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Internal Medicine & Immuno-Oncology (MedI2O), Institute for Regenerative Medicine and Biotherapy (IRMB), Saint Eloi Hospital, Montpellier University Hospital, Montpellier, France
ICI-induced hepatitis can be mixed cholestatic or hepatocellular with almost the same frequency.
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Cholestatic patterns are more frequently associated with microscopic or macroscopic biliary injury.
•
Severity according to the CTCAE classification is not correlated with hepatic severity.
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Only 23.5% of patients with ICI rechallenge had a hepatitis recurrence.
Abstract
Background and Aims
Immune checkpoint inhibitors (ICIs), have changed the landscape of cancer therapy. Liver toxicity occurs in up to 25% of patients treated with ICIs. The aim of our study was to describe the different clinical pattern of ICI-induced hepatitis and to assess their outcome.
Methods
We conducted a retrospective, observational study of patients with checkpoint inhibitor-induced liver injury (CHILI) discussed in multidisciplinary meetings between December 2018 and March 2022 in three French centers specialized in ICI toxicity management (Montpellier, Toulouse, Lyon). The hepatitis clinical pattern was analyzed by the ratio of serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) [R value = (ALT/ULN)/(ALP/ULN)] for characterization as cholestatic (R≤2), hepatocellular (R≥5), or mixed (2<R<5).
Results
We included 117 patients with CHILI, clinical pattern was hepatocellular in 38.5%, cholestatic in 36.8%, and mixed in 24.8% of patients. High-grade hepatitis severity (grade ≥ 3 according to the CTCAE system) was significantly associated with the hepatocellular hepatitis (p < 0.05). No cases of severe acute hepatitis were reported. Liver biopsy was performed in 41.9% of patients: granulomatous lesions, endothelitis or lymphocytic cholangitis were describe. Biliary stenosis occurred in 8 patients (6.8%) and was significantly more frequent in the cholestatic clinical pattern (p < 0.001). Steroids alone were mainly administered to patients with a hepatocellular clinical pattern (26.5%) and UDCA was more frequently used in the cholestatic (19.7%) versus hepatocellular or mixed clinical pattern (p < 0.001). Seventeen patients improved without any treatment. Among the 51 patients (43.6%) rechallenged with ICIs, 12 patients (23.5%) developed CHILI recurrence.
Implications for patient care and conclusion: This large cohort indicates the different clinical pattern of ICI-induced liver injury and highlights that cholestatic and hepatocellular patterns are the most frequent with different outcomes.
Lay summary
ICIs can induce hepatitis. In this retrospective series, we report 117 cases of ICI-induced hepatitis, mostly grade 3 and 4. We find a similar distribution of the different pattern of hepatitis. ICI could be resumed without systematic recurrence of hepatitis.
The authors declare no conflicts of interest related to this work.
Funding
The authors did not receive any funding for this research from agencies in the public, private, or non-profit sectors.
Data are available on request
Author contributions
LM, LH, CF, TC, ATJM: study conception and design.
LH, CF: data acquisition.
LM, LH, CF, TC, ATJM: data analysis and interpretation.
LM, LH, CF, TC, ATJM: manuscript preparation and drafting.
AZ, LH: statistical data analysis.
All authors: manuscript reviewing. All authors have approved the final manuscript submitted.
Introduction
Immune checkpoint inhibitors (ICIs) are an evolving class of anti-tumor immunotherapy drugs that have become a cornerstone for cancer treatment in the last decade by revolutionizing the prognosis of many advanced solid and hematological neoplasia
PD-1 (programmed cell death-1), its ligand PDL-1 (programmed cell death ligand-1), CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) and recently a new ICI targeting the inhibitory receptor LAG3 (lymphocyte-activation gene 3).
Unlike conventional chemotherapies that have a direct cytotoxic effect on tumor cells, ICIs aim to reverse the tumor cell-driven and immune checkpoint-mediated inhibition of antitumor cytotoxic T cell activity. However, via restoring anti-tumor immunity, ICIs can induce multisystem immune-related adverse events (irAEs) that can affect up to 90% of treated patients according to the immune checkpoint targeted and the drug combination.
