Adherence and dosing interval of subcutaneous antitumour necrosis factor biologics among patients with inflammatory arthritis: analysis from a Canadian administrative database.

OBJECTIVES: Subcutaneous tumour necrosis factor alpha TNFαinhibitors (SC-TNFis) such as golimumab (GLM), adalimumab (ADA), etanercept (ETA) and certolizumab pegol (CZP) have been used for many years for the treatment of inflammatory arthritis. Non-adherence to therapy is an important modifiable factor that may compromise patient outcomes. The aim of this analysis was to compare adherence and dosing interval of SC-TNFis in the treatment of people with inflammatory arthritis. DESIGN: We used the IMS Brogan database combining both Canadian private and public drug plan databases of Ontario and Quebec. Target drugs included SC-TNFis for inflammatory arthritis. The index period was from 1 January 2010 to 30 June 2012 and patients were followed for 24 months through 30 June 2014. Inclusion criteria were adult patients newly prescribed a SC-TNFis with at least three prescriptions and retained on therapy at 24 months.Dosing regimens as per the product monographs were used to compare actual versus expected drug utilisation. The mean possession ratio was used as a marker for adherence. Patients who scored >80% were considered adherent. The average days between units was estimated by taking the total days on therapy and divided by the number of units the patient received. RESULTS: 4035 patients were included: 683 (16.9%), 1400 (34.7%), 1765 (43.7%) and 187 (4.6%) were treated with GLM, ADA, ETA and CZP, respectively. The proportion of adherent patients in the GLM cohort (n=595/683, 87%, p<0.0001) was greater compared with ADA (n=1044/1400, 75%), ETA (n=1285/1765, 73%) and CZP-treated patients (132/187, 71%). In addition, the number of patients receiving biological drug at a shorter dosing interval was similar between cohorts, and was 5%, 6%, 12% and 4% in GLM (≤26 days), ADA (≤12 days), ETA (≤6 days) and CZP-treated patients (≤12 days), respectively. CONCLUSIONS: In this real-life administrative database, GLM had better adherence compared with other SC-TNFis.

Real-world validation of the minimal disease activity index in psoriatic arthritis: an analysis from a prospective, observational, biological treatment registry.

OBJECTIVE: To describe the minimal disease activity (MDA) rate over time in patients with psoriatic arthritis (PsA) receiving antitumour necrosis factor agents, evaluate prognostic factors of MDA achievement and identify the most common unmet criteria among MDA achievers. DESIGN: Biologic Treatment Registry Across Canada (BioTRAC): ongoing, prospective registry of patients initiating treatment for rheumatoid arthritis, ankylosing spondylitis or PsA with infliximab (IFX), golimumab (GLM) or ustekinumab. SETTING: 46 primary-care Canadian rheumatology practices. PARTICIPANTS: 223 patients with PsA receiving IFX (enrolled since 2005) and GLM (enrolled since 2010) with available MDA information at baseline, 6 months and/or 12 months. PRIMARY AND SECONDARY OUTCOME MEASURES: MDA was defined as ≥5 of the following criteria: 28-item tender joint count (TJC28) ≤1, 28-item swollen joint count (SJC28) ≤1, Psoriasis Area and Severity Index (PASI) ≤1 or body surface area≤3, Pain Visual Analogue Scale (VAS) ≤15 mm, patient's global assessment (PtGA) (VAS) ≤20 mm, Health Assessment Questionnaire (HAQ) ≤0.5, tender entheseal points ≤1. Independent prognostic factors of MDA achievement were assessed with multivariate logistic regression. RESULTS: MDA was achieved by 11.7% of patients at baseline, 43.5% at 6 months, 44.8% at 12 months and 48.8% at either 6 or 12 months. Among MDA achievers at 6 months, 75.7% had sustained MDA at 12 months. Lower baseline HAQ (OR=0.210; 95% CI: 0.099 to 0.447) and lower TJC28 (OR=0.880; 95% CI: 0.804 to 0.964), were significant prognostic factors of MDA achievement over 12 months of treatment. The most commonly unmet MDA criteria among MDA achievers was patient reported pain (25%), PtGA (15%) and PASI (12%). CONCLUSIONS: Almost 50% of patients treated with IFX or GLM in routine clinical care achieved MDA within the first year of treatment. Lower baseline HAQ and lower TJC28, were identified as significant prognostic factors of MDA achievement. The most commonly unmet criteria in patients who achieved MDA were pain, PtGA and PASI. TRIAL REGISTRATION NUMBER: BioTRAC (NCT00741793).

