate that BV suppresses LPS-induced iNOS activation through regulation of PKC-alpha. Accordingly, BV exerts a potent suppressive effect on pro-inflammatory responses in rat C6 glioma cells.

Melittin enhances apoptosis through suppression of IL-6/sIL-6R complex-induced NF-κB and STAT3 activation and Bcl-2 expression for human fibroblast-like synoviocytes in rheumatoid arthritis

OBJECTIVE Resistance to apoptosis of fibroblast-like synoviocytes (FLS) is considered as a major characteristic in RA. This study was designed to identify whether melittin has a pro-apoptotic effect in IL-6/sIL6R-stimulated human FLS by investigating the expression of mitochondrial apoptosis-related genes, nuclear factor-κB (NF-κB), and signal transducer and activators of transcription (STAT) activation. METHODS Cell viability was determined using a MTT assay after melittin treatment. Expressions of STAT3 and mitochondrial apoptosis-related genes induced by the IL-6/sIL-6R complex were determined by real time-polymerase chain reaction and western blotting. The expression of NF-κB p65 following IL-6 stimulation was determined by western blot analysis. The effects of melittin on the expression of apoptosis-related genes and the transcription factors NF-κB p65 and STAT3 were assessed in FLS. Apoptosis of FLS was determined by TUNEL-labeling to detect DNA strand breaks and DNA fragmentation assays. Caspase-3 activity was determined by a colorimetric assay. RESULTS IL-6/sIL-6R induced the activation of the transcription factors, STAT3, NF-κB p65 (nucleus), and Bcl-2. Melittin increased the expression of pro-apoptosis-related molecules, namely caspase-3, caspase-9, Apaf-1, and cytosolic cytochrome c, in a dose-dependent manner after treatment with IL-6/sIL-6R. Melittin inhibited STAT3 activation, translocation of NF-κB p65 into the nucleus, and expression of anti-apoptotic genes such as Bcl-2 and mitochondrial cytochrome c. CONCLUSIONS The pro-apoptotic effects of melittin likely result from inhibition of the activation of the transcription factors, STAT3 and NF-κB p65, and regulation of mitochondrial apoptosis-related genes. Melittin is thus a promising therapeutic option for RA as it induces apoptosis in apoptosis-resistant synoviocytes.

Effect of n-3 polyunsaturated fatty acid supplementation in patients with rheumatoid arthritis: a 16-week randomized, double-blind, placebo-controlled, parallel-design multicenter study in Korea☆☆☆

N-3 polyunsaturated fatty acids (PUFA) have anti-inflammatory effects and may be useful for the treatment of inflammatory diseases such as rheumatoid arthritis (RA).We examined the efficacy of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on RA on top of standard anti-inflammatory treatment. Patients with RA were randomized into two groups in a double-blind, placebo-controlled, parallel-design multicenter study. One hundred nine patients received five capsules of either n-3 PUFA (2.090 g of EPA and 1.165 g of DHA) or high-oleic-acid sunflower oil for 16 weeks. Eighty-one patients completed the study, and no adverse effects were reported. Dietary intake did not change significantly during the study. There were significant increases in n-3 PUFA and EPA levels in erythrocytes in the n-3 PUFA group versus the placebo group, but decreases in n-6 PUFA, 18:2n6, 20:4n6 and 18:1n9 levels in the n-3 PUFA group versus the placebo group. N-3 PUFA supplementation had no significant effects on nonsteroidal anti-inflammatory drug (NSAID) requirements, clinical symptoms of RA or the concentration of cytokines, eicosanoids and bone turnover markers. However, n-3 PUFA supplementation significantly decreased NSAID requirements and leukotriene B4 levels in patients who weighed more than 55 kg. Our results suggest that n-3 PUFA supplementation has no significant effect on RA but may decrease the requirement for NSAIDs in Korean patients with RA who weigh more than 55 kg.

A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis

Objective To demonstrate pharmacokinetic equivalence of CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate responses or intolerances to antitumour necrosis factor agents. Methods In this randomised phase I trial, patients with active RA were randomly assigned (2:1) to receive 1000 mg CT-P10 or RTX at weeks 0 and 2 (alongside continued methotrexate therapy). Primary endpoints were area under the serum concentration–time curve from time zero to last quantifiable concentration (AUC0–last) and maximum serum concentration after second infusion (Cmax). Additional pharmacokinetic parameters, efficacy, pharmacodynamics, immunogenicity and safety were also assessed. Data are reported up to week 24. Results 103 patients were assigned to CT-P10 and 51 to RTX. The 90% CIs for the ratio of geometric means (CT-P10/RTX) for both primary endpoints were within the bioequivalence range of 80%–125% (AUC0–last: 97.7% (90% CI 89.2% to 107.0%); Cmax: 97.6% (90% CI 92.0% to 103.5%)). Pharmacodynamics and efficacy were comparable between groups. Antidrug antibodies were detected in 17.6% of patients in each group at week 24. CT-P10 and RTX displayed similar safety profiles. Conclusions CT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety. Trial registration number NCT01534884.