Checkpoint inhibitor-induced liver injury (CHILI) develops in up to 25% of patients treated with ICIs and primarily among patients under combination therapy involving an anti-CTLA-4.
In contrast, the incidence of severe hepatitis requiring ICI discontinuation has been reported at below 5% (≥ grade 3 CHILI according to the Common Terminology Criteria for Adverse Events (CTCAE) severity classification).
(14). However, these international recommendations were based on small patient inclusions with heterogeneous hepatitis clinical pattern. In addition, some case series studies have shown that 37.5–50% of patients with severe acute hepatitis can improve without treatment with corticosteroids
(15). In the case of corticosteroid-resistant hepatitis, many agents have been studied and appear to be effective: mycophenolate mofetil (MMF), azathioprine, ciclosporin, tacrolimus, and anti-thymocyte globulin. Nonetheless, data remains scarce regarding the benefit-risk balance in the context of cancer.
Immune-mediated sclerosing cholangitis has been more recently recognized as a secondary sclerosing cholangitis induced by ICIs
Moreover, a case series study has shown that patients with severe steroid-resistant cholestatic hepatitis, induced by anti-PD-1, may benefit from ursodeoxycholic acid (UDCA) treatment.
to date there is still a lack of data for the official recommendation of ruling out ICI rechallenge following CHILI.
Overall, there is great heterogeneity in the clinical presentation, evolution, and outcomes of CHILI (with or without treatment with steroids) as well as a lack of up-to-date recommendations for ICI rechallenge in daily practice. Therefore, we collected a large number of cases having developed CHILI to evaluate the clinical characteristics and evolution of CHILI, as well as response to treatment and risk of recurrence after rechallenge according to the clinical pattern of drug-induced liver injury (DILI): cholestatic, hepatocellular, or mixed.
Methods
Patients and data collection
We conducted a retrospective study of patients with CHILI discussed during multidisciplinary meetings between December 2018 and March 2022 in three French university centers specialized in ICI toxicity (Montpellier, Toulouse, and Lyon). Inclusion criteria were i) patients with previous normal liver tests (defined as normal transaminase and bilirubin levels); ii) ICI-treated; iii) having developed a clinical presentation of CHILI after ruling out other causes of hepatitis. Patients with underlying liver disease but with normal baseline liver tests were included for study. CHILI-related data were collected at diagnosis, after weeks 1, 2 and 4, and then weekly until recovery from hepatitis. Data regarding cancer, treatment of CHILI, and ICI rechallenge were also collected.
Characterization of the hepatitis
Diagnosis of CHILI was defined according to CTCAEv5 criteria as patients enrolled presented with normal baseline liver tests. CHILI was defined by elevations in alanine aminotransferase (ALT) > 3-fold the upper limit of normal (ULN) (CTCAE grade 1), ALT > 3 to 5-fold the ULN (CTCAE grade 2), ALT > 5 to 20-fold the ULN (CTCAE grade 3), or ALT > 20-fold the ULN (CTCAE grade 4) in subjects with normal previous liver tests (defined as normal transaminase and bilirubin levels).
The Drug-Induced Liver Injury Network (DILIN) score was also used for grading liver injury severity as mild, moderate, moderate-to-severe, severe, or fatal according to the presence of jaundice, international normalized ratio (INR) >1.5, hospitalization, liver or other organ failure, liver transplant, or death.
All patients were referred to the liver unit and an extensive work-up was carried out to rule out other causes of liver enzyme abnormalities, including viral hepatitis, autoimmune disease, cancer progression, vascular complications, or other potential treatments causing DILI. Liver imaging (ultrasound, CT, or MRI) was systematically performed. Liver biopsy was carried out at the discretion of the referring physician. The Roussel Uclaf Causality Assessment Method (RUCAM) was used to assess the causality of CHILI diagnosis after ICI treatment; a RUCAM score ≥ 5 was retained for a positive diagnosis of CHILI
Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries.
(22). The hepatitis pattern was analyzed by the serum ALT and ALP ratio [R value = (ALT/ULN)/(ALP/ULN), and categorized as cholestatic (R≤2), hepatocellular (R≥5), or mixed (2<R<5).
