title: Newly identified antiatherosclerotic activity of methotrexate and adalimumab: complementary effects on lipoprotein function and macrophage cholesterol metabolism.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis. The reduction in cardiovascular risk that is induced by methotrexate (MTX) and anti-tumor necrosis factor α agents in RA is considered secondary to their anti-inflammatory action, but their effects on serum lipoprotein function and foam cell formation are unknown. The reduced capacity of high-density lipoprotein (HDL) to promote cell cholesterol efflux and the increased serum cell cholesterol-loading capacity (CLC) demonstrated in RA may contribute to foam cell development. The aim of this study was to investigate the influence of MTX and adalimumab treatment on serum cholesterol efflux capacity (CEC) and CLC in RA patients and to study the in vitro effects of the two drugs on macrophage cholesterol handling.
  
  
  METHODS
  Sera from RA patients treated with MTX (n = 34) or with adalimumab and MTX (n = 22) obtained before treatment, after 6 weeks of treatment, and after 6 months of treatment were analyzed for CEC and CLC by radioisotopic and fluorometric techniques, respectively. The influence of MTX and adalimumab on macrophage cholesterol efflux and uptake was evaluated in vitro using human THP-1-derived macrophages.
  
  
  RESULTS
  MTX treatment was associated with increases in serum HDL, low-density lipoprotein, and total cholesterol levels and with ATP-binding cassette G1-mediated and scavenger receptor class B type I (SR-BI)-mediated increases in CEC; MTX treatment was not associated with modifications in CLC. Adalimumab treatment was associated with increases in serum HDL levels, a transient increase in SR-BI-mediated CEC, a transient decrease in ATP-binding cassette A1-mediated CEC, and a significant reduction in CLC; in addition, adalimumab reduced macrophage cholesterol uptake in vitro.
  
  
  CONCLUSIONS
  Antiatherosclerotic activity associated with MTX and adalimumab may be mediated by beneficial and complementary effects on lipoprotein functions and on macrophage cholesterol handling. As a whole, these mechanisms may oppose foam cell formation.
authors.affiliation: University of Parma, Parma, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ronda
authors.forename: Daniela
authors.initials: D
authors.lastname: Greco
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Adorni
authors.forename: Francesca
authors.initials: F
authors.lastname: Zimetti
authors.forename: Elda
authors.initials: E
authors.lastname: Favari
authors.forename: Gunnbjørg
authors.initials: G
authors.lastname: Hjeltnes
authors.forename: Knut
authors.initials: K
authors.lastname: Mikkelsen
authors.forename: Maria Orietta
authors.initials: MO
authors.lastname: Borghi
authors.forename: Ennio Giulio
authors.initials: EG
authors.lastname: Favalli
authors.forename: Rita
authors.initials: R
authors.lastname: Gatti
authors.forename: Ivana
authors.initials: I
authors.lastname: Hollan
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Meroni
authors.forename: Franco
authors.initials: F
authors.lastname: Bernini
mesh_terms: D000068879:Adalimumab; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D050197:Atherosclerosis / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D051122:Scavenger Receptors, Class B
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D000068879:Adalimumab; D008727:Methotrexate