ObjectivesTo 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).MethodsPhase 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.ResultsGeometric 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.ConclusionsThe 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.

ObjectivesTo 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).MethodsThis 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).ResultsOverall, 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.ConclusionsThis 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 numberNCT01571206; Results.

ObjectiveTo 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.MethodsIn 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.Results103 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.ConclusionsCT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety.Trial registration numberNCT01534884.

The aim of this study was to determine whether skin temperature measurement by digital thermography on hands and feet is useful for diagnosis of Raynaud's 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 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.

BackgroundCT-P10 is a biosimilar candidate of innovator rituximab (RTX) that demonstrated a comparable clinical profile to RTX in a phase I randomized controlled trial (RCT) in rheumatoid arthritis (RA) (ClinicalTrials.gov identifier: NCT01534884).ObjectiveThis open-label extension (OLE) study (NCT01873443) compared the efficacy and safety of CT-P10 in patients with RA who received CT-P10 from the outset (i.e., from the start of the RCT and also in the OLE; ‘maintenance group’) with those who received RTX during the RCT and switched to CT-P10 during the OLE (‘switch group’).MethodsPatients who completed the RCT were recruited. Based on the Disease Activity Score using 28 joints (DAS28) and predefined safety criteria, patients could receive up to two courses of CT-P10 during the OLE. Efficacy [DAS28 and European League Against Rheumatism (EULAR) response], safety and immunogenicity were assessed.ResultsEighty-seven patients were enrolled; 58 and 29 had previously received CT-P10 or RTX, respectively, in the RCT. Of these, 38 (65.5%) and 20 (69.0%) were treated with CT-P10 in the OLE and therefore comprised the maintenance and switch groups, respectively. The mean change in DAS28-erythrocyte sedimentation rate (ESR) from baseline (week 0 of RCT) at week 24 of the first OLE treatment course in the maintenance and switch groups was −2.7 and −2.4, respectively. The proportion of patients with good/moderate EULAR responses was also comparable between groups. Antidrug antibodies were detected in 13.2 and 15.0% of patients in the maintenance and switch groups, respectively, at week 24 of the first OLE course. CT-P10 treatment was well-tolerated when administered for up to 2 years or after switching from RTX.ConclusionIn this study population, comparable efficacy and safety profiles were observed in patients who switched from RTX to CT-P10 and those maintained on CT-P10 throughout treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s40259-017-0233-6) contains supplementary material, which is available to authorized users.

Osteoporosis in rheumatic diseases is a very well-known complication. Systemic inflammation results in both generalized and localized bone loss and erosions. Recently, increased knowledge of inflammatory process in rheumatic diseases has resulted in the development of potent inhibitors of the cytokines, the biologic DMARDs. These treatments reduce systemic inflammation and have some effect on the generalized and localized bone loss. Progression of bone erosion was slowed by TNF, IL-6 and IL-1 inhibitors, a JAK inhibitor, a CTLA4 agonist, and rituximab. Effects on bone mineral density varied between the biological DMARDs. Medications that are approved for the treatment of osteoporosis have been evaluated to prevent bone loss in rheumatic disease patients, including denosumab, cathepsin K, bisphosphonates, anti-sclerostin antibodies and parathyroid hormone (hPTH 1-34), and have some efficacy in both the prevention of systemic bone loss and reducing localized bone erosions. This article reviews the effects of biologic DMARDs on bone mass and erosions in patients with rheumatic diseases and trials of anti-osteoporotic medications in animal models and patients with rheumatic diseases.

BackgroundCT-P10 is a biosimilar of innovator rituximab (RTX), a biological therapy used to treat patients with rheumatoid arthritis (RA) who have responded inadequately to anti-tumor necrosis factor agents.ObjectiveOur objective was to compare the clinical profile of CT-P10 versus RTX in patients with RA who received up to two courses of treatment and were followed for up to 72 weeks.MethodsIn this multicenter double-blind phase I study, patients were randomized 2:1 to receive CT-P10 1000 mg or RTX 1000 mg at weeks 0 and 2. Based on disease activity, patients could receive a second course of treatment between weeks 24 and 48. Efficacy endpoints, including mean change from baseline in Disease Activity Score using 28 joints (DAS28), safety, immunogenicity, pharmacokinetics, and pharmacodynamics were evaluated.ResultsIn total, 154 patients were randomized to CT-P10 or RTX (n = 103 and 51, respectively); 137 (n = 92 and 45) completed the first course of treatment, of whom 83 (n = 60 and 23) were re-treated. Improvements from baseline in all efficacy endpoints were highly similar between the CT-P10 and RTX groups over both treatment courses. At week 24 after the second course, mean change from week 0 of the first course in DAS28 erythrocyte sedimentation rate was −2.47 and −2.04 for CT-P10 and RTX, respectively, (p = 0.1866) and in DAS28 C-reactive protein was −2.32 and −2.00, respectively (p = 0.3268). The proportion of patients positive for antidrug antibodies at week 24 after the second treatment course was 20.0% and 21.7% in the CT-P10 and RTX groups, respectively. The safety profile of CT-P10 was comparable to that of RTX, and pharmacokinetic and pharmacodynamic properties were similar.ConclusionsIn patients with RA, efficacy, safety, and other clinical data were comparable between CT-P10 and RTX after up to two courses of treatment over 72 weeks.(ClinicalTrials.gov identifier NCT01534884).Electronic supplementary materialThe online version of this article (doi:10.1007/s40259-017-0232-7) contains supplementary material, which is available to authorized users.