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Background and Purpose: Millions of patients with inflammatory diseases are treated with tumour necrosis factor (TNF) inhibitors (TNFi). Individual treatment response varies, in part related to variable drug clearance. The role of TNF–TNFi complexes in clearance of the different TNFi is controversial. Moreover, mechanistic insight into the structural aspects and biological significance of TNF–TNFi complexes is lacking. We hypothesized a role for Fc‐mediated clearance of TNF–TNFi immune complexes. Therefore, we investigated circulating TNF–TNFi complexes upon treatment with certolizumab—lacking Fc tails—in comparison with adalimumab, golimumab, infliximab and etanercept. Experimental Approach: Drug‐tolerant ELISAs were developed and used to quantify TNF during adalimumab, golimumab, etanercept, certolizumab and infliximab treatment in patients with inflammatory arthritis or ulcerative colitis for a maximum follow‐up of 1 year. Effects on in vitro TNF production and Fc‐mediated uptake of TNF–TNFi complexes were investigated for all five TNFi. Key Results: Circulating TNF concentrations were >20‐fold higher during certolizumab treatment compared with adalimumab, reaching up to 23.1 ng·ml−1. Internalization of TNF–TNFi complexes by macrophages depended on Fc valency, with efficient uptake for the full antibody TNFi (three Fc tails), but little or no uptake for etanercept and certolizumab (one and zero Fc tail, respectively). TNF production was not affected by TNFi. Total TNF load did not affect clearance rate of total TNFi. Conclusions and Implications: Differences in TNFi structure profoundly affect clearance of TNF, while it is unlikely that TNF itself significantly contributes to target‐mediated drug disposition of TNFi. [ABSTRACT FROM AUTHOR]

Objective: High adalimumab serum concentrations do not result in better response in patients with rheumatoid arthritis (RA), suggesting overexposure. We investigated whether patients with adalimumab concentrations >8 µg/mL can prolong their dosing interval by 50% without a clinically relevant change in disease activity.Methods: Consecutive patients with RA, treated with adalimumab 40 mg every other week for at least 28 weeks, were approached for this randomised, open-label, non-inferiority trial. Patients with adalimumab trough concentrations >8 µg/mL were randomly (1:1) assigned to dose-interval prolongation of once every 3 weeks or continuation of every other week. Primary outcome was the change in disease activity score of 28 joints (ΔDAS28-ESR) after 28 weeks, with a non-inferiority margin of 0.6 points.Results: In total, 147 patients were screened. Fifty-five patients had concentrations >8 µg/mL and were randomised. Mean ΔDAS28 after 28 weeks was -0.14±SD 0.61 in the prolongation group and 0.30±0.52 in the continuation group. Mean difference was significantly in favour of the prolongation group: 0.44 (95% CI 0.12 to 0.76, p=0.01).Conclusions: Adalimumab-treated patients with RA with trough concentrations >8 µg/mL can prolong their standard dosing interval to once every 3 weeks without loss of disease control.Trial Registration Number: NTR3509; Results. [ABSTRACT FROM AUTHOR]

Immunogenicity is a major issue of concern for monoclonal antibodies used in human diseases and is by default mainly determined in non-human primates (NHP), as target molecules are considered most similar in NHP compared to human. In this manuscript the predictive value of immunogenicity testing in minipigs for human safety is evaluated, as the immune system of the pig is functionally similar to that in other mammalian species. Adalimumab and infliximab (both monoclonal antibodies blocking TNFα) were used as model substances. Female Göttingen minipigs (4/group) were treated every other week with low (0.1 mg/kg), mid (1.0 mg/kg), or high dose (5 mg/kg) adalimumab or 5 mg/kg infliximab subcutaneous (SC) over a period of 8 weeks. After first and last dosing, pharmacokinetic analysis was performed. Anti-drug antibodies (ADAs) were measured on several time points. Furthermore, hematology, clinical chemistry, body weight, clinical signs, and histopathology of several organs were evaluated. No signs of toxicity of the treatments were observed in the limited organs and tissues collected. Eleven out of 12 minipigs treated with adalimumab elicited a detectable ADA response. Induction of ADA was correlated with decreased plasma levels of adalimumab. Infliximab clearance was comparable after first and last dose. Therefore, the presence of ADA directed to infliximab was considered highly unlikely. It was concluded that the minipig and NHP showed comparable suitability for immunogenicity prediction in humans. More studies with other biopharmaceutical products are needed to strengthen the status of the minipig as an alternative model for immunotoxicity testing including immunogenicity. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of anti-tumor necrosis factor (TNF) treatment on rheumatoid factor (IgM-RF) and anticitrullinated protein antibodies (ACPA) and its association with treatment response and acute-phase reactants., Methods: In a cohort of 188 consecutive patients with rheumatoid arthritis (RA) treated with adalimumab, baseline IgM-RF and ACPA were determined by ELISA, and compared to levels after 28 weeks of treatment. ACPA were measured as antibodies to cyclic citrullinated peptide (anti-CCP). The relative change of antibody levels was correlated to the European League Against Rheumatism response criteria and to the change in acute-phase reactants [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)]., Results: The median decline in IgM-RF levels was greater than the decline in ACPA levels (31% vs 8%; p<0.001). The decrease in antibody levels was greater in the group of good responders than in the group of nonresponders [43% vs 7% for IgM-RF (p<0.0001) and 16 vs -4% for ACPA (p=0.03)]. Seventeen percent of IgM-RF-positive patients at baseline turned negative at 28 weeks; this qualitative effect was not observed for ACPA. Further, the decline in IgM-RF, but not ACPA, was associated with a decrease in CRP and ESR (p=0.004 and p=0.006, respectively)., Conclusion: TNF treatment directly influences IgM-RF and ACPA levels, but in those responding to treatment only. The effect on IgM-RF levels and positivity status is greater than on ACPA levels and is associated with the decline in markers of inflammation. These results further emphasize the differential role these autoantibodies may play in RA; IgM-RF as marker of inflammatory activity, and ACPA as qualitatively stable hallmark of RA.