Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay

Abstract

Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a “drug-tolerant” assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of >50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.

Fri0095 changes in B Cell Profile as Indicator of Clinical Remission to TNF Inhibitors in Patients With Rheumatoid Arthritis

“…This is in line with what has been found for adalimumab treatment. However, TNF concentrations measured in this study were at least twice as low as TNF concentrations during adalimumab treatment (1). The high baseline TNF concentrations in 25% of the patients were also surprising, as it indicates that patients switch to golimumab while their TNF is still in complex with a previous TNF-inhibitor.…”

“…Berkhout et al (2019) described the development of a novel drug-tolerant assay to quantify TNF during TNFinhibitor treatment. Using this assay, they analyzed the dynamics of TNF during treatment of rheumatoid arthritis (RA) patients with adalimumab and found that TNF levels shortly after treatment initiation predict nonresponse (1).…”

Fri0096 tnf Concentrations During Treatment of Inflammatory Diseases With Golimumab

“…The prevalence of clustered ADRs between the various bDMARDs was compared using a c 2test and the average burden was compared using a Mann-Whitney U test. Results: In the Dutch Biologic Monitor 583 consecutive (44.8%) RA patients were included (71.2% female, average age 59 years, SD±12.4) using the originator or a biosimilar of etanercept (ETN, 265), adalimumab (ADA,196), tocilizumab (41), abatacept (35), certolizumab pegol (23), rituximab (19), infliximab (18), golimumab (15), sarilumab (2), secukinumab (1), anakinra (1)…”

“…Background: Golimumab is a monoclonal antibody that binds TNF, counteracting its pro-inflammatory effects. Berkhout et al (2019) described the development of a novel drug-tolerant assay to quantify TNF during TNFinhibitor treatment. Using this assay, they analyzed the dynamics of TNF during treatment of rheumatoid arthritis (RA) patients with adalimumab and found that TNF levels shortly after treatment initiation predict nonresponse (1).…”

“…Berkhout et al (2019) described the development of a novel drug-tolerant assay to quantify TNF during TNFinhibitor treatment. Using this assay, they analyzed the dynamics of TNF during treatment of rheumatoid arthritis (RA) patients with adalimumab and found that TNF levels shortly after treatment initiation predict nonresponse (1). Our study is the first to measure TNF levels during golimumab treatment, using the same drug-tolerant assay.…”