Yeon-Ah Lee

A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study

Objectives To compare the pharmacokinetics (PK), safety and efficacy of innovator infliximab (INX) and CT-P13, a biosimilar to INX, in patients with active ankylosing spondylitis (AS). Methods Phase 1 randomised, double-blind, multicentre, multinational, parallel-group study. Patients were randomised to receive 5 mg/kg of CT-P13 (n=125) or INX (n=125). Primary endpoints were area under the concentration-time curve (AUC) at steady state and observed maximum steady state serum concentration (Cmax,ss) between weeks 22 and 30. Additional PK, efficacy endpoints, including 20% and 40% improvement response according to Assessment in Ankylosing Spondylitis International Working Group criteria (ASAS20 and ASAS40), and safety outcomes were also assessed. Results Geometric mean AUC was 32 765.8 μgh/ml for CT-P13 and 31 359.3 μgh/ml for INX. Geometric mean Cmax,ss was 147.0  μg/ml for CT-P13 and 144.8 μg/ml for INX. The ratio of geometric means was 104.5% (90% CI 94% to 116%) for AUC and 101.5% (90% CI 95% to 109%) for Cmax,ss. ASAS20 and ASAS40 responses at week 30 were 70.5% and 51.8% for CT-P13 and 72.4% and 47.4% for INX, respectively. In the CT-P13 and INX groups more than one adverse event occurred in 64.8% and 63.9% of patients, infusion reactions occurred in 3.9% and 4.9%, active tuberculosis occurred in 1.6% and 0.8%, and 27.4% and 22.5% of patients tested positive for anti-drug antibodies, respectively. Conclusions The PK profiles of CT-P13 and INX were equivalent in patients with active AS. CT-P13 was well tolerated, with an efficacy and safety profile comparable to that of INX up to week 30.

Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study

Objectives To investigate the efficacy and safety of switching from infliximab reference product (RP) to its biosimilar or maintaining biosimilar treatment in patients with ankylosing spondylitis (AS). Methods This open-label extension study recruited patients with AS who completed a 54-week, randomised controlled study comparing CT-P13 with RP (PLANETAS). CT-P13 (5 mg/kg) was administered intravenously every 8 weeks from week 62 to week 102. Efficacy end points included the proportion of patients achieving Assessment of SpondyloArthritis international Society (ASAS)20. Antidrug antibodies (ADAs) were measured using an electrochemiluminescent method. Data were analysed for patients treated with CT-P13 in the main PLANETAS study and the extension (maintenance group) and those who were switched to CT-P13 during the extension study (switch group). Results Overall, 174 (82.9%) of 210 patients who completed the first 54 weeks of PLANETAS and agreed to participate in the extension were enrolled. Among these, 88 were maintained on CT-P13 and 86 were switched to CT-P13 from RP. In these maintenance and switch groups, respectively, ASAS20 response rates at week 102 were 80.7% and 76.9%. ASAS40 and ASAS partial remission were also similar between groups. ADA positivity rates were comparable (week 102: 23.3% vs 27.4%). Adverse events led to treatment discontinuation during the extension study in 3 (3.3%) and 4 (4.8%) patients, respectively. Conclusions This is the first study to show that switching from RP to its biosimilar CT-P13 is possible without negative effects on safety or efficacy in patients with AS. In the maintenance group, CT-P13 was effective and well tolerated over 2 years of treatment. Trial registration number NCT01571206; Results.

Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population

The PD-1 (programmed death 1) molecule is a negative regulator of T cells. PDCD1 (programmed cell death 1) has been reported to have a genetic association in systemic lupus erythematosus and rheumatoid arthritis in Caucasians. However, there are no reports on the association between this gene and ankylosing spondylitis (AS). The present study investigated the association of the PD-1 polymorphisms and the haplotypes with AS in a Korean population sample. In a case-control association study, two single-nucleotide polymorphisms, PD-1.5 C/T and PD-1.9 T/C, were genotyped in 95 AS patients and 130 healthy controls. The T allele of the PD-1.9 polymorphism was more frequent in the Korean male population with AS than in the Korean male controls (21.0% versus 6.9%, odds ratio 1.89, 95% confidence interval 1.483 to 2.408). The frequency of the CT haplotype (PD-1.5 C/T and PD-1.9 T/C) was higher in the AS patients (19%) than the controls (5.4%) (odds ratio 1.83, 95% confidence interval 1.559 to 2.521). The PD-1 polymorphism was demonstrated in Korean AS patients. The results suggest a genetic association between the PD-1 polymorphism and susceptibility to AS.