Investigation of the binding of Cr(III) complexes to bovine and human serum proteins: a proteomic approach.

Chromium (Cr) compounds are widely used in alloys manufacturing and forming processes. One of the main concerns in the use of cobalt-chromium (Co-Cr) alloy-based implants is the long-term fate of Co and Cr ions in the blood, organs, and urine of patients. Our previous studies have shown that Cr(III) forms complexes in different cell culture media, whereas Cr(VI) does not form any detectable structure under the same conditions. Because Cr(VI) is known to be more toxic than Cr(III), we hypothesized that the presence of serum proteins in the molecular structure of Cr(III) may be responsible for the difference in toxicity. We investigated the interaction of the Cr(III) complexes with serum proteins and their internalization by U937 macrophage-like cells. By using a proteomic approach, we showed that in the presence of fetal bovine serum, Cr(III) complexes interacted only with albumin, whereas they interacted mainly with albumin, transferrin, and immunoglobulins (Ig) in the presence of human serum (HS). Cr(III) complexes were more easily engulfed by U937 macrophage-like cells when they were formed with HS. To the best of our knowledge, this is the first report on the formation of Cr(III) complexes in the presence of serum proteins and the interaction of these complexes with U937 macrophage-like cells. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.

Effect of chromium and cobalt ions on the expression of antioxidant enzymes in human U937 macrophage-like cells.

The main concern associated with metal-on-metal (MM) hip prosthesis is the presence of metal ions, mainly chromium (Cr) and cobalt (Co), which are found both systemically and locally in the organism of patients. Previous studies revealed that Cr(III) and Co(II) ions could induce damages to proteins in macrophage-like cells in vitro, probably through the formation of reactive oxygen species (ROS). We then hypothesized that these ions can modify the expression of antioxidant enzymes in these cells. Results showed that Cr(VI) induced the protein expression of Mn-superoxide dismutase, Cu/Zn-superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase-1 (HO-1) but had no effect of the expression of their mRNA. Cr(III) have no effect on the expression of all these antioxidant enzymes. Co(II) induced the expression of both protein and mRNA of HO-1 only. In conclusion, results showed that Cr(VI), Cr(III), and Co(II) had differential effects on the expression of antioxidant enzymes in macrophage-like cells in vitro.

Significance of Elevated Blood Metal Ion Levels in Patients with Metal-on-Metal Prostheses: An Evaluation of Oxidative Stress Markers.

It is widely known that cobalt and chromium ions can enhance the production of reactive oxygen species, known to be damaging to cells by disturbing their redox status and then generating oxidative stress. The aim of the present study was to determine if increased metal ion levels induce a state of oxidative stress in patients with metal-on-metal (MM) hip arthroplasty. Results indicated that there was no significant difference in the concentration of oxidative stress markers (total antioxidants, peroxides, and nitrated proteins) in the patients with MM bearings compared to patients without prostheses. The activity antioxidant enzymes was stable (catalase and glutathione peroxidase) or slightly decreased (superoxide dismutase and heme oxygenase-1) over time. This work is the first to determine the biological effects of metal ions released from MM hip implants with regards to mid-term systemic oxidative stress and showed that the increased levels of Co and Cr ions are not associated with significant oxidative stress damage in the plasma of patients with these implants.

The molecular structure of complexes formed by chromium or cobalt ions in simulated physiological fluids.

It is well recognized that workers in mines and manufacturers of hard metals in contact with metal ions have increased risk of cancer. However, the various chemical forms of these ions in living organisms are not well characterized, and little is known of how they interact with biological environments. Here, we sought to elucidate the molecular structures formed by cobalt (Co) and chromium (Cr) ions in simulated biological fluids. Transmission electron microscopy observations revealed that Cr(III) formed nanoscale complexes which precipitate in both RPMI 1640 and DMEM high glucose media. However, no complexes were observed with Co(II) and Cr(VI). Energy-dispersive X-ray analysis, elemental analysis, and Fourier transform infrared (FT-IR) spectroscopy indicated that Cr(III) ions act as chelating entities between PO(4) groups, amino acids, and calcium. Although the exact nature of the bonds remains to be investigated, the presence of PO(4) may favor the formation of low energy hydrogen bonds. Interestingly, the nature of amino acids varied in Cr(III) complexes formed in RPMI 1640 compared to those formed in DMEM high glucose. The absence of sulphur in the elemental analysis spectrum suggested that methionine and cystine, two amino acids containing sulphur, are not involved in the formation of Cr(III) complexes. Thus, the lower toxicity of Cr(III) compared to Co(II) and Cr(VI) may be related to the formation of these chemical complexes. These results may bring some insight in understanding the relationship between toxicity and the chelating capabilities of various metal ions in vitro and in vivo.

