247therapy [ 69 ]. When identifying cases of drug-induced liver injury (DILI) caused by
anti-TNF agents in Iceland from 2009 to 2013, Bjornsson et al. noted that DILI
developed in 1 of 120 patients who received infliximab, 1 in 270 who received adali-
mumab, and 1 in 430 patients who received etanercept [ 71 ].
Clinical symptoms of anti-TNF-associated hepatotoxicity can vary. Some
patients can be asymptomatic with abnormal liver enzymes discovered on routine
laboratory monitoring [ 69 , 72 ]. Others may present with jaundice, nausea, and/or
fever [ 70 , 71 ]. In examining six cases of hepatotoxicity associated with anti-TNF
therapy, Ghabril et al. found that the median latency of onset from initiation of inf-
liximab to hepatotoxicity was 16 weeks (range, 2–52 weeks) [ 70 ]. The pattern of
hepatic injury was mainly hepatocellular; one patient had significantly impaired
coagulation (international normalized ratio [INR], 3.5). None of these patients had
ascites or signs of hepatic failure [ 70 ].
Combining the six cases above with the 28 cases from the DILI network, Ghabril
et al. noted that the peak alanine aminotransferase (ALT) ranged from 140 U/L to
2250 U/L and the bilirubin level ranged from normal to 27.7 mg/dL [ 70 ]. Similarly,
Bjornsson et al. found that majority of patients (8 out of 11) with DILI from anti- TNF
therapy had a pattern of hepatocellular injury, though a cholestatic pattern was also
seen [ 71 ]. The mean peak ALT, aspartate aminotransferase (AST), alkaline phospha-
tase, and bilirubin were 704 U/L, 503 U/L, 261 U/L, and 47 ųmol/L, respectively [ 71 ].
Risk Factors for Anti-TNF-Induced Hepatotoxicity
A number of anti-TNF agents have been associated with drug-induced hepatotoxic-
ity. Among the 34 cases described by Ghabril et al., 26 were due to infliximab, 4
from etanercept, and 4 from adalimumab; there were no reported cases from golim-
umab or certolizumab pegol [ 70 ]. Infliximab-associated hepatotoxicity is most fre-
quently documented, likely because of its earlier approval and widespread use [ 70 ,
71 ]. Due to limited data, it remains unclear whether there is cross-reactivity between
different anti-TNF agents in regard to hepatotoxicity. However, in the rheumatology
literature, there have been case reports of patients with infliximab, etanercept, or
adalimumab-associated hepatotoxicity who subsequently tolerated a different anti-
TNF therapy without recurrence of hepatotoxicity [ 71 , 73 – 75 ].
Duration and dosing of anti-TNF therapy do not appear to affect the likelihood of
its associated hepatotoxicity. Hepatotoxicity has been noted to occur, on average,
14–18 weeks after initiation of therapy [ 68 , 70 , 71 ]. However, drug-induced liver
injury associated with infliximab has been reported after just one infusion [ 76 ]. Based
on the available data, there does not appear to be a dose-dependent hepatotoxicity
with anti-TNF therapy. In a case control study, patients who developed ALT elevation
were noted to be on a lower dose of infliximab than the controls (5.7 vs. 6.7 mg/kg,
p = 0.02). Similarly, in a case series consisting of eight IBD patients with anti-TNF-
associated hepatotoxicity, Rodrigues et al. noted that all patients were on a standard
dose of infliximab (5 mg/kg) and adalimumab (40 mg every other week) [ 69 ].
14 Noninfectious and Nonmalignant Complications of Anti-TNF Therapy