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

TNF concentrations stabilize in patients with rheumatoid arthritis during long-term adalimumab therapy and are associated with antidrug antibodies. Tracking TNF TNF inhibitors are used to treat some inflammatory or autoimmune diseases, but individual responses vary. To overcome issues with accurately measuring TNF during anti-TNF therapy, Berkhout et al. developed a drug-tolerant assay. They examined longitudinal samples from patients with rheumatoid arthritis on anti-TNF treatment and found that TNF actually increased upon treatment and was stable over time. They also assessed clinical responses and development of antidrug antibodies. Their results indicate that TNF concentrations in patients may be used as biomarker to predict antidrug antibody-associated unresponsiveness towards adalimumab treatment. 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.