title: Adalimumab regulates intracellular TNFα production in patients with rheumatoid arthritis.
abstract: BACKGROUND
  Adalimumab is a fully human anti-tumor necrosis factor α (anti-TNFα) monoclonal antibody that specifically blocks the interaction of TNFα with its receptors. It binds both soluble and transmembrane TNFα. We hypothesized that blocking these TNFα signals regulates the altered TNFα production in rheumatoid arthritis (RA) patients.
  
  
  METHODS
  We compared, by flow cytometry, Toll-like receptor induction levels of membrane and intracellular TNFα in monocytes (iTNFα + CD14+ cells) from 12 patients before and after adalimumab treatment with those from 5 healthy donors.
  
  
  RESULTS
  Before starting the treatment, the percentage of iTNFα+ CD14+ cells in the RA patients was significantly lower than that in healthy donors (mean ± SEM = 33.16 ± 4.82% vs 66.51 ± 2.4%, P < 0.001). When we added in vitro TNFα to healthy donor culture cells, levels of iTNFα+ CD14+ cells decreased, suggesting that the TNFα signal was responsible for the iTNFα+ CD14+ cell downregulation observed in the RA patients. After 2, 6 and 12 adalimumab injections, we observed significant blocking of membrane and soluble TNFα and a progressive increase in iTNFα+ CD14+ cells in ten patients with a good to moderate response as defined by the European League Against Rheumatism (EULAR) criteria. Levels of iTNFα+ CD14+ cells after 12 injections in these 10 patients were comparable to levels in healthy donors. In two patients, iTNFα+ 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 TNFα. In the second patient, adalimumab was discontinued because of adverse effects, which led to a decrease in iTNFα+ CD14+ cells to levels measured before treatment.
  
  
  CONCLUSIONS
  Our findings suggest that adalimumab treatment in RA patients can return iTNFα levels to those of healthy donors. This effect was not observed in the presence of neutralizing antiadalimumab antibodies.
authors.forename: Carlos
authors.initials: C
authors.lastname: Zamora-Atenza
authors.forename: Cesar
authors.initials: C
authors.lastname: Diaz-Torne
authors.forename: Carme
authors.initials: C
authors.lastname: Geli
authors.forename: Cesar
authors.initials: C
authors.lastname: Diaz-Lopez
authors.forename: M Angels
authors.initials: MA
authors.lastname: Ortiz
authors.forename: Patricia
authors.initials: P
authors.lastname: Moya
authors.forename: Ivan
authors.initials: I
authors.lastname: Castellví
authors.forename: Juan C
authors.initials: JC
authors.lastname: Nieto
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cantó
authors.forename: Jordi
authors.initials: J
authors.lastname: Casademont
authors.forename: Candido
authors.initials: C
authors.lastname: Juarez
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llobet
authors.forename: Silvia
authors.initials: S
authors.lastname: Vidal
mesh_terms: D000068879:Adalimumab; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab