title: Non-autoimmune combined factor XIII A and B subunit deficiencies in rheumatoid arthritis patients treated with anti-interleukin-6 receptor monoclonal antibody (tocilizumab).
abstract: BACKGROUND
  Coagulation factor XIII (FXIII) is a plasma fibrin-stabilizing factor comprising A and B subunits (FXIII-A and FXIII-B, respectively) in the form of a heterotetramer (FXIII-A2B2). A humanized monoclonal antibody to the interleukin-6 receptor (tocilizumab, TCZ) has emerged as an effective treatment for rheumatoid arthritis (RA), because it drastically reduces the inflammation of RA. We previously reported that two TCZ-treated RA patients with acquired FXIII deficiency developed pelvic hemorrhage.
  
  
  METHODS
  Because TCZ treatment had been shown to be related to low FXIII ammonia release activity and FXIII antigen in the two RA cases, we further examined FXIII-related parameters in 36 TCZ-treated RA patients and compared to 29 healthy controls by employing functional and immunologic assays for FXIII.
  
  
  RESULTS
  FXIII-A antigen and FXIII amine incorporation and ammonia release activities were significantly lower in the TCZ-treated group than the control group. The TCZ-treated group also showed mildly low FXIII-A2B2 and FXIII-B levels, and their fibrinogen levels were the lower limit of normal. A significant correlation between FXIII-B and fibrinogen was observed in the control and the TCZ groups, suggesting a common metabolic mechanism(s) for these two hepatic proteins. Because the specific activities of FXIII were normal and neither anti-FXIII-A nor anti-FXIII-B antibody was detected, the overall low FXIII level may have resulted from its impaired synthesis under an unbalanced cytokine milieu caused by TCZ treatment.
  
  
  CONCLUSIONS
  Concomitant deficiencies in multiple hemostatic factors, including FXIII, may lead to an increased risk for hemorrhage in TCZ-treated RA patients.
authors.affiliation: Department of Molecular Patho-Biochemistry & -Biology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Souri
authors.affiliation: Department of Internal Medicine, Center for Rheumatic Diseases, Dohgo Spa Hospital, Matsuyama, Ehime, Japan; Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Mokuda
authors.affiliation: Department of Internal Medicine, Center for Rheumatic Diseases, Kobe Midori Hospital, Kobe, Hyogo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inanami
authors.affiliation: Department of Molecular Patho-Biochemistry & -Biology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Osaki
authors.affiliation: Department of Internal Medicine, Center for Rheumatic Diseases, Dohgo Spa Hospital, Matsuyama, Ehime, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takasugi
authors.affiliation: Department of Molecular Patho-Biochemistry & -Biology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Electronic address: aichinos@med.id.yamagata-u.ac.jp.
authors.forename: Akitada
authors.initials: A
authors.lastname: Ichinose
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology; D005176:Factor XIII / Q000032:analysis / Q000276:immunology; D005177:Factor XIII Deficiency / Q000150:complications* / Q000276:immunology; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D006801:Humans; D008297:Male; D019947:Receptors, Interleukin-6 / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019947:Receptors, Interleukin-6; D005340:Fibrinogen; D005176:Factor XIII; C502936:tocilizumab
keywords: Acquired coagulation disorders; Autoimmune diseases; Bleeding disorder; Chemokines; Factor XIII/transglutaminases