Cobalt and chromium ions induce nitration of proteins in human U937 macrophages in vitro.

The in situ localization of nitrotyrosine, a product of the nitration of tyrosine residues by peroxynitrite, in the interface membranes from Co--Cr--Mo and Ti--Al--V prostheses provided evidence of nitric oxide-induced oxidative damage in the periprosthetic environment. In the present study, we compared the effects of different wear products from hip prostheses on the nitration of proteins in macrophages in vitro. Nitration of proteins was measured by Western blot using a polyclonal antibody directed against nitrotyrosines. Results showed that Co(2+) and Cr(3+) ions induced the nitration of a 79 +/- 4 kDa protein in a time- and dose-dependent manner. Indeed, the stimulation was significant (p < 0.05) after 24 h with 10 ppm Co(2+) and reached a plateau level between 48 and 72 h. With Cr(3+), the stimulation was significant (p < 0.05) only after 48 and 72 h. The effect of both Co(2+) and Cr(3+) ions was inhibited by glutathione monoethyl-ester that provides protection against oxidative stress. However, ultrahigh-molecular-weight-polyethylene and alumina ceramic particles had no significant effect on the nitration of proteins. Finally, the results showed that nitrated proteins are mainly found in the cytoplasmic fraction of cells and are absent from the nucleus. In conclusion, our results show that Co(2+) and Cr(3+) ions induce the nitration of cytoplasmic proteins in human U937 macrophages, suggesting that metal ions from MM prostheses have the potential to modify protein function in the periprosthetic environment and in circulating cells.

Delivery platform for hydrophobic drugs: prodrug approach combined with self-assembled multilayers.

We report the design of a platform for the delivery of hydrophobic drugs via a macromolecular prodrug approach combined with LbL-assembled polyelectrolyte multilayers. A hyaluronan ester prodrug of the chemotherapeutic drug paclitaxel has been synthesized. Conjugation of the drug to hyaluronan through a labile succinate ester did not inhibit its activity. Using quartz crystal microbalance, atomic force microscopy, and UV spectroscopy, we have shown that the presence of the hydrophobic paclitaxel moieties does not prohibit the layer-by-layer construction of the multilayers. Release of the drug from the paclitaxel-loaded multilayers upon hydrolysis of the ester linkage resulted in a drastic cell death. Application of this delivery platform to substrates such as colloids, biomedical implants, or vascular tissues may lead to new therapeutic strategies.

Induction of protein oxidation by cobalt and chromium ions in human U937 macrophages.

Metal particles and ions from hip prostheses have the potential to induce the production of reactive oxygen species (ROS), making them prime suspects for disturbing the cellular balance of oxidants/antioxidants (redox state of the cell). To better understand the cellular effect of metal ions from metal-on-metal prostheses, the aim of this study was to examine the effect of cobalt (Co2+) and chromium (Cr3+) ions on protein oxidation in human U937 macrophages. Protein oxidation was measured by Western blot using antibodies directed against dinitrophenylhydrazine (DNP)-derivatized protein carbonyls, the most commonly measured products of protein oxidation in biological samples. Three DNP-derived proteins were detected. The first has a molecular weight of 16 kDa and is expressed at a very low level. The second has a molecular weight of 48 kDa and its level is not regulated by metal ions. The third is a 69 kDa protein and its level is regulated by Co2+ and Cr3+ ions. Therefore, the last band served as a marker of protein oxidation in the present study. Results showed that Co2+ and Cr3+ ions induced a time- and dose-dependent protein oxidation reaching 6.5 and 2.9 times the control after 72 h, respectively, which were inhibited by the antioxidant glutathione monoethyl-ester. Finally, results showed that the oxidized proteins are mainly found in the cytoplasmic fraction of the cells and are absent from the nucleus. In conclusion, our results suggest that metal ions from metal-on-metal prostheses have the potential to modify the redox state of cells both locally (periprosthetic environment) or systematically (circulating cells). The long term effect of these ions on protein oxidation in vivo remains to be investigated.