title: High levels of natural killer cells are associated with response to tocilizumab in patients with severe rheumatoid arthritis.
abstract: OBJECTIVE
  We aimed to assess the effect of tocilizumab (TCZ), an IL-6 receptor inhibitor, on B, T, NK and NKT cells in patients with RA and to study the cell type predictors of remission. We also compared NK cells in patients with RA and in controls.
  
  
  METHODS
  RA patients included in the study met the 2010 ACR/European League Against Rheumatism (EULAR) criteria, were receiving stable doses of steroids and had not received rituximab in the previous year. Different B and T cell subsets, NK cells and NKT cells were assessed by flow cytometry along with perforin A and granzyme B to estimate NK cell cytotoxicity.
  
  
  RESULTS
  We included 92 RA patients, including 20 requiring TCZ treatment and 15 requiring anti-TNF drugs, and 25 controls. At baseline, the proportion of CD56(dim)CD16(+)CD3(-) NK cells was inversely correlated with the 28-joint DAS (DAS28). In TCZ-treated patients, the baseline proportion of CD3(-)CD56(+) NK cells was inversely correlated with the change in DAS28 at 3 months and the proportion was 3-fold greater for patients with DAS28 remission at 3 months than other patients. Change in the proportion of CD56(bri)CD16(-) NK cells was linearly correlated with change in the DAS28 at 3 months. The baseline proportion of NK cells did not predict change in disease activity at 3 months with anti-TNF therapy. The perforin content in NK cells increased with TCZ treatment.
  
  
  CONCLUSIONS
  This study supports NK cell involvement in RA and in the TCZ mechanism of action. NK cells at baseline could be a predictive factor of TCZ response if results are confirmed.
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France. Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France. c-daien@chu-montpellier.fr.
authors.forename: Claire Immediato
authors.initials: CI
authors.lastname: Daïen
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gailhac
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Audo
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mura
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France. Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Hahne
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France. Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Combe
authors.affiliation: Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France. Department of Rheumatology, Lapeyronie Hospital and Montpellier University I, TNF-alpha Laboratory, UMR5535, CNRS, Clinical Investigation Center, University Hospital of Montpellier and INSERM, CIC 1001, Montpellier, France, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Université Montpellier Sud de France, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Morel
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D000068582:Certolizumab Pegol; D000068800:Etanercept; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011446:Prospective Studies; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C508603:IL6R protein, human; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D019947:Receptors, Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D000068879:Adalimumab; C502936:tocilizumab; D000068800:Etanercept; D000068582:Certolizumab Pegol
keywords: B cells; anti-TNF drug; granzyme; interleukin-6 inhibitor; natural killer cells; perforin; regulatory T cells; tocilizumab