Formation and clearance of TNF-TNF inhibitor complexes during TNF inhibitor treatment.

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.

Implementing a Clostridium difficile testing algorithm and its effect on isolation duration and treatment initiation: a pre- and post-implementation study.

A proportion of patients suspected of Clostridium difficile infection are unnecessarily placed in contact isolation. By introducing a random-access glutamate dehydrogenase (GDH) test for C. difficile, we aimed to reduce isolation time. In addition, we investigated whether the result of the toxin A&B enzyme immunoassay (EIA) was associated with the decision to initiate antibiotic treatment against C. difficile. This retrospective pre- and post-implementation study was from June 3, 2016, to June 4, 2018. Pre-implementation, only a NAAT was performed. In the post-implementation period, a GDH test was performed; if positive, a toxin A&B EIA followed the same day and subsequently a NAAT. Contact isolation for CDI was discontinued when the GDH test was negative. Median time in isolation was 50.8 h pre-implementation (n = 189) versus 28.0 h post-implementation (n = 119), p < 0.001. The GDH test had a negative predictive value of 98.8% (95% CI 97.9-99.4). In 7/31 (22.6%) patients with a positive NAAT and GDH test and a negative toxin A&B EIA, no antibiotics against C. difficile were initiated versus 4/28 (14.3%) patients who were NAAT, GDH and toxin A&B EIA positive. Introducing a random-access screening test resulted in a significant decrease in patient isolation time. The GDH test had a high negative predictive value making it suitable to determine whether contact isolation can be discontinued. Furthermore, the result of a toxin A&B EIA had limited added value on the percentage of patients in whom antibiotic treatment against C. difficile was initiated.