Statistical analysis
Descriptive statistics are presented as medians (ranges) for quantitative variables and frequencies (percentages) for qualitative variables. The Wilcoxon rank-sum test was applied for comparing the distribution of continuous variables and the Chi-squared test (or Fisher’s exact test when appropriate) was used to test for association between categorical variables. Data were statistically analyzed by two-way analysis of variance (ANOVA). A p-value <0.05 was considered statistically significant and all statistical tests were two-sided. All statistical analyzes were performed using the SPSS software version 28.0 (IBM Corporation, Armonk, NY). The study was approved by the local Research Ethics Committee (IRB ID 202100908).
Results
Patient baseline characteristics
Among the patients discussed during multidisciplinary meetings in Montpellier (n=479), Toulouse (n=329), and Lyon (n=250) between December 2018 and March 2022 for ICI toxicity, 145 patients had abnormal liver tests. After exclusion of 28 patients (4 for HEV infection), 117 patients with CHILI were included for study (Figure 1).
The characteristics of the cohort are summarized in Table 1. The median age was 63 (23-89) years with a sex ratio of 1.2 (63 males, 53.8 %). Twenty-two patients had pre-existing liver disease.
Table 1Characteristics of patients with immune checkpoint-induced liver injury.
N = 117
Age at diagnosis (years), median (range)
63 (23-89)
Sex, n (%) Female Male
54 (46.2) 63 (53.8)
Medical history, n (%) Chronic alcohol consumption IGG4 mesenteric panniculitis Diabetes Liver transplant
ICIs were mostly used for treating melanoma (n= 49, 41.9%), non-small cell lung cancer and squamous cell lung carcinoma (n= 33, 28%), and renal cell carcinoma (n= 16, 13.7%). Cancer was localized (stage I-II) in 19.6% (n=23) and advanced (III-IV) in 48% (n=56) of patients. Most patients received PD-1 inhibitors (n= 104, 88.9%), either alone (n= 62, 53%) or with a CTLA-4 inhibitor (n= 42, 35.6%). The RUCAM scores were as expected in majority probable
and highly probable (≥9) (n= 110, 94%). CHILI was associated with non-hepatic irAEs in 48 patients (41%), including cutaneous (13/48, 27%), gastrointestinal (12/48, 25%), and endocrine (11/48, 22.9%) disorders.
General characteristics of CHILI
The CHILI pattern was cholestatic in 36.8% (n=43), hepatocellular in 38.5% (n=45), and mixed in 24.8% (n=29) of patients. There was no difference in sex ratio, age, cancer type, mean number of ICI infusion cycles, and mean time to onset of CHILI between these three groups (Table 2). Regarding severity, 96 patients (82.1%) were CTCAE grade ≥ 3 as shown in figure 2: grade 3 (62%, n= 73) and grade 4 (19.7%, n= 23). The DILIN severity score was mild in 72 patients (61.5%) and moderate in 45 patients (38.5%). There were no patients with acute liver failure. Severity was significantly associated with clinical pattern; CTCAE grade 4 was more frequently associated with a hepatocellular pattern (n= 18, 40%, p < 0.05). Anti-CTLA4 inhibitor-containing regimen were also significantly associated with severity; 13 patients under such regimen developed CTCAE grade 4 hepatitis (13/45 vs 9/71 for non CTLA-4-treated patients, p < 0.001). Moreover, the clinical pattern was significantly associated with the ICI used; a hepatocellular pattern was more frequent under anti-CTLA4 inhibitor-containing regimen (n= 27, 31%, p < 0.001) and a cholestatic pattern was more frequent with anti-PD-1/PDL-1 inhibitors (n = 35, 30%, p < 0.001).
Table 2Clinico-biological, histological characteristics, and treatment in the three groups of the study.
Cholestatic hepatitis n= 43 (36.8 %)
Mixed hepatitis n= 29 (24.8 %)
Hepatocellular hepatitis n= 45 (38.5 %)
p value
Age (years), mean (SD)
67.8 (13.7)
63.2 (9.9)
58.8 (14.9)
0.106
Sex, n (%) Female Male
17 (14.5) 26 (22.2)
12 (10.3) 17 (14.5)
25 (21.4) 20 (17.1)
0.269
Cancer, n (%) Lung Melanoma Renal and urothelial Other cancer
Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries.
Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: Case reports with positive rechallenge.
Data are expressed as mean (SD). The Chi-square test was used for comparison between qualitative variables and the ANOVA test and T student test used for quantitative variables.
Liver biopsy was performed in 49 patients (41.9%): 20 in the cholestatic (41%), 23 in the hepatocellular (47%), and 6 in the mixed (12%) patterns. Granulomatous lesions were similar among the three groups (p = 0.697). When comparing cholestatic and hepatocellular patterns (Supplement data table S1), endothelitis was significantly more frequent in the hepatocellular pattern (p = 0.042). Endothelitis was observed in three patients under anti-CTLA-4/anti-LAG-3-containing regimen and a specific histological lesion of fibrin ring granuloma was only observed in one patient under anti-CTLA-4 immunotherapy. Over half of the biopsies performed in the cholestatic group showed biliary injury with lymphocytic cholangitis, non-suppurative destructive or granulomatous cholangitis, and/or ductal dystrophy (figure 3). Furthermore, CT scan or MRI detected bile duct injury in 8 patients (7%) with bile duct injury being significantly associated with the cholestatic pattern (cholestatic n= 8, hepatocellular and mixed n= 0, p < 0.001). Bile duct injury was radiologically defined as the development of bile duct stenosis without obstruction after the initiation of ICI therapy (figure 3). Bile duct injury tended to be more associated with anti PD-1/PDL-1 regimen (n= 7, 88%, p = 0.254).
CHILI spontaneously resolved without any treatment in 17 patients (14.5%): 5 patients (29.4%) had CTCAE grade 2 hepatitis, 11 patients (64.7%) grade 3 hepatitis, and 1 patient (5.9%) grade 4 hepatitis. Other patients were treated with steroids alone (n= 62, 53%), associated with UDCA (n= 31, 26.5%), or with UDCA alone (n= 7, 6%). Steroids alone were mainly administered to patients developing a hepatocellular pattern (n=31, 26.5%, p < 0.001) and UDCA-containing regimen were more frequently used in patients developing a cholestatic pattern (n=23, 19.7%, p<0.001) (Table 2). However, 18 patients (15.3%) received second-line immunosuppressive treatment (table 3): 17 patients received MMF (94%) and 1 patient received rituximab. Immunosuppressive therapy was indicated, according to the guidelines, in case of resistance or dependence of the hepatitis to corticosteroids. CHILI severity was CTCAE grade 3 in 11 patients (61%) and grade 4 in 7 patients (39%). The CHILI pattern did not affect the likelihood of receiving second-line treatment (p = 0.306).
Table 3Main characteristics of patients with second-line immunosuppressant.
Patient
Sex, age (years); cancer, sites of metastases
Previous ICI exposure
ICI agents
Time to CHILI onset (days)
Other irAEs
CHILI phenotype, CTCAE grade
Serum autoantibody
Serum IgG (g/l)
Histology
First line treatment for CHILI
Second-line treatment, time from CHILI (days)
Time until resolution to grade 1 (days)
1
M, 49; melanoma, lymph node
No
Combo ipilimumab + nivolumab
20
Vitiligo, thyroiditis
Cholestatic, grade 3
ANA 1/320, ASMA negative
6.84
interface hepatitis, eosinophilia, fibrin ring granulomas
Checkpoint inhibitor at rechallenge, n (%) Anti-PD-1 Anti-PDL-1 Anti-PD-1 + anti-CTLA-4
10 (21.7) 0 1 (2.2)
33 (71.8) 1 (2.2) 1 (2.2)
0.258
Simultaneous treatment, n (%)
7 (17.5)
28 (70)
0.316
Cancer status (RECIST 1.1), n (%) Progressive disease Stable disease Partial response Complete response
2 (4.3) 3 (6.5) 5 (10.9) 1 (2.2)
11 (23.9) 3 (6.5) 12 (26.1) 5 (10.9)
0.570
Other irAEs, n (%)
1 (8.3)
0
0.640
Data are expressed as mean (SD). The Chi-square test was used for comparison between qualitative variables and the ANOVA test and T student test used for quantitative variables.
