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.
Supplementary appendix S1
METHODSStudy population Patients were observed in the Reade Rheumatology Registry (Dutch Trial Registry, number 6868) at the Amsterdam Rheumatology and immunology Center, location Reade. Patients had to have rheumatoid arthritis (RA) according to the American College of Rheumatology (ACR) criteria of 1987 or European League Against Rheumatism (EULAR)/ACR 2010. To receive a biological agent; treatment with at least two disease modifying anti-rheumatic drugs (DMARDs), including methotrexate (MTX), should have failed. Treatment allocation was at the discretion of the patients' treating rheumatologist. Patients were included between December 2004 and November 2012 and a proportion of patients from the registry are previously reported on (1, 2). Patients received etanercept treatment as monotherapy or in combination with concomitant DMARD therapy or prednisone and this could be changed during the follow-up of the study by the treating rheumatologist. Discontinuation of biologic treatment was a decision of the treating rheumatologist and either due to failure or side effects. This study was performed in accordance with the ethical principles of the Declaration of Helsinki.
No significant difference was found between AS patients treated with etanercept and those treated with adalimumab in mean ASDAS-CRP and reaching ASDAS-CRP minimal disease activity at 2 year follow-up. Drug survival rate was higher in etanercept- compared to adalimumab-treated patients. However, this should be interpreted cautiously as the risk of allocation bias cannot be excluded.
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