Expression levels and association of gelatinases MMP-2 and MMP-9 and collagenases MMP-1 and MMP-13 with VEGF in synovial fluid of patients with arthritis.

This study was performed to provide evidence, albeit indirectly, as to which matrix metalloproteinases (MMPs), among the gelatinases MMP-2 and MMP-9 and the collagenases MMP-1 and MMP-13, play a more proactive role in the angiogenic process in arthritic joint. Joint fluid was collected from 33 patients with rhuematoid arthritis (RA) and osteoarthritis (OA), and protein (MMPs and vascular endothelial growth factor (VEGF)) levels were measured by ELISA, and the association of MMPs with VEGF was evaluated in joint fluid of patients with RA or OA. The levels of collagenases (total MMP-1 and total MMP-13) and gelatinases (total MMP-2 and total MMP-9) in RA joint fluid were significantly higher than those in OA fluid. Total MMP-9 levels were significantly associated with VEGF levels in RA fluids, but not in OA fluid, while total MMP-13 levels were strongly associated with VEGF levels in both RA and OA fluid. However, total MMP-2 and total MMP-1 levels were not associated with VEGF levels in either RA or OA joint fluid. Our results indirectly suggest that in RA and OA, MMP-9 and MMP-13 may play a more important role in angiogenesis than MMP-2 and MMP-1.

Synovial proliferation differentially affects hypoxia in the joint cavities of rheumatoid arthritis and osteoarthritis patients

This study was performed to investigate whether synovial proliferation (SP) differentially affects hypoxia in the joint cavities of rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Thirty RA and 42 OA patients who underwent synovitis assessment were classified into two groups based on the presence or absence of SP, as revealed by musculoskeletal ultrasonography. Synovial fluids (SFs) from the knee joints were analyzed for interleukin (IL)-8, pO2, and white blood cell counts and blood samples were analyzed for erythrocyte sedimentation rate (ESR). No difference was found between the OA patients with and without SP in terms of SF oxygen tension (SF pO2) or IL-8 level, whereas the RA patients had significantly lower SF pO2 levels in their knee joints than did the OA patients with SP, and the RA patients had higher levels of IL-8 in their joints than did the OA patients. The counts of infiltrated immune cells in the SF and tissues were much higher for patients with RA and SP than for those with OA and SP. The ESRs were not found to be correlated with SP in OA patients but were negatively correlated with SF pO2 levels in RA patients. We conclude that ultrasonographically detected SP in OA patients does not generate a more hypoxic SF than that found in OA patients without SP. The SFs from RA patients with SP are hypoxic, which indicates that SP may have different impacts on hypoxia in the joint cavities of RA and OA patients.

Taurine chloramine differentially inhibits matrix metalloproteinase 1 and 13 synthesis in interleukin-1β stimulated fibroblast-like synoviocytes

It has been suggested that taurine chloramine (TauCl) plays an important role in the downregulation of proinflammatory mediators. However, little is known about its effect on the expression of matrix metalloproteinases (MMPs). In this study, we investigated the effects of TauCl on synovial expression of MMPs. The effects of TauCl on MMP expression in IL-1β stimulated fibroblast-like synoviocytes (FLSs) were studied using the following techniques. Real-time PCR and semi-quantitative PCR were employed to analyze the mRNA expression of MMPs. ELISA was used to determine protein levels of MMPs. Western blot analyses were performed to analyze the mitogen-activated protein kinase and inhibitor of nuclear factor-κB (IκB) kinase signalling pathways. Finally, electrophoretic mobility shift assay and immunohistochemistry were used to assess localization of transcription factors. IL-1β increased the transcriptional and translational levels of MMP-1 and MMP-13 in rheumatoid arthritis FLSs, whereas the levels of MMP-2 and MMP-9 were unaffected. TauCl at a concentration of 400 to 600 μmol/l greatly inhibited the transcriptional and translational expression of MMP-13, but the expression of MMP-1 was significantly inhibited at 800 μmol/l. At a concentration of 600 μmol/l, TauCl did not significantly inhibit phosphorylation of mitogen-activated protein kinase or IκB degradation in IL-1β stimulated rheumatoid arthritis FLSs. The degradation of IκB was significantly inhibited at a TauCl concentration of 800 μmol/l. The inhibitory effect of TauCl on IκB degradation was confirmed by electrophoretic mobility shift assay and immunochemical staining for localization of nuclear factor-κB. TauCl differentially inhibits the expression of MMP-1 and MMP-13, and inhibits expression of MMP-1 primarily through the inhibition of IκB degradation, whereas it inhibits expression of MMP-13 through signalling pathways other than the IκB pathway.