Increased insulin resistance and serum resistin in Korean patients with Behçet's disease.

BACKGROUND AND AIMS This study was designed to identify susceptibility to insulin resistance and the association of serum resistin and adiponectin with insulin resistance in patients with Behçets disease (BD). Also, we identify risk determinants for insulin resistance in BD patients. METHODS The study population consisted of 82 BD patients (n = 26 males) and 89 healthy controls (n = 40 males). Clinical data were collected at the time of enrollment, and serum resistin and adiponectin levels were measured using enzyme-linked immunosorbent assays. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated by measuring fasting plasma glucose and insulin levels. RESULTS BD patients and healthy controls differed significantly in insulin resistance (HOMA-IR) (1.3 +/- 1.1 vs. 0.7 +/- 0.5, p<0.001) and serum resistin level (7901.7 +/- 1314.9 vs. 7444.2 +/- 1841.6, p = 0.001) but not in serum adiponectin level (p = 0.223). No differences in HOMA-IR, serum adiponectin, and serum resistin were found between patients with active and inactive BD. It is determined that plasma glucose, plasma insulin, and serum resistin may be determinant for the HOMA-IR. The number of metabolic syndrome components is closely correlated with HOMA-IR in BD patients (r = 0.245, p = 0.029). CONCLUSION This study demonstrates that there is an increased susceptibility to insulin resistance in patients with BD as compared to healthy controls. Serum resistin level may be an independent determinant for insulin resistance in BD patients.

Regulatory effect of calcineurin inhibitor, tacrolimus, on IL-6/sIL-6R-mediated RANKL expression through JAK2-STAT3-SOCS3 signaling pathway in fibroblast-like synoviocytes

IntroductionThis study investigated whether the calcineurin inhibitor, tacrolimus, suppresses receptor activator of NF-κB ligand (RANKL) expression in fibroblast-like synoviocytes (FLS) through regulation of IL-6/Janus activated kinase (JAK2)/signal transducer and activator of transcription-3 (STAT3) and suppressor of cytokine signaling (SOCS3) signaling.MethodsThe expression of RANKL, JAK2, STAT3, and SOCS3 proteins was assessed by western blot analysis, real-time PCR and ELISA in IL-6 combined with soluble IL-6 receptor (sIL-6R)-stimulated rheumatoid arthritis (RA)-FLS with or without tacrolimus treatment. The effects of tacrolimus on synovial inflammation and bone erosion were assessed using mice with arthritis induced by K/BxN serum. Immunofluorescent staining was performed to identify the effect of tacrolimus on RANKL and SOCS3. The tartrate-resistant acid phosphatase staining assay was performed to assess the effect of tacrolimus on osteoclast differentiation.ResultsWe found that RANKL expression in RA FLS is regulated by the IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. Inhibitory effects of tacrolimus on RANKL expression in a serum-induced arthritis mice model were identified. Tacrolimus inhibits RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing STAT3. Among negative regulators of the JAK/STAT pathway, such as CIS1, SOCS1, and SOCS3, only SOCS3 is significantly induced by tacrolimus. As compared to dexamethasone and methotrexate, tacrolimus more potently suppresses RANKL expression in FLS. By up-regulating SOCS3, tacrolimus down-regulates activation of the JAK-STAT pathway by IL-6/sIL-6R trans-signaling, thus decreasing RANKL expression in FLS.ConclusionsThese data suggest that tacrolimus might affect the RANKL expression in IL-6 stimulated FLS through STAT3 suppression, together with up-regulation of SOCS3.

Clinical significance of 18F-fluoro-dexoxyglucose positron emission tomography in patients with adult-onset Still’s disease: report of two cases and review of literatures

Adult-onset Still’s disease (AOSD) is a multi-systemic inflammatory disease that usually presents with high fever and variable systemic features. The pathogenesis and etiology of AOSD have not yet been clearly determined. In addition, there is no diagnostic test for AOSD. Even though some useful diagnostic criteria or laboratory findings, such as serum ferritin levels, have been proposed, useful imaging studies for the diagnosis or follow-up of AOSD have not been developed. We performed 18F-fluoro-dexoxyglucose positron emission tomography (18F-FDG PET) on two AOSD patients who presented with a fever of unknown origin. In these patients, we initially identified abnormally increased FDG uptake in multiple lymph nodes, the spleen, or bone marrow. We then identified significantly decreased uptake during a follow-up study. On the basis of these cases, we suggest that 18F-FDG PET may have the potential in the diagnosis of AOSD, as well as monitor clinical changes in the disease. More further investigation of 18F-FDG PET in AOSD is needed in larger population.