Mie Jin Lim

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.

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.

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

Serum Procalcitonin for Differentiating Bacterial Infection from Disease Flares in Patients with Autoimmune Diseases

Early differentiation between bacterial infections and disease flares in autoimmune disease patients is important due to different treatments. Seventy-nine autoimmune disease patients with symptoms suggestive of infections or disease flares were collected by retrospective chart review. The patients were later classified into two groups, disease flare and infection. C-reactive protein (CRP) and serum procalcitonin (PCT) levels were measured. The CRP and PCT levels were higher in the infection group than the disease flare group (CRP,11.96 mg/dL ± 9.60 vs 6.42 mg/dL ± 7.01, P = 0.003; PCT, 2.44 ng/mL ± 6.55 vs 0.09 ng/mL ± 0.09, P < 0.001). The area under the ROC curve (AUC; 95% confidence interval) for CRP and PCT was 0.70 (0.58-0.82) and 0.84 (0.75-0.93), which showed a significant difference (P < 0.05). The predicted AUC for the CRP and PCT levels combined was 0.83, which was not significantly different compared to the PCT level alone (P = 0.80). The best cut-off value for CRP was 7.18 mg/dL, with a sensitivity of 71.9% and a specificity of 68.1%. The best cut-off value for PCT was 0.09 ng/mL, with a sensitivity of 81.3% and a specificity of 78.7%. The PCT level had better sensitivity and specificity compared to the CRP level in distinguishing between bacterial infections and disease flares in autoimmune disease patients. The CRP level has no additive value when combined with the PCT level when differentiating bacterial infections from disease flares.

Digital thermography of the fingers and toes in Raynaud's phenomenon.

The aim of this study was to determine whether skin temperature measurement by digital thermography on hands and feet is useful for diagnosis of Raynauds phenomenon (RP). Fifty-seven patients with RP (primary RP, n = 33; secondary RP, n = 24) and 146 healthy volunteers were recruited. After acclimation to room temperature for 30 min, thermal imaging of palmar aspect of hands and dorsal aspect of feet were taken. Temperature differences between palm (center) and the coolest finger and temperature differences between foot dorsum (center) and first toe significantly differed between patients and controls. The area under curve analysis showed that temperature difference of the coolest finger (cutoff value: 2.2℃) differentiated RP patients from controls (sensitivity/specificity: 67/60%, respectively). Temperature differences of first toe (cutoff value: 3.11℃) also discriminated RP patients (sensitivity/specificity: about 73/66%, respectively). A combination of thermographic assessment of the coolest finger and first toe was highly effective in men (sensitivity/specificity : about 88/60%, respectively) while thermographic assessment of first toe was solely sufficient for women (sensitivity/specificity: about 74/68%, respectively). Thermographic assessment of the coolest finger and first toe is useful for diagnosing RP. In women, thermography of first toe is highly recommended. Graphical Abstract

Early effects of tumor necrosis factor inhibition on bone homeostasis after soluble tumor necrosis factor receptor use

Background/Aims Our aim was to assess whether short-term treatment with soluble tumor necrosis factor (TNF) receptor affects circulating markers of bone metabolism in rheumatoid arthritis (RA) patients. Methods Thirty-three active RA patients, treated with oral disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids for > 6 months, were administered etanercept for 12 weeks. Serum levels of bone metabolism markers were compared among patients treated with DMARDs at baseline and after etanercept treatment, normal controls and naive RA patients not previously treated with DMARDs (both age- and gender-matched). Results Bone-specific alkaline phosphatase (BSALP) and serum c-telopeptide (CTX)-1 levels were lower in RA patients treated with DMARDs than in DMARD-naive RA patients. After 12 weeks of etanercept treatment, serum CTX-1 and sclerostin levels increased. In patients whose DAS28 improved, the sclerostin level increased from 1.67 ± 2.12 pg/mL at baseline to 2.51 ± 3.03 pg/mL, which was statistically significant (p = 0.021). Increases in sclerostin levels after etanercept treatment were positively correlated with those of serum CTX-1 (r = 0.775), as were those of BSALP (r = 0.755). Conclusions RA patients treated with DMARDs showed depressed bone metabolism compared to naive RA patients. Increases in serum CTX-1 and sclerostin levels after short-term etanercept treatment suggest reconstitution of bone metabolism homeostasis.

Prevention of Comorbidity and Acute Attack of Gout by Uric Acid Lowering Therapy

The object of this study was to evaluate the effect of uric acid lowering therapy in reducing the new development of comorbidities and the frequency of acute attacks in gout patients. We retrospectively reviewed patients who were diagnosed to have gout with at least 3 yr of follow up. They were divided into 2 groups; 53 patients with mean serum uric acid level (sUA)<6 mg/dL and 147 patients with mean sUA≥6 mg/dL. Comorbidities of gout such as hypertension (HTN), type II diabetes mellitus (DM), chronic kidney disease, cardiovascular disease (CVD) and urolithiasis were compared in each group at baseline and at last follow-up visit. Frequency of acute gout attacks were also compared between the groups. During the mean follow up period of 7.6 yr, the yearly rate of acute attack and the new development of HTN, DM, CVD and urolithiasis was lower in the adequately treated group compared to the inadequately treated group. Tight control of uric acid decreases the incidence of acute gout attacks and comorbidities of gout such as HTN, DM, CVD and urolithiasis. Graphical Abstract

A comparison of three different guidelines for osteoporosis treatment in patients with rheumatoid arthritis in Korea.

Background/Aims Osteoporotic fractures are an important comorbidity with rheumatoid arthritis (RA). We determined the overall fracture risk as assessed by the World Health Organization (WHO)s FRAX® tool in Korean patients with seropositive RA. Additionally, we compared treatment eligibility according to the criteria of the Korean Health Insurance Review Agency (HIRA), FRAX, and the National Osteoporosis Foundation (NOF). Methods Postmenopausal women and men ≥ 50 years of age with seropositive RA were recruited from one rheumatism center in Korea. The FRAX score was estimated using the Japanese model. Patients were classified as eligible for treatment using the HIRA, NOF, and FRAX thresholds for intervention. Results The study of 234 patients included 40 men (17%). The mean age was 60 ± 9 years, and 121 (52%) patients had osteoporosis according to the WHO criteria. The overall median 10-year fracture risk was 13% for major osteoporotic fractures and 3.5% for hip fractures. HIRA guidelines identified 130 patients (56%) eligible for treatment, FRAX included 126 patients (54%), and 151 patients (65%) were included according to NOF guidelines. Older patients with a greater number of risk factors were included by FRAX compared to HIRA. The overall concordance between HIRA and FRAX, expressed as the kappa index, was 0.67, but was as low as 0.44 when limited to patients ≥ 60 years of age. Conclusions One-half of the patients had osteoporosis requiring treatment. RA patients have a high risk of fracture, and the adoption of a risk-scoring system should be considered.

Induction of Remission is Difficult due to Frequent Relapse during Tapering Steroids in Korean Patients with Polymyalgia Rheumatica

Polymyalgia rheumatica is an inflammatory disease affecting elderly and involving the shoulder and pelvic girdles. No epidemiological study of polymyalgia rheumatica was conducted in Korea. We retrospectively evaluated patients with polymyalgia rheumatica followed up at the rheumatology clinics of 10 tertiary hospitals. In total 51 patients, 36 patients (70.6%) were female. Age at disease onset was 67.4 yr. Twenty-three patients (45.1%) developed polymyalgia rheumatica in winter. Shoulder girdle ache was observed in 45 patients (90%) and elevated erythrocyte sedimentation rate (> 40 mm/h) in 49 patients (96.1%). Initial steroid dose was 23.3 mg/d prednisolone equivalent. Time to normal erythrocyte sedimentation rate was 4.1 months. Only 8 patients (15.7%) achieved remission. Among 41 patients followed up, 28 patients (68.3%) had flare at least once. Number of flares was 1.5 ± 1.6. The frequency of flare was significantly lower in patients with remission (P = 0.02). In Korea, polymyalgia rheumatica commonly develops during winter. Initial response to steroid is fairly good, but the prognosis is not benign because remission is rare with frequent relapse requiring long-term steroid treatment.