Hypoxia differentially affects IL-1β-stimulated MMP-1 and MMP-13 expression of fibroblast-like synoviocytes in an HIF-1α-dependent manner

OBJECTIVES To further understand the expression regulation of MMP-1 and MMP-13 under physiological and pathological conditions, we investigated the combined effects of hypoxia and pro-inflammatory stimuli on the expression of MMP-1 and MMP-13 in rheumatoid synovial fibroblasts. METHODS Synovial fibroblasts were cultured under either hypoxic or normoxic conditions in the presence of IL-1β stimulation. The culture supernatant was analysed for secreted levels of VEGF, MMP-1 and MMP-13. Their gene expression was quantified with real-time and semi-quantitative PCR. Another group of cells was transfected with small-interfering RNA (siRNA) specific for hypoxia-inducible factor-1 α (HIF-1α). The protein levels of HIF-1α were detected by western blot analysis. RESULTS In response to 10 ng/ml of IL-1β under normoxia, the levels of MMP-1 and MMP-13 increased compared with the levels observed under hypoxia. IL-1β stimulation under hypoxia induced a 2-fold increase in the level of MMP-1 and a 2-fold decrease in the level of MMP-13 compared with cells cultured under normoxia. A similar pattern of differential expression for MMP-1 and MMP-13 was observed with 1 and 5 ng/ml IL-1β, but not at 0.1 ng/ml. The differential expression of MMPs under the combined effect of IL-1β and hypoxia was significantly attenuated by silencing HIF-1α with siRNA. CONCLUSIONS Hypoxia in arthritic joints may differentially affect the IL-1β-stimulated expression of MMP-1 and MMP-13 in rheumatoid synovial fibroblasts. This effect is dependent on HIF-1α expression. This hypoxia-mediated differential effect should be taken into consideration when testing the efficiency of therapies that target HIF-1α.

The role of adiponectin in the production of IL-6, IL-8, VEGF and MMPs in human endothelial cells and osteoblasts: implications for arthritic joints

This study was performed to evaluate the contribution of adiponectin to the production of interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-1 and MMP-13 in human endothelial cells and osteoblasts in arthritic joints. Cultured human umbilical vascular endothelial cells (HUVECs) and osteoblasts were stimulated with adiponectin (1 or 10 μg ml−1) or IL-1β (0.1 ng ml−1) in the presence or absence of hypoxia for 24 h. The protein expression patterns were examined by analyzing culture supernatants using the enzyme-linked immunosorbent assay (ELISA). Adiponectin significantly stimulated the production of VEGF, MMP-1 and MMP-13 in osteoblasts but not in endothelial cells, whereas it significantly stimulated the production of IL-6 and IL-8 in both endothelial cells and osteoblasts. The increase in VEGF production induced by adiponectin was significantly greater than that induced by IL-1β. The production of IL-6 and IL-8 in adiponectin-stimulated endothelial cells was approximately 10-fold higher than that in IL-1β-stimulated endothelial cells; in osteoblasts, adiponectin-induced IL-6 and IL-8 secretion was approximately twofold higher than that induced by IL-1β. In addition, IL-8 production in endothelial cells was approximately sevenfold higher than in osteoblasts. However, IL-6 levels were similar between the two cell types, suggesting that adiponectin may be involved in the production of IL-8 in endothelial cells, which may have an important role in neutrophil recruitment to arthritic joints. Furthermore, the increases in protein expression induced by adiponectin were differentially regulated by hypoxia. In conclusion, adiponectin has a more important role than does IL-1β in the production of mediators that drive synovitis and joint destruction in endothelial cells and osteoblasts at physiological concentrations.

