A new study published in Science Translational Medicine shows that high concentrations of circulating TNF after adalimumab (TNF inhibitor) therapy are representative of high levels of biologically inactive TNF in complex with the inhibitor.

Credit: Springer Nature Limited

TNF inhibitors are the most widely prescribed biologic DMARDs for rheumatic diseases, particularly for rheumatoid arthritis (RA). Counter-intuitively, concentrations of circulating TNF have previously been noted to increase shortly after beginning TNF inhibitor therapy, which is thought to result from the TNF inhibitor interfering with standard TNF detection methods.

This confusion, as well as the complexity in the dynamics of circulating TNF, has made it difficult to calculate the association between TNF levels and RA disease and remission, or to make clinical decisions about when a patient should cease TNF inhibitor therapy.

To study the dynamics of TNF in the blood, the researchers developed an ELISA that could be used to detect low levels of TNF and that could discriminate between free TNF and TNF–adalimumab complexes. Using this method in combination with chromatography, the researchers confirmed that there is a sharp rise in blood TNF concentration in patients with RA 4 weeks after beginning adalimumab therapy. A similar effect occurred in healthy volunteers treated with a single dose of adalimumab. The majority of TNF circulating in patients with RA was in complex with adalimumab and was biologically inactive. Furthermore, the TNF concentration remained high over the course of a 1-year follow-up.

Despite substantial inter-patient variation in TNF levels, the researchers noted little intra-patient variation between 4-weeks and 1-year follow-up, regardless of whether patients went into remission or not.

By contrast, a strong association was noted between low levels of TNF in the first 4 weeks of adalimumab therapy and the later emergence of anti-drug antibodies. Furthermore, patients with low levels of TNF in these early stages of therapy were less likely than other patients to enter remission within a year of therapy.

a similar effect occurred in healthy volunteers

Together these data show that measuring total TNF concentration in the blood is not useful as a biomarker to decide whether or not to continue TNF inhibitor therapy, but that measuring TNF levels in the first few weeks of starting TNF inhibitor therapy might predict the chances of remission.