The mean time until resolution of the hepatitis was similar among the three patterns (p = 0.356). This delay was significantly longer among patients with bile duct injury (17.7 weeks ±3.8, p < 0.001) compared to without bile duct injury (7.2 weeks ±6.4). The type of cancer (p=0.026), the presence of macroscopic bile duct injury (p=0.021), and the need for second-line immunosuppressive therapy (p=0.030) were significantly associated with the resolution of hepatitis (Figure 4).
Figure 4Hepatitis resolution estimated using Kaplan-Meyer method
Mean time until hepatitis resolution was significantly longer among patients who underwent second-line treatment (14.1 weeks vs 7.4 weeks, p = 0.035) and significantly shorter among untreated patients (23.2 days vs 63.8 days, p = 0.007) compared to first-line only treated patients.
All patients recovered after second-line treatment and no patients developed liver failure. After a median follow-up of 48.6 (1.6–228.6) weeks, no CHILI-related deaths were reported but 25 patients (22%) died due to cancer progression.
Rechallenge with ICI and recurrence of CHILI (table 4)
Fifty-one patients (43.6%) underwent ICI rechallenge, including 37 patients with CTCAE grade ≥ 3 hepatitis. The same ICI was reintroduced for 31 patients (31/51, 60,8%) and mainly by monotherapy (49/51, 96,1%). Two patients (CTCAE grade 2 and 3) were rechallenged with combination therapy (nivolumab/ipilimumab) mainly due to their young age and partial oncological response. At the time of rechallenge, treatment for CHILI was continued in 35 patients: low-dose steroid (5-15 mg of prednisone or budesonide) in 26 patients, steroid and UDCA in 3 patients, UDCA only in 5 patients, and MMF in 1 patient. Recurrence of CHILI occurred after rechallenge in 12 patients (12/51, 23.5%). Severity of CHILI recurrence was CTCAE grade 2 in 4 patients (4/12, 33.3%), grade 3 in 5 patients (5/12, 41.7%), and grade 4 in 3 patients (3/12, 25%). The former CHILI pattern did not affect the likelihood of CHILI recurrence (p = 0.651) and the CHILI recurrence rate was similar among patients rechallenged with anti-PD-1/PDL-1 or anti-CTLA-4-containing regimens. The rate of patients with significant (titers ≥ 1:160) antinuclear antibodies (ANA) (p = 0.581) and anti-smooth muscle antibodies (ASMA) (p = 0.390) was similar between patients with and without recurrence. Previous biliary injury was significantly associated to the likelihood of recurrence (30.8%, p = 0.009). Among patients with recurrence of CHILI, 7 patients (7/12, 58.3%) underwent ICI rechallenge with steroids only (4/7, 57.1%), UDCA only (1/7, 14.3%), or steroids with UDCA (2/7, 28.6%). ICI rechallenge containing steroids did not modify the risk of CHILI recurrence (p = 0.316). Overall, 1 patient (1/51, 2%) developed a different irAE after ICI rechallenge (immune-related hemolytic anemia) and 19 patients had recurrence of their previous irAE (19/51, 37.3%) (table S6).
Discussion
This retrospective, observational study describes a cohort of 117 patients with CHILI, including 96 patients with CTCAE grade ≥ 3 hepatitis. Using the ratio R (ALAT/ULN)/(PAL/ULN), as used in other forms of DILI, we found that CHILI develops with various clinical pattern: cholestatic, hepatocellular, and mixed.
European Association for the Study of the Liver Electronic address: [email protected], Clinical Practice Guideline Panel: Chair:, Panel members, EASL Governing Board representative: EASL Clinical Practice Guidelines: Drug-induced liver injury.
In this study, cholestatic (36.8%) and hepatocellular (38.5%) patterns presented at approximately the same frequency. The hepatocellular pattern was significantly associated with hepatitis severity and anti-CTLA-4 inhibitor-containing regimen. In contrast, the cholestatic pattern was associated with microscopic biliary injury and anti-PD-(L)-1 inhibitor regimen.