OP0167 A randomized, double-blind, phase 1 study demonstrates equivalence in pharmacokinetics, safety, and efficacy of CT-P13 and infliximab in patients with ankylosing spondylitis

Background CT-P13 was developed as a biosimilar product to infliximab (Remicade®), a chimeric monoclonal antibody approved in the European Union in 1999 for the treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn’s disease, ulcerative colitis, psoriasis, and psoriatic arthritis. Objectives To compare the pharmacokinetic (PK) profile of CT-P13 with that of infliximab at steady state in terms of area under the concentration-time curve over a dosing interval (AUCτ) and observed maximum serum concentration (Cmax,ss), and evaluate the efficacy and overall safety of both treatments in patients with AS. Methods Two hundred fifty patients with active AS were randomized 1:1 to receive either CT-P13 or infliximab (5 mg/kg, 2-hour IV infusion per dose) at weeks 0, 2, and 6 (dose-loading phase) and at weeks 14, 22, and 30 (maintenance phase). Ratios of geometric means of primary PK parameters (AUCτ and Cmax,ss) from the 2 treatment arms between weeks 22 and 30 were subjected to ANCOVA analysis at 90% confidence intervals (CIs). Efficacy measures (including ASAS20 and ASAS40), and safety parameters (including the incidence of adverse events [AEs]) were also evaluated. This report presents PK, efficacy, and safety results up to week 30 (as approved by the European Medicines Agency). Results The mean (% CV) AUCτ was 34855.45 (34.3%) μg-h/mL and 34688.71 (45.4%) μg-h/mL in the CT-P13 and infliximab arms, respectively. The mean (% CV) Cmax,ss was 153.52 (27.6%) μg/mL and 150.39 (26.9%) μg/mL in the CT-P13 and infliximab arms, respectively. The ratio (%) between the geometric means of the AUCτ and Cmax,ss values in the CT-P13 and infliximab arms were 104.1% (90% CI 93.9% to 115.4%) and 101.5% (90% CI 94.6% to 108.9%), respectively, between weeks 22 and 30, indicating PK equivalence in terms of AUCτ and Cmax,ss. Secondary parameters at week 30 were also comparable, including ASAS20 and ASAS40 response rates (70.5% for CT-P13 vs 72.4% for infliximab and 51.8% vs 47.4%, respectively). AEs considered by the investigators to be related to study treatment were reported in 57 (44.5%) patients and 58 (47.5%) patients in the CT-P13 and infliximab arms, respectively. Related AEs due to infection were reported for 24/128 (18.8%) patients and 22/122 (18.0%) patients in the CT-P13 and infliximab treatment groups, respectively. AEs due to infusion reactions considered related to study drug were reported in 5 patients in the CT-P13 arm, and 6 patients in the infliximab arm. Tuberculosis was reported in 2 patients in the CT-P13 arm and in 1 patient in the infliximab arm. Conclusions CT-P13 and infliximab are equivalent in terms of AUCτ and Cmax,ss in patients with AS. In addition, CT-P13 was well tolerated, with an efficacy and safety profile comparable to that of infliximab up to week 30. Disclosure of Interest W. Park: None Declared, P. Hrycaj: None Declared, V. Kovalenko: None Declared, P. Miranda: None Declared, S. Gutierrez-Ureña: None Declared, Y. Lee: None Declared, M. Lim: None Declared, C. Ahn: None Declared, H. Kim Employee of: Celltrion, D. Yoo: None Declared, J. Braun: None Declared

Human leukocyte antigen-B*2705 is the predominant subtype in the Korean population with ankylosing spondylitis, unlike in other Asians

This study was performed to investigate the frequency of human leukocyte antigen (HLA)-B27 subtypes in the Korean population with spondyloarthropathy (SpA). We determined the HLA subtypes of 267 SpA patients who were positive for the B27 antigen (as determined by serology) by using a PEL-FREEZ kit (Dynal Biotech, Wisconsin, USA). Clinical features, including sex, peripheral joint involvement, and the presence of uveitis, were analyzed in a retrospective cohort study. Among 267 patients, 244 were B*2705-positive and 22 were B*2704-positive. One patient was positive for B*2704/2705. No other subtype was observed among the analyzed patients. We found that HLA-B*2705 was the predominant subtype in Koreans with SpA; this finding is remarkable because other Asians such as the Han or the Japanese exclusively have the B*2704 subtype. This result suggests that the clinical features and prevalence of SpA in Koreans may be similar to those observed in Europeans.