Objective. Modification of antigens represents a trigger for the generation of autoantibodies. In the pathogenesis of rheumatoid arthritis (RA), citrullination of proteins has been shown to be a critical process, and the determination of antibodies against citrullinated antigens has been a diagnostic milestone. We undertook this study to determine whether antibodies to mutated and citrullinated vimentin (MCV) could serve as a diagnostic and prognostic marker for RA.Methods. We identified novel isoforms of human MCV in the synovial fluid of RA patients. The significance of these disease-related modifications was investigated by the analysis of autoantibody reactivities. In a group of 1,151 RA patients, the diagnostic significance and the prognostic value of an anti-MCV enzyme-linked immunosorbent assay (ELISA) were compared with that of an anti-cyclic citrullinated peptide (anti-CCP) ELISA.Results. In RA, sensitivities of 82% and 72% were calculated for the anti-MCV and anti-CCP assays, respectively. The specificity of both assays was comparable (98% and 96%, respectively). In followup analyses of 16 RA patients with moderate disease activity (mean Disease Activity Score in 28 joints [DAS28] of 2.72) and 26 RA patients with active disease (mean DAS28 of 5.07), disease stratification of RA was possible using the anti-MCV assay (P ‫؍‬ 0.0084). A significant correlation of anti-MCV antibodies with the DAS28 was documented (r ‫؍‬ 0.5334, P ‫؍‬ 0.0003), in 42 RA patients (n ‫؍‬ 427 antibody determinations at different time points).

Summary Background  Patients with rheumatic diseases receiving antitumour necrosis factor (TNF)‐α‐based treatment may develop cutaneous reactions. Objectives  To analyse the new onset or aggravation of skin lesions in patients with a rheumatic disease during treatment with TNF‐α antagonists. Methods  We conducted a prospective analysis of 35 of 150 patients with a long history of rheumatic disease, including rheumatoid arthritis, ankylosing spondylitis (Bechterew's disease) and psoriatic arthritis, to test for the development of cutaneous manifestations during anti‐TNF‐α (infliximab, adalimumab or etanercept) treatment. Results  Chronic inflammatory skin diseases such as psoriasis and eczema‐like manifestations represented the majority of cases (16 of 35). Cutaneous infections caused by viral, bacterial and fungal agents were also observed in many patients (13 of 35). Skin diseases such as dermatitis herpetiformis, leucocytoclastic vasculitis and alopecia occurred in single cases only. Conclusions  We observed a broad, diverse clinical spectrum with a majority of chronic inflammatory and infectious skin diseases. However, we did not identify individual risk factors and a discontinuation of the anti‐TNF‐α treatment was not necessary if adequate dermatological treatment was performed. The onset of cutaneous side‐effects in anti‐TNF‐α‐based treatments should be determined by nationwide registries.

AimsSB4 has been developed as a biosimilar of etanercept. The primary objective of the present study was to demonstrate the pharmacokinetic (PK) equivalence between SB4 and European Union ‐sourced etanercept (EU‐ETN), SB4 and United States‐sourced etanercept (US‐ETN), and EU‐ETN and US‐ETN. The safety and immunogenicity were also compared between the treatments.MethodsThis was a single‐blind, three‐part, crossover study in 138 healthy male subjects. In each part, 46 subjects were randomized at a 1:1 ratio to receive a single 50 mg subcutaneous dose of the treatments (part A: SB4 or EU‐ETN; part B: SB4 or US‐ETN; and part C: EU‐ETN or US‐ETN) in period 1, followed by the crossover treatment in period 2 according to their assigned sequences. PK equivalence between the treatments was determined using the standard equivalence margin of 80–125%.ResultsThe geometric least squares means ratios of AUCinf, AUClast and Cmax were 99.04%, 98.62% and 103.71% (part A: SB4 vs. EU‐ETN); 101.09%, 100.96% and 104.36% (part B: SB4 vs. US‐ETN); and 100.51%, 101.27% and 103.29% (part C: EU‐ETN vs. US‐ETN), respectively, and the corresponding 90% confidence intervals were completely contained within the limits of 80–125 %. The incidence of treatment‐emergent adverse events was comparable, and the incidence of the antidrug antibodies was lower in SB4 compared with the reference products.ConclusionsThe present study demonstrated PK equivalence between SB4 and EU‐ETN, SB4 and US‐ETN, and EU‐ETN and US‐ETN in healthy male subjects. SB4 was well tolerated, with a lower immunogenicity profile and similar safety profile compared with those of the reference products.

