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Thesis defense Lea Berkhout

Dynamics of TNF during TNF inhibitor treatment

On 23 June 2021 Lea Berkhout defended her thesis 'Dynamics of TNF during TNF inhibitor treatment' at the University of Amsterdam

Promotores:
Prof SM van Ham PhD and Prof MT Nurmohamed MD PhD

Copromotores:
T Rispens PhD and GJ Wolbink MD PhD

Venue:
Universiteit van Amsterdam, Agnietenkapel (invitation only) and online

Summary

Tumor necrosis factor (TNF) is an important pro-inflammatory cytokine driving inflammation in auto-immune diseases, including rheumatoid arthritis (RA). Blocking TNF with TNF inhibitors (TNFi) is effective in the treatment of these diseases. TNFi treatment can be that effective that a proportion of patients can successfully stop treatment. This led to the hypothesis that TNF levels decrease in patients who are in clinical remission. Monitoring TNF during TNFi treatment could therefore be a potential biomarker in predicting successful treatment discontinuation, and might help to personalize TNFi treatment.
The development of new, so called ┬┤drug-tolerant┬┤ TNF assays allowed the quantification of TNF in presence of large amounts of TNFi. Using these assays, we demonstrated that after an initial increase, TNF concentrations remained remarkably stable. This was irrespective of disease activity. Surprisingly, a similar increase in TNF was found in healthy volunteers after one dose of TNFi. The amount of TNF at steady-state varied for the five different TNFi, and depended on differences in clearance of TNF-TNFi complexes. So, in contrast to what was expected, TNF levels did not decrease in patients in remission and TNF can therefore not be used as a biomarker for treatment discontinuation. We did find that low TNF concentrations early after the start of TNFi treatment associated with future anti-drug antibody (ADA) formation and a reduced clinical response. Together, the results presented in this thesis are in contrast with the original idea that too much TNF contributes to inflammation in chronic autoimmune diseases. Our studies do provide new insights in the relation between TNF concentrations and immunogenicity, which may contribute to the optimization of TNFi treatment.