Adalimumab regulates intracellular TNF[alpha] production in patients with rheumatoid arthritis

• Published in: Arthritis research & therapy Vol. 16
• Main Authors: Zamora-Atenza, Carlos, Diaz-Torne, Cesar, Geli, Carme, Diaz-Lopez, Cesar, O, Moya, Patricia, Castellví, Ivan, Nieto, Juan C, Cantó, Elisabet, Casademont, Jordi, Juarez, Candido, Llobet, Josep M, Vidal, Silvia
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 18.07.2014
• Subjects: Comparative analysis; Complications and side effects; Monoclonal antibodies; Tumor necrosis factor
• ISSN: 1478-6354
• DOI: 10.1186/ar4615

Introduction Adalimumab is a fully human anti-tumor necrosis factor [alpha] (anti-TNF[alpha]) monoclonal antibody that specifically blocks the interaction of TNF[alpha] with its receptors. It binds both soluble and transmembrane TNF[alpha]. We hypothesized that blocking these TNF[alpha] signals regulates the altered TNF[alpha] production in rheumatoid arthritis (RA) patients. Methods We compared, by flow cytometry, Toll-like receptor induction levels of membrane and intracellular TNF[alpha] in monocytes (iTNF[alpha] + CD14+ cells) from 12 patients before and after adalimumab treatment with those from 5 healthy donors. Results Before starting the treatment, the percentage of iTNF[alpha]+ CD14+ cells in the RA patients was significantly lower than that in healthy donors (mean [+ or -] SEM = 33.16 [+ or -] 4.82% vs 66.51 [+ or -] 2.4%, P < 0.001). When we added in vitro TNF[alpha] to healthy donor culture cells, levels of iTNF[alpha]+ CD14+ cells decreased, suggesting that the TNF[alpha] signal was responsible for the iTNF[alpha]+ CD14+ cell downregulation observed in the RA patients. After 2, 6 and 12 adalimumab injections, we observed significant blocking of membrane and soluble TNF[alpha] and a progressive increase in iTNF[alpha]+ CD14+ cells in ten patients with a good to moderate response as defined by the European League Against Rheumatism (EULAR) criteria. Levels of iTNF[alpha]+ CD14+ cells after 12 injections in these 10 patients were comparable to levels in healthy donors. In two patients, iTNF[alpha]+ CD14+ cell upregulation was not observed, and their EULAR-defined responses had not improved. The first patient developed antiadalimumab antibodies, explaining why adalimumab was not able to block membrane and soluble TNF[alpha]. In the second patient, adalimumab was discontinued because of adverse effects, which led to a decrease in iTNF[alpha]+ CD14+ cells to levels measured before treatment. Conclusions Our findings suggest that adalimumab treatment in RA patients can return iTNF[alpha] levels to those of healthy donors. This effect was not observed in the presence of neutralizing antiadalimumab antibodies.