Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy‐associated hepatitis in Japan

Kitagataya, Takashi; Suda, Goki; Nagashima, Kazunori; Katsurada, Takehiko; Yamamoto, Kōji; Kimura, Megumi; Maehara, Osamu; Yamada, Ryoichi; Shigesawa, Taku; Suzuki, Kazuharu; Nakamura, Akihisa; Ohara, Masatsugu; Umemura, Machiko; Kawagishi, Naoki; Nakai, Masato; Sho, Takuya; Natsuizaka, Mitsuteru; Morikawa, Kenichi; Ogawa, Koji; Ohnishi, Shunsuke; Hata, Hiroo; Takeuchi, Satoshi; Abe, Takashige; Sakakibara‐Konishi, Jun; Teshima, Takanori; Homma, Akihiro; Sakamoto, Naoya

doi:10.1111/jgh.15041

Cited by 34 publications

(35 citation statements)

References 27 publications

(43 reference statements)

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“…Few studies have assessed the differences in clinical characteristics of immune-related liver injury between multisystem and single irAEs. We found that immune-related liver injuries in multisystem irAEs occurred later than those in cases with liver irAEs alone, and the use of the anti-CTLA-4 antibody was associated with the incidence of multisystem irAEs, consistent with previous reports 23,24 . Our study demonstrated that the common types of irAEs accompanying liver injury were endocrine and GI injuries.…”

Section: Discussionsupporting

confidence: 91%

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies

et al. 2021

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BackgroundThe clinical course of liver injury induced by immune checkpoint inhibitors (ICIs) varies among individuals, and there were few reports on the therapeutic effects of corticosteroids based on the patterns of liver injury. MethodsWe evaluated the characteristics and clinical course of immune-related liver injury in 1087 patients treated with ICIs for advanced malignancies between August 2014 and December 2020. ResultsDuring the follow-up period (median, 270 days), 56 patients (5.2%) had immune-related liver injury (≥Grade 3). The liver-injury patterns were hepatocellular (n = 25, 44.6%), mixed (n = 10, 17.9%), or cholestatic (n = 21, 37.5%), and the median time to onset of liver injury was 36, 85, and 53 days, respectively; the hepatocellular pattern occurred earlier than the other types (P = 0.036). Corticosteroids were administered to 29 (51.8%) patients. While liver injury was improved in almost all patients with the hepatocellular pattern (n = 13/14, 92.9%), that failed to show improvement in over half of the patients with the non-hepatocellular patterns (mixed, n = 8; cholestatic, n = 7), and three patients with mixed patterns needed secondary immunosuppression with mycophenolate mofetil. Liver biopsies performed in 13 patients mainly showed lobular injury, endothelialitis, and spotty necrosis with in ltration of T cells positive for CD3 and CD8, but not CD4 or CD20. ConclusionThe incidence pattern and therapeutic response to corticosteroids in immune-related liver injury differs according to the injury type. Although corticosteroids were effective for the hepatocellular pattern, an additional strategy for refractory non-hepatocellular patterns is needed.

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Section: Discussionsupporting

confidence: 91%

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies

et al. 2021

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“…In a study from Oxford, 19/21 patients (90.5%) with hepatotoxicity due to Check Point Inhibitors were treated with corticosteroids (Cheung et al, 2019) (Table 1), but only 50% had a treatment response, which was similar to a study from Japan (Kitagataya et al, 2020). The study by Ito et al from Japan was somewhat of an outlier showing a response to steroid treatment in only 33% of cases (Ito t al.…”

Section: Steroid Use In Check Point Inhibitor Induced Liver Injurysupporting

confidence: 62%

Role of Corticosteroids in Drug-Induced Liver Injury. A Systematic Review

et al. 2022

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Introduction: Apart from cessation of the implicated agent leading to drug-induced liver injury (DILI), there is no standard therapy for DILI. Corticosteroids have been used in DILI, although their efficacy is unclear. Published data showed either beneficial effects or no improvement associated with steroid therapy. The aim of the current study was to perform a systematic review of the role of corticosteroids in the treatment of DILI.Methods: A search was performed in PubMed, searching for the terms: “corticosteroids” and “drug-induced liver injury”. Observation studies were included, but case reports excluded.Results: A total of 24 papers were retrieved. Most of these were observational studies on the effects of corticosteroids in moderate/severe DILI (n = 8), reports on the corticosteroid treatment in patients with drug-induced autoimmune hepatitis (DI-AIH) (n = 5), and effects of corticosteroids in drug-induced fulminant acute liver failure (ALF, n = 2). Furthermore, treatment of corticosteroids in patients with liver injury due to check point inhibitors (CPIs) was addressed in nine studies. In moderate/severe DILI, six out of eight studies suggested steroid treatment to be beneficial, whereas two studies showed negative results. All five observational studies on the effects of corticosteroids in DI-AIH showed good therapeutic response with rapid and long lasting effects after discontinuation of corticosteroids and without evidence of relapse. Steroid therapy was not associated with improved overall survival in patients with drug-induced fulminant ALF. CPIs-induced liver injury was found to improve spontaneously in 33–50% without corticosteroids, and the rate of patients who were treated responded to steroids in 33–100% (mean 72%).Conclusions: The majority of studies analyzing the effects of corticosteroids in moderate/severe DILI have demonstrated beneficial effects. However, this was not the case in drug-induced fulminant ALF. Patients with DI-AIH had an excellent response to corticosteroids. The majority of those with CPIs-induced liver injury responded to corticosteroids; however, patients without treatment usually recovered spontaneously. The observational design and comparison with historical controls in these studies makes it very difficult to draw conclusions on the efficacy of corticosteroids in DILI. Therefore, there is a strong need for a randomized controlled trial to properly assess the role of corticosteroids in DILI.

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“…Thus, our results fit very well to what is known. Furthermore, Kitagataya et al [ 20 ] reported an association between female sex and autoimmune hepatitis under immunotherapy. However, the underlying pathomechanism is not fully understood yet.…”

Section: Discussionmentioning

confidence: 99%

Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma

Wölffer

Battke

Schulze³

et al. 2022

Cancers

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Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies.

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Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy‐associated hepatitis in Japan

Cited by 34 publications

References 27 publications

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies

Role of Corticosteroids in Drug-Induced Liver Injury. A Systematic Review

Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma

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