title: Pro-atherogenic lipid changes and decreased hepatic LDL receptor expression by tocilizumab in rheumatoid arthritis.
abstract: OBJECTIVE
  Blocking the interleukin-6 pathway by tocilizumab (TCZ) has been associated with changes in the lipoprotein profile, which could adversely impact cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). In the present study, we addressed the effect of TCZ on lipoproteins in both fasting and non-fasting state in RA patients and tested the effect of TCZ on LDL receptor (LDLr) expression in vitro.
  
  
  METHODS
  Twenty patients with active RA and an inadequate response to TNF blockers received monthly TCZ intravenously. On week 0, 1 and 6 blood was drawn before and after an oral fat load, the lipid profiles and HDL antioxidative capacity were measured. Effects of TCZ on LDLr expression in transfected HepG2 cells were subjected.
  
  
  RESULTS
  After 6 weeks of TCZ, total cholesterol increased by 22% (4.8 ± 0.9 to 5.9 ± 1.3 mmol/L; p < 0.001), LDLc by 22% (3.0 ± 0.6 to 3.6 ± 0.8 mmol/L; p < 0.001) and HDLc by 17% (1.4 ± 0.4 to 1.7 ± 0.7 mmol/L; p < 0.016). Fasting triglycerides (TG) increased by 48% (1.0 ± 0.4 to 1.4 ± 0.8 mmol/L; p = 0.011), whereas postprandial incremental area under the curve TG increased by 62% (p = 0.002). Lipid changes were unrelated to the change in disease activity or inflammatory markers. No difference in HDL antioxidative capacity was found. In vitro, LDLr expression in cultured liver cells was significantly decreased following TCZ incubation (P < 0.001).
  
  
  CONCLUSIONS
  TCZ adversely impacts on both LDLc as well as fasting and postprandial TG in patients with RA. The changes in hepatic LDLr expression following TCZ imply that adverse lipid changes may be a direct hepatic effect of TCZ. The net effect of TCZ on CV-morbidity has to be confirmed in future clinical trials.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. a.c.strang@amc.uva.nl
authors.forename: Aart C
authors.initials: AC
authors.lastname: Strang
authors.forename: Radjesh J
authors.initials: RJ
authors.lastname: Bisoendial
authors.forename: Ruud S
authors.initials: RS
authors.lastname: Kootte
authors.forename: Dominik M
authors.initials: DM
authors.lastname: Schulte
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: Johannes H M
authors.initials: JH
authors.lastname: Levels
authors.forename: Marc
authors.initials: M
authors.lastname: Kok
authors.forename: Koen
authors.initials: K
authors.lastname: Vos
authors.forename: Sander W
authors.initials: SW
authors.lastname: Tas
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.forename: Nike
authors.initials: N
authors.lastname: Müller
authors.forename: Matthias
authors.initials: M
authors.lastname: Laudes
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Gerlag
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects*; D000975:Antioxidants / Q000378:metabolism; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007262:Infusions, Intravenous; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000975:Antioxidants; D018501:Antirheumatic Agents; D008055:Lipids; D011973:Receptors, LDL; C502936:tocilizumab