TNF concentration during anti-TNF treatment predicts anti-drug antibody formationNews
Researchers from Sanquin and Reade Rheumatology have found that the TNF concentration in blood of adalimumab-treated rheumatoid arthritis (RA) patients increases after start of treatment. They explain this by a prolonged TNF half-life after binding to adalimumab. The authors further suggest a potential role for TNF measurements as predictive biomarker for the formation of anti-drug antibodies (ADAs) and for the identification of non-responders in the early phase of treatment. The research was published in Science Translational Medicine.
For the first time researchers have been able to quantify TNF concentrations in patients during treatment with TNF inhibitor adalimumab. Surprisingly, little is known about what happens with the target, TNF, during TNF inhibitor treatment. In order to measure TNF during TNF inhibitor treatment (in this study adalimumab) co-authors Lea Berkhout (Sanquin, photo: right) and Merel l’Ami (Reade, photo: left) developed a new assay which is able to measure TNF in the presence of large amounts of adalimumab.
TNF is a signaling protein (cytokine) that has an important role in the regulation of inflammation. Overexpression of TNF can lead to several inflammatory auto-immune diseases, including Crohn’s disease, psoriasis and rheumatoid arthritis (RA). It has been shown that treatment of these diseases has significantly improved with the introduction of therapeutic monoclonal antibodies that specifically bind TNF (TNF inhibitors). Adalimumab is one of the five TNF inhibitors that is frequently used.
The new assay was used to measure TNF concentrations before start of treatment and during two years of adalimumab treatment in 193 adalimumab-treated RA patients. The authors found that TNF concentrations were low before start of treatment, but significantly increased upon adalimumab treatment. Increased TNF concentrations upon treatment might seem counterintuitive, since most patients do respond to TNF inhibitor treatment. However, TNF bound to drug is inactive. TNF itself is an unstable molecule and is rapidly cleared from the circulation, but TNF half-life is prolonged due to TNF-adalimumab complex formation. The prolonged half-life explains the rise in TNF concentrations upon treatment.
After the initial increase, TNF concentrations did not go down over time in patients that responded to adalimumab treatment, but were very stable in the majority of patients for at least two years. Surprisingly, the authors observed a similar increase in TNF in healthy volunteers after one dose of adalimumab. As the increase in TNF concentrations was similar in RA patients as compared to healthy volunteers, and TNF concentrations remained extremely stable in patients independent of disease activity, this raises questions about the role of TNF in pathophysiology and the mechanism of action of current anti-TNF treatments.
Predicative for anti-drug antibody formation
Furthermore, the authors observed that although TNF levels were extremely stable in most patients, some patients had significantly lower TNF concentrations at week four. Although not detectable at week four yet, it appeared that in particular these patients with early low TNF concentrations started to produce substantial amounts of ADAs over time, a phenomenon that can lead to a diminished response to adalimumab.
Although further studies should elucidate the underlying mechanism (why do TNF concentrations drop early in time, when in the future ADAs can be detected, which associate with non-response?) these results suggest a potential role for TNF measurements as predictive biomarker for future ADA formation and for the identification of non-responders in the early phase of treatment