Hepatotoxicity Associated with the Use of Anti-TNF-α Agents

Abstract

Medications to inhibit the actions of tumour necrosis factor alpha have revolutionized the treatment of several pro-inflammatory autoimmune conditions. Despite their many benefits, several serious side effects exist and adverse reactions do occur from these medications. While many of the medications’ potential adverse effects were anticipated and recognized in clinical trials prior to drug approval, several more rare adverse reactions were recorded in the literature as the popularity, availability and distribution of these medications grew. Of these potential adverse reactions, liver injury, although uncommon, has been observed in some patients. As case reports accrued over time and ultimately case series developed, the link became better established between this family of medicines and various patterns of liver injury. Interestingly, it appears that the majority of cases exhibit an autoimmune hepatitis profile both in serological markers of autoimmune liver disease and in classic autoimmune features seen on hepatic histopathology. Despite the growing evidence of this relationship, the pathogenesis of this reaction remains incompletely understood, but it appears to depend on characteristics of the medications and the genetic composition of the patients; it is likely more complicated than a simple medication class effect. Because of this still incomplete understanding and the infrequency of the occurrence, treatments have also been limited, although it is clear that most patients improve with cessation of the offending agent and, in certain cases, glucocorticoid use. However, more needs to be done in the future to unveil the underlying mechanisms of this adverse reaction.

Biologic and Checkpoint Inhibitor‐Induced Liver Injury: A Systematic Literature Review

“…Six of the nine cases went on to emergent transplantation, with the other three recovering liver function with steroid therapy. Given the wide range of latency, this may suggest an idiosyncratic DILI rather than a dose‐dependent toxicity, which has been described in other studies as well …”

“…N‐acetyl‐cysteine has been shown to improve transplant‐free survival for patients not only with acetaminophen‐induced ALF but also with non‐acetaminophen ALF; however, patients with liver injury due to biologics have not been included in these studies . Corticosteroids have also been administered with better results in patients with DILI or AIH from TNF‐α inhibitor therapy . Data from a single‐center retrospective cohort study support these findings and also showed that corticosteroids were most effective for severe liver injury with peak total bilirubin >243 μmol/L .…”

“…The most common form of liver injury related to TNF‐α inhibitors has been shown to be hepatocellular injury with autoantibodies, mostly with positive ANA and some with anti‐smooth muscle antibody, and histologic features consistent with AIH. Development of this pattern of injury has been reported in up to 92% of TNF‐α inhibitor‐induced DILI . Additionally, there seems to be a lack of cross‐reactivity between TNF‐α inhibitors, possibly due to the difference in molecular structure of these agents.…”

“…Infliximab was the first agent to be approved by the U.S. Food and Drug Administration (FDA) in 1998 for the treatment of Crohn’s disease . Initially, FDA labels for these TNF‐α inhibitors only included cautions on injection site reactions, headache, nausea, rash, and arthralgias . It was not until an FDA postmarketing surveillance program that documented over 130 reports of liver injury from either infliximab or etanercept treatment within 5 years did the labels start to include hepatobiliary adverse effects…”

Clinical experience of combination therapy of infliximab and total glucosides of paeony for severe psoriasis with liver disorder history

“…While biological agent such as infliximab may be an appropriate option for patients with liver disorder history, it is still important to be cautious about the risk of HBV reactivation and other adverse effects [5,6] . Though the incidence of liver injury is relatively low, the existing several cases suggest that liver injury has a strong correlation with anti-TNF-α medications [7,8] . In addition, it is suggested that some patients lack a complete response to infliximab treatment.…”