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BackgroundSB4, a biosimilar to etanercept reference product (ETN), has an identical amino acid sequence, similar physicochemical and in vitro functional properties to its reference drug.ObjectivesThe primary objective of this study was to demonstrate pharmacokinetic (PK) equivalence between SB4 and EU sourced ETN (EU-ETN), between SB4 and US sourced ETN (US-ETN), and between EU-ETN and US-ETN. Safety, tolerability, and immunogenicity were investigated as secondary objectives.MethodsThis study was a randomised, single-blind, three-part (Part A, Part B and Part C), 2-treatment, 2-period cross-over study in 138 healthy male subjects. In each part, 46 subjects were randomised in a 1:1 manner to receive a single 50 mg subcutaneous dose of SB4 or the reference drug (Part A: SB4 or EU-ETN, Part B: SB4 or US-ETN, Part C: EU-ETN or US-ETN) in Period 1 followed by the cross-over treatment in Period 2 according to their assigned treatment sequence. Study treatments were separated by a 28 day washout period. PK assessment was performed 21 days after the treatment in each period. Immunogenicity was assessed at pre-dose and 28 days after the first treatment in Period 1.The primary PK parameters were area under the concentration-time curve from time zero to infinity (AUCinf) and maximum concentration (Cmax). Equivalence for the primary PK parameters was to be concluded if the 90% confidence interval (CI) of the ratio of geometric least squares means (LSMeans) of the groups compared were completely contained within the pre-defined equivalence margin of 0.8 to 1.25 using an analysis of variance (ANOVA).ResultsThe geometric LSMeans ratio of AUCinf and Cmax were 0.990 and 1.037 (Part A), 1.011 and 1.044 (Part B), and 1.005 and 1.033 (Part C), respectively. All 90% CIs for the primary PK parameter comparisons in Part A, B, and C were completely contained within the pre-defined equivalence margin (Table).The proportion of subjects who experienced treatment-emergent adverse events (TEAEs) was comparable between SB4 and EU-ETN (39.1% vs. 34.8%), SB4 and US-ETN (50.0% vs. 43.5%), and between EU-ETN and US-ETN (37.0% vs. 30.4%) in each part. The most frequent TEAEs reported were nasopharyngitis, headache, and injection site reaction. The majority of TEAEs reported was mild or moderate in severity and transient. There were no serious adverse events (SAEs) or deaths reported during the study.Table 1.Comparison of primary PK parameters between the treatmentsPK parametersRatio90% CIPart A: SB4 vs EU-ETNAUCinf (μg·h/mL)0.9900.947; 1.036Cmax (μg/mL)1.0370.985; 1.092Part B: SB4 vs US-ETNAUCinf (μg·h/mL)1.0110.958; 1.067Cmax (μg/mL)1.0440.977; 1.114Part C: EU-ETN vs US-ETNAUCinf (μg·h/mL)1.0050.915; 1.104Cmax (μg/mL)1.0330.947; 1.127 ConclusionsThis study demonstrated PK equivalence of SB4 to EU-ETN, of SB4 to US-ETN, and of EU-ETN to US-ETN in healthy male subjects. All three etanercept products were generally well tolerated with similar safety profiles.Disclosure of InterestY. J. Lee Employee of: Samsung Bioepis, D. Shin Employee of: Samsung Bi...