Immune‐related hepatitis related to checkpoint inhibitors: Clinical and prognostic factors

Abstract

Background & Aims: Check point inhibitors (CPI) have improved survival of oncology patients but adverse effects that mimic autoimmune disorders have been reported. Our aim was describe the characteristics of immune-related hepatitis (irH) and prognosis, and compared them to those of patients with autoimmune hepatitis (AIH). Methods: This is a retrospective study including all grade ≥ 3 (severe) irH diagnosed among 414 patients treated with CPI from 2016 to 2018. Results: Twenty-eight cases of severe irH were recorded: 10 on anti-CTLA-4 ± anti-PD1/PD-L1 and 18 on anti-PD1/PD-L1. Half were female, age 63 years, median time on CPI three cycles. Four (14.3%) presented acute liver injury or failure and one (3.6%) died as consequence. 94% presented normal immunoglobulin G (IgG). Six (21.4%) patients were retreated with CPI and none presented relapse or new immune-related adverse events after a median cycles of 11 (range 6-36). Subjects with irH were older and had lower IgG values than a cohort of AIH (N = 38). Presentation tended to be more severe in AIH. Twenty-five percent of irH and 84% AIH presented ANAs ≥ 1:80 (P = .001). In irH Initial dose of corticosteroids was higher (60 vs 30 mg, P < .001) but duration shorter (2.3 vs 7 months, P < .001) and frequently in monotherapy (41.7% vs 91.3%, P < .001). Conclusions: Immune-related hepatitis can lead to acute liver failure, with absence of increased values of IgG and ANAs. In contrast to autoimmune hepatitis, initial corticosteroids dose were higher, duration shorter with few requiring additional immunosuppression. Retreatment with CPI was not associated with recurrence.

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors

“…Patients with liver toxicity on ICIs are usually asymptomatic and the symptoms, when present, are particularly non-specific; they may present with fever, skin rash and, in rare cases, jaundice. 66,67 Symptoms deriving from concomitant toxicity affecting another organ, such as colitis, hypophysitis or pneumonitis, may also occur. 68 No male or female preponderance has been described and age does not appear to constitute a risk factor for the development of liver toxicity.…”

“…68 No male or female preponderance has been described and age does not appear to constitute a risk factor for the development of liver toxicity. 66,67 The interval elapsing between the initiation of therapy and the onset of liver toxicity varies considerably, and toxicity may even occur after treatment discontinuation. In patients treated with ipilimumab as adjuvant therapy for stage III melanoma, the median time to the onset of hepatic irAE was 8.9 weeks (ranging from 1.9 weeks to 145.4 weeks).…”

“…71 In the paper by Riveiro-Barciela, the interval between ICI treatment initiation and liver toxicity was shorter in patients on anti-CTLA-4 than in those receiving anti-PD-1/PD-L1 antibodies, although the difference was not statistically significant. 67 The combination of anti-CTLA-4 and anti-PD-1 was reported not to be associated with an earlier onset of grade > − 3 liver toxicity in a study by Sznol et al, who reported a median interval of 8.4 (2.1-48) weeks, 72 while it was significantly shorter (median 2.9 weeks) with the combination therapy in the study by Gauci et al 70 In most patients, the profile of liver injury is usually hepatocellular, but cases of cholestatic presentation have been described. 66,73,74 Seven patients with nivolumab-induced cholangitis with predominant ALP and GGT elevations have been reported.…”

“…Several examples of re-challenge have been reported in the literature, with hepatitis recurrence rates ranging from 0 to 60%, differentially distributed as a function of the type of molecule used. 66,67,70,73,110,121 However, when we pooled all the cases reported in the literature regarding a re-challenge with ICIs after liver toxicity, we found that among 58 retreated patients, 11 (19%) experienced a recurrence of liver toxicity. When we looked solely at patients who had experienced initial toxicity of grade > − 3 (a total of 29 patients) the recurrence rate rose to 40% (Table 3).…”

Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit

“…Termed immune related adverse events (irAEs), the side effects of these novel therapeutic antibodies result from the loss of immune homeostasis and off-target effects in peripheral tissues [2,3]. Although the skin, endocrine glands and digestive tract are mostly affected, pulmonary [4][5][6], neurologic [7][8][9][10], hepatic [11][12][13] and cardiologic [14][15][16][17][18][19] side effects have also been described and may be life-threatening.…”