title: Prothrombotic biomarkers in patients with rheumatoid arthritis: the beneficial effect of IL-6 receptor blockade.
abstract: OBJECTIVE
  The pro-inflammatory cytokine interleukin (IL)-6 is involved in the pathogenesis of both rheumatoid arthritis (RA) and cardiovascular events. We evaluated the correlation of prothrombotic biomarkers, in particular those of thrombin generation, with inflammatory and clinical parameters in RA patients treated with tocilizumab, an IL-6 receptor (IL-6R) inhibitor. Naïve and maintenance patients were compared.
  
  
  METHODS
  We studied 15 RA patients undergoing tocilizumab infusions at a University Outpatient Clinic. Eight received tocilizumab for the first time and were evaluated at baseline. Seven were in maintenance therapy (9 to 77 months). All 15 patients were evaluated four weeks after the last administration of tocilizumab. At each time, we assessed disease activity score 28 (DAS28), erythrocyte sedimentation rate (ESR) and plasma levels of C-reactive protein (CRP), IL-6, soluble (s)IL-6R, tumour necrosis factor-alpha (TNF-alpha), prothrombin fragment F1+2 and fibrin fragment D-dimer. Forty healthy subjects served as basal controls.
  
  
  RESULTS
  At baseline, RA patients showed a moderate-to-high disease activity and median ESR of 51 mm/1(st) hour (interquartile range 25-63). Plasma levels of CRP (p=0.0001), IL-6 (p=0.043), sIL-6R (p=0.003), TNF-alpha (p=0.0001), F1+2 (p=0.0001) and D-dimer (p=0.002) were higher than those of healthy controls. After four weeks we observed reduction of DAS28 (p=0.0001), ESR (p=0.0001), CRP (p=0.014), TNF-alpha (p=0.006), F1+2 (p=0.009) and D-dimer (p=0.04). No differences were observed between naïve and maintenance patients.
  
  
  CONCLUSIONS
  The reduction of prothrombotic biomarkers parallels the reduction of inflammatory parameters and clinical symptoms in RA patients treated with tocilizumab, both four weeks after the first administration and during maintenance therapy.
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Cattedra di Reumatologia, Istituto G. Pini, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Gualtierotti
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Cattedra di Reumatologia, Istituto G. Pini, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ingegnoli
authors.affiliation: Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda, Milan, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Griffini
authors.affiliation: Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Grovetti
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Cattedra di Reumatologia, Istituto G. Pini, Milan; and IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Meroni
authors.affiliation: Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti,Università degli Studi di Milano, Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda, Milan, Italy. massimo.cugno@unimi.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cugno
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D062072:Patient Acuity; D011516:Prothrombin / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000097:blood; D013223:Statistics as Topic; D013927:Thrombosis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D000093242:Interleukin-6 Inhibitors; D015850:Interleukin-6
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D002097:C-Reactive Protein; D005338:Fibrin Fibrinogen Degradation Products; D011516:Prothrombin; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; D015850:Interleukin-6; C036309:fibrin fragment D; C502936:tocilizumab