Risk of elevated liver enzymes associated with TNF inhibitor utilisation in patients with rheumatoid arthritis

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.

Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels >1x upper limit of normal (ULN) were considered elevations and ALT/AST levels >2x 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.

6861 patients (ADA: 849; ETN: 1383; INF: 1449) with 22 522 determinations were analysed. LFT elevations >1x ULN with TNF-I use were seen in 5.9% of AST/ALT determinations and abnormalities >2x ULN in 0.77%. In the primary model the adjusted ORs for LFT elevations >1x 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 2x 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.

The overall incidence of LFT elevations >1x ULN with TNF-I use was uncommon and abnormalities >2x 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.