title: Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry.
abstract: BACKGROUND
  The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice.
  
  
  METHODS
  This prospective cohort study included RA patients starting TCZ [TCZ group, n=302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n=304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis.
  
  
  RESULTS
  Patients in the TCZ group had longer disease duration (P<0.001), higher disease activity (P=0.019) and more frequently used concomitant corticosteroids (P<0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37).
  
  
  CONCLUSIONS
  The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. sakai.phv@tmd.ac.jp.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. sakai.phv@tmd.ac.jp.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Sakai
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. aushalten@naver.com.|Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, South Korea. aushalten@naver.com.
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Cho
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. nanki.rheu@tmd.ac.jp.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. nanki.rheu@tmd.ac.jp.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. watanabe.rheu@tmd.ac.jp.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. watanabe.rheu@tmd.ac.jp.
authors.forename: Kaori
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. yamazaki.rheu@tmd.ac.jp.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. yamazaki.rheu@tmd.ac.jp.
authors.forename: Hayato
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. tanaka.phv@tmd.ac.jp.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. tanaka.phv@tmd.ac.jp.
authors.forename: Michi
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. koike.rheu@tmd.ac.jp.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. koike.rheu@tmd.ac.jp.|Clinical Research Center, Tokyo Medical and Dental University Hospital, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. koike.rheu@tmd.ac.jp.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Koike
authors.affiliation: The First Department of Internal medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Kitakyushu Yahatanishi-ku, Fukuoka, 807-0804, Japan. tanaka@med.uoeh-u.ac.jp.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: The First Department of Internal medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Kitakyushu Yahatanishi-ku, Fukuoka, 807-0804, Japan. kazu-s@med.uoeh-u.ac.jp.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Saito
authors.affiliation: The First Department of Internal medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Kitakyushu Yahatanishi-ku, Fukuoka, 807-0804, Japan. s-hirata@med.uoeh-u.ac.jp.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hirata
authors.affiliation: Department of Rheumatology/Clinical Immunology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe-shi, Saitama, 350-8550, Japan. amanokoi@saitama-med.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Amano
authors.affiliation: Department of Rheumatology/Clinical Immunology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe-shi, Saitama, 350-8550, Japan. nagasawa@saitama-med.ac.jp.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nagasawa
authors.affiliation: Division of Clinical Immunology, Doctoral Program in Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-0006, Japan. tsumida@md.tsukuba.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
authors.affiliation: Division of Clinical Immunology, Doctoral Program in Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-0006, Japan. taichi8.th@gmail.com.
authors.forename: Taichi
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Department of Rheumatology, Tokyo Metropolitan Geriatric Hospital, 35-2, Sakaecho, Itabashi-ku, Tokyo, 173-0015, Japan. takahiko_sugihara@tmghig.jp.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Sugihara
authors.affiliation: Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan. hdobashi@med.kagawa-u.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Dobashi
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Kita 15. Nishi 7, Kita-ku, Sapporo, 060-8638, Japan. syasuda@med.hokudai.ac.jp.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yasuda
authors.affiliation: Department of Rheumatology, Tokyo Medical University, Nishi-Shinjuku 6-7-1, Shinjuku-ku, Tokyo, 160-0023, Japan. tsawada@tokyo-med.ac.jp.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Sawada
authors.affiliation: Department of Internal Medicine, Kurashiki Kousai Hospital, 3542-1, Nakasho, Kurashiki-shi, Okayama, 710-0016, Japan. wakoukai@po.harenet.ne.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ezawa
authors.affiliation: Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. aueda@med.yokohama-cu.ac.jp.
authors.forename: Atsuhisa
authors.initials: A
authors.lastname: Ueda
authors.affiliation: Department of the Control for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Yoshidakonoecho, Sakyo-ku, Kyoto, 606-8501, Japan. takfujii@kuhp.kyoto-u.ac.jp.
authors.forename: Takao
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Rheumatology, National Hospital Organization Nagasaki Medical Center, 2-1001-1, Kubara, Omura, Nagasaki, 856-8562, Japan. migita@nagasaki-mc.com.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Migita
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. miya.rheu@tmd.ac.jp.|Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. miya.rheu@tmd.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.affiliation: Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. mharigai.mpha@tmd.ac.jp.|Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. mharigai.mpha@tmd.ac.jp.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Harigai
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012042:Registries; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014409:Tumor Necrosis Factor-alpha; C502936:tocilizumab