title: Remodeling of plasma lipoproteins in patients with rheumatoid arthritis: Interleukin-6 receptor-alpha inhibition with tocilizumab.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is associated with increased cardiovascular risk, mediated in part by elevated circulating interleukin-6 levels and proinflammatory changes in plasma lipoproteins. We hypothesized that RA patients acquire inflammation-induced modifications to the protein cargo of circulating lipoproteins that may be reversed by tocilizumab, an interleukin-6 receptor-alpha inhibitor.
  
  
  METHODS
  Size-exclusion chromatography and reverse-phase protein arrays using 29 antibodies against 26 proteins were applied at baseline and after tocilizumab treatment to analyze the distributions of apolipoproteins, enzymes, lipid transfer proteins, and other associated proteins in plasma lipoprotein fractions from 20 women with RA.
  
  
  RESULTS
  A 30% reduction in high-density lipoprotein (HDL)-associated serum amyloid A4 and complement C4 occurred with tocilizumab. Levels of C-reactive protein, associated or comigrating with HDL and low-density lipoprotein (LDL) peaks, were reduced on treatment by approximately 80% and 24%, respectively. Reductions in lipoprotein-associated phospholipase A2, lipoprotein (a), and cholesteryl ester transfer protein in the LDL fraction suggest reductions in LDL-associated proatherogenic factors. Elevations in very low-density lipoprotein (VLDL) enriched with apolipoprotein E were equally observed.
  
  
  CONCLUSIONS
  Tocilizumab treatment led to reductions in proinflammatory components and proatherogenic proteins associated with HDL. Whether changes in the proteome of VLDL, LDL, and HDL induced by anti-inflammatory tocilizumab treatment in RA patients modify cardiovascular disease risk requires further investigation.
authors.affiliation: Roche, Nutley, NJ, USA.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: INSERM Dyslipidemia and Atherosclerosis Research Unit, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.affiliation: Pvalue Research S.R.L, Piacenza, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Piraino
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Lamerz
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schindler
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Cutler
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: Gregor
authors.initials: G
authors.lastname: Dernick
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy*; D002850:Chromatography, Gel; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053698:Interleukin-6 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D040081:Protein Array Analysis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D061067:Antibodies, Monoclonal, Humanized; D053698:Interleukin-6 Receptor alpha Subunit; D008074:Lipoproteins; C502936:tocilizumab
keywords: Apolipoproteins; Biologic disease-modifying antirheumatic drugs; Cardiovascular disease; HDL; Inflammation; LDL; Lipid transfer proteins