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Extended report
Risk of elevated liver enzymes associated with TNF inhibitor utilisation in patients with rheumatoid arthritis
  1. Jeremy Sokolove1,
  2. Vibeke Strand1,
  3. Jeffrey D Greenberg2,
  4. Jeffrey R Curtis3,
  5. Arthur Kavanaugh4,
  6. Joel M Kremer5,
  7. Alina Anofrei6,
  8. George Reed6,
  9. Leonard Calabrese7,
  10. Michele Hooper8,
  11. Scott Baumgartner8,
  12. Daniel E Furst9
  13. on behalf of the CORRONA Investigators
  1. 1Stanford University, Palo Alto, California, USA
  2. 2New York University, New York, New York, USA
  3. 3University of Alabama at Birmingham, Birmingham, Alabama, USA
  4. 4University of California, San Diego, San Diego, California, USA
  5. 5Albany Medical Center, Albany, New York, USA
  6. 6University of Massachusetts Medical Center, Worcester, Massachusetts, USA
  7. 7Cleveland Clinic, Cleveland, Ohio, USA
  8. 8Amgen Inc, Thousand Oaks, California, USA
  9. 9University of California, Los Angeles, Los Angeles, California, USA
  1. Correspondence to Daniel E Furst, Division of Rheumatology, University of California, Los Angeles, Los Angeles, CA 90095, USA; defurst{at}


Objective Liver function test (LFT) elevations are reported with the use of tumour necrosis factor inhibitors (TNF-Is). The aim of this study was to compare LFT elevations in patients with rheumatoid arthritis receiving adalimumab (ADA), etanercept (ETN) or infliximab (INF) enrolled in the Consortium of Rheumatology Researchers of North America from October 2001 to March 2007.

Methods Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels >1× upper limit of normal (ULN) were considered elevations and ALT/AST levels >2× ULN were considered abnormalities. Treatments included TNF-Is, methotrexate (MTX), leflunomide and other disease-modifying antirheumatic agents (DMARDs). Patients were censored after their first LFT elevation. Three analytical models were evaluated: (1) individual TNF-I vs non-biological DMARDs (primary model); (2) individual TNF-I plus MTX vs MTX monotherapy; and (3) limited to new users of individual TNF-I vs non-biological DMARDs. ORs for LFT elevations were estimated using generalised estimating equation logistic regression.

Results 6861 patients (ADA: 849; ETN: 1383; INF: 1449) with 22 522 determinations were analysed. LFT elevations >1× ULN with TNF-I use were seen in 5.9% of AST/ALT determinations and abnormalities >2× ULN in 0.77%. In the primary model the adjusted ORs for LFT elevations >1× ULN were ADA 1.35 (95% CI 1.09 to 1.66), ETN 1.00 (95% CI 0.83 to 1.21) and INF 1.58 (95% CI 1.35 to 1.86). For 2× ULN, adjusted ORs were ADA 1.72 (95% CI 0.99 to 3.01), ETN 1.10 (95% CI 0.64 to 1.88) and INF 2.40 (95% CI 1.53 to 3.76). Similar results were obtained in other models.

Conclusion The overall incidence of LFT elevations >1× ULN with TNF-I use was uncommon and abnormalities >2× ULN were rarely observed. Significant differences were most consistently observed with INF, less commonly with ADA and were not observed with ETN compared with comparator DMARDs.

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  • Funding This work was funded by the Consortium of Rheumatology Researchers of North America.

  • Competing interests Amgen, as part of its subscription of CORRONA, requested the analysis and were involved in the early design and manuscript review and comment for this study. The final analysis plan, the study results and interpretations of the study data were those of the non-Amgen authors. A professional medical writer was not employed. The manuscript was written by the first and senior authors with editorial input from all academic co-authors. Amgen employees were not involved in the writing of the manuscript.

    VS has worked as an independent biopharmaceutical consultant in clinical development and regulatory affairs since September 1991 for the following companies: Abbot Immunology, Alder, Allergan, Almirall, Amgen Corporation, AstraZeneca, Bexel, BiogenIdec, CanFite, Centocor, Chelsea, Crescendo, Cypress Biosciences, Eurodiagnostica, Fibrogen, Forest Laboratories, Genentech, Human Genome Sciences, Idera, Incyte, Jazz Pharmaceuticals, Lexicon Genetics, Logical Therapeutics, Lux Biosciences, Medimmune, Merck Serono, Novartis Pharmaceuticals, NovoNordisk, Nuon, Ono Pharmaceuticals, Pfizer, Procter and Gamble, Rigel, Roche, Sanofi-Aventis, Savient, Schering Plough, SKK, UCB, Wyeth and Xdx. She serves on the advisory boards for the following: Abbott, Amgen, BiogenIdec, BMS, CanFite, Centocor, Chelsea, Crescendo, Cypress, Eurodiagnostica, Fibrogen, Forest, Idera, Incyte, Jazz, Nicox, Novartis, Pfizer, Rigel, Roche, Savient, Schering Plough, UCB and Wyeth. JDG serves as a paid independent consultant in the function of Chief Scientific Officer for CORRONA for the current year. He also has served as a consultant on advisory boards to BMS, Centocor, Genentech, Roche and UCB. JRC is on the advisory boards and/or is a consultant for Roche, UCB, Procter and Gamble, Amgen, Centocor and CORRONA. He also has served as a speaker for Novartis, Procter and Gamble, Eli Lilly, Roche and Merck. His research grants are with Novartis, Amgen, Merck, Procter and Gamble, Eli Lilly, Roche, Centocor and CORRONA. AK has conducted research trials for Amgen, Abbott, Centocor and UCB. JMK has received grant support from Abbott, Amgen, BMS, Centocor, HGS, Genentech, Pfizer, Roche and UCB. He receives consulting fees from BMS, Centocor, Pfizer, Roche and UCB. GR has a research contract with CORRONA through the University of Massachusetts Medical School. LC has received consultant fees from Roche, Amgen and Genentech and as a speaker for Centocor, Genentech and Abbott. MH and SB are employed full time with Amgen and owns stock and stock options. DEF receives research grants from Abbott, Actelion, Amgen, BMS, Genentech, Gilead, GSK, Nitec, Novartis, Roche, UCB, Wyeth and Xoma. He is a consultant and serves on the advisory board of the following (honoraria where indicated): Abbott (honoraria), Actelion (honoraria), Amgen (honoraria), BMS (honoraria), BiogenIDec (honoraria), Centocor (honoraria), Genentech (honoraria), Gilead (honoraria), GSK, Merck (honoraria), Nitec (honoraria), Novartis, Roche, UCB, Wyeth and Xoma.

  • Provenance and peer review Not commissioned; externally peer reviewed.