PMID- 28597609
OWN - NLM
STAT- MEDLINE
DCOM- 20170921
LR  - 20180119
IS  - 2326-5205 (Electronic)
IS  - 2326-5191 (Linking)
VI  - 69
IP  - 9
DP  - 2017 Sep
TI  - Transaminase Levels and Hepatic Events During Tocilizumab Treatment: Pooled 
      Analysis of Long-Term Clinical Trial Safety Data in Rheumatoid Arthritis.
PG  - 1751-1761
LID - 10.1002/art.40176 [doi]
AB  - OBJECTIVE: To investigate liver enzyme abnormalities and hepatic adverse events 
      (AEs) during long-term tocilizumab treatment for rheumatoid arthritis in clinical 
      trials. METHODS: Data were pooled from patients who received intravenous 
      tocilizumab (4, 8, or 10 mg/kg with or without disease-modifying antirheumatic 
      drugs [DMARDs]) in phase III or IV clinical trials, long-term extensions, and a 
      pharmacology study. Alanine aminotransferase (ALT) and aspartate aminotransferase 
      (AST) levels were measured routinely in these trials. AE rates were measured per 
      100 patient-years of tocilizumab exposure for this pooled analysis. RESULTS: 
      Overall, 16,204.8 patient-years of tocilizumab exposure (mean +/- SD duration of 
      exposure 3.9 +/- 2.0 years) were evaluated for 4,171 patients. ALT and AST 
      elevations greater than the upper limit of normal (ULN) occurred in 70.6% and 
      59.4% of patients, respectively. ALT/AST elevations were >1-3x ULN in 59%/55% of 
      patients, >3-5x ULN in 8.9%/3.3% of patients, and >5x ULN in 2.9%/0.9% of 
      patients. Most elevations occurred during the first year of treatment. Single 
      ALT/AST elevations >3x ULN occurred in 7.7%/3.6% of patients, and >/=2 consecutive 
      elevations >3x ULN occurred in 1.9%/0.4% of patients. Elevations >3x ULN returned 
      to normal in 80% of patients (median of 5.6 weeks to normalization). A total of 
      2.5% of patients withdrew from tocilizumab treatment following ALT/AST 
      elevations. A total of 7 hepatic serious AEs (SAEs) (0.04 per 100 patient-years 
      [95% confidence interval 0.02-0.09]) occurred in the tocilizumab studies. 
      CONCLUSION: Transaminase elevations with tocilizumab were frequent, but rates of 
      hepatic SAEs were low in this clinical trial data set. Regular monitoring, with 
      dose adjustment of tocilizumab/DMARDs for persistent elevations, is recommended.
CI  - (c) 2017, American College of Rheumatology.
FAU - Genovese, Mark C
AU  - Genovese MC
AUID- ORCID: 0000-0001-5294-4503
AD  - Stanford University Medical Center, Palo Alto, California.
FAU - Kremer, Joel M
AU  - Kremer JM
AD  - Albany Medical College, Albany, New York.
FAU - van Vollenhoven, Ronald F
AU  - van Vollenhoven RF
AD  - Karolinska Institute, Stockholm, Sweden (current address: Amsterdam Rheumatology 
      and Immunology Center, Academic Medical Center, Amsterdam, The Netherlands).
FAU - Alten, Rieke
AU  - Alten R
AD  - University of Berlin, Berlin, Germany.
FAU - Scali, Juan Jose
AU  - Scali JJ
AD  - Durand University Hospital, Buenos Aires, Argentina.
FAU - Kelman, Ariella
AU  - Kelman A
AD  - Genentech, Inc., South San Francisco, California.
FAU - Dimonaco, Sophie
AU  - Dimonaco S
AD  - Roche Products Ltd., Welwyn Garden City, UK.
FAU - Brockwell, Laura
AU  - Brockwell L
AD  - Roche Products Ltd., Welwyn Garden City, UK.
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
DEP - 20170801
PL  - United States
TA  - Arthritis Rheumatol
JT  - Arthritis & rheumatology (Hoboken, N.J.)
JID - 101623795
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antirheumatic Agents)
RN  - EC 2.6.1.1 (Aspartate Aminotransferases)
RN  - EC 2.6.1.2 (Alanine Transaminase)
RN  - I031V2H011 (tocilizumab)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Alanine Transaminase/*blood
MH  - Antibodies, Monoclonal, Humanized/*adverse effects
MH  - Antirheumatic Agents/*adverse effects
MH  - Arthritis, Rheumatoid/blood/*drug therapy
MH  - Aspartate Aminotransferases/*blood
MH  - Chemical and Drug Induced Liver Injury/*epidemiology/etiology
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Liver/drug effects/enzymology
MH  - Male
MH  - Middle Aged
MH  - Randomized Controlled Trials as Topic
EDAT- 2017/06/10 06:00
MHDA- 2017/09/22 06:00
CRDT- 2017/06/10 06:00
PHST- 2015/07/20 00:00 [received]
PHST- 2017/06/06 00:00 [accepted]
PHST- 2017/06/10 06:00 [pubmed]
PHST- 2017/09/22 06:00 [medline]
PHST- 2017/06/10 06:00 [entrez]
AID - 10.1002/art.40176 [doi]
PST - ppublish
SO  - Arthritis Rheumatol. 2017 Sep;69(9):1751-1761. doi: 10.1002/art.40176. Epub 2017 
      Aug 1.