Among the cholestatic group, eight patients had macroscopic bile duct injury with image-detected dilatation or stenosis. These forms of secondary sclerosing cholangitis have already been reported in the literature
In our study, all the patients with macroscopic biliary injury had the cholestatic pattern. These results support that radiological assessment is relevant for evaluating macroscopic bile duct injury, especially in patients with cholestatic CHILI. All patients with bile duct injury had been treated with anti PD(L)-1-containing regimen alone, and not with anti-CTL-4 alone as reported by Takinami et al. in their case series study.
The authors showed that CD8+ T cell-derived IL-17 induced the expression of PDL-1 on antigen-presenting cholangiocytes and limited the expansion of self-reactive T cells in cholangitis. PDL-1 presented by antigen-presenting cells is well known to inhibit T cell proliferation after binding to the PD-1 receptor, and cholangiocytes have been previously described to upregulate the expression of PDL-1 in vitro, protecting themselves by reducing CD8+ T cell cytotoxicity. Thus, it can be assumed that anti-PD(L)-1 can induce cholangitis by promoting CD8+ T cell cytotoxicity in cholangiocytes.
Interestingly, IgG-4-related disease, a cause of secondary sclerosing cholangitis, has also been reported in association with cancer and could be a novel paraneoplastic entity. Recently, a few cases of IgG-4-related disease related to pancreatitis, pleural involvement, and cholangitis have been reported
In our patient cohort, only one patient with severe interstitial pneumonia and refractory cholangitis had histological features fulfilling the criteria of IgG-4-related disease. We thus decided to treat this patient with rituximab and the outcome was complete resolution of both aforementioned irAEs. We think clinicians should be aware of this peculiar association and thus consider measuring serum IgG-4 levels and investigate IgG-4 positive staining in cases of ICI-induced cholangitis with lymphoplasmacytic infiltrates and biliary duct involvement.
Liver biopsy was performed in CTCAE grade ≥ 2 hepatitis in our study, as recommended, and at the discretion of the referring physicians in the university hospital centers. Liver biopsy analysis was available for 49 patients in our cohort. Endothelitis was significantly associated with the hepatocellular pattern, whereas granulomatous hepatitis developed in all patterns and was not exclusively associated with anti-CTLA-4-containing regimen in contrary to first reports in the literature.
However, our study suggests that endotheliitis could be associated with anti-LAG3-induced liver injury. Biliary injury occurred in all patterns, but was significantly more frequent in the cholestatic pattern with primary biliary cholangitis-like biliary injury, such as lymphocytic cholangitis and non-suppurative destructive or granulomatous cholangitis. These results are consistent with those from Cohen J et al. finding an association between the cholestatic pattern and histologic biliary duct injury.
This correlation between biological pattern and histology could therefore limit the need of performing routine liver biopsies in these patients. Instead, liver biopsy could be reserved for cases evoking differential diagnosis or cases with aggravation despite optimal treatment.
Another important finding from this study is the discrepancy between the grade of hepatitis according to CTCAE system versus the DILIN score. While the majority of CHILI were CTCAE grade ≥ 3 in our study, none of the patients evoked criteria of severe hepatitis, required transplantation, or died. The CTCAE classification does not correlate with liver function and should not be used alone to assess the severity of hepatitis.
Regarding treatment in this study, 79.5% of patients were treated with steroid-containing regimen and 14.5% of patients with CHILI spontaneously recovered without any treatment, even patients with high-grade hepatitis (10.3%). This evolution has already been reported by several teams among 38–50% of patients
(15). In our study, untreated hepatitis improved significantly faster than treated hepatitis (23.2 versus 63.8 days, p = 0.007). This faster improvement could thus explain the non-implementation of treatment for some patients. Additionally, due to the covid pandemic and resulting non-covid, unscheduled admissions, many patients improved before liver biopsy and without any treatment; but this was only after ICI discontinuation.
Consensus guidelines recommend treatment of 1-2 mg/kg/day methylprednisolone in high-grade hepatitis
(14). Recently, Li et al. showed that treatment with 1 mg/kg/day methylprednisolone in high-grade CHILI provides similar hepatitis outcomes and reduces the risk of steroid-related complications in comparison with higher dose regimens.
Here our results support these findings and favor lower and delayed steroid therapy to allow spontaneous resolution in some cases and therefore reduce steroid-related adverse events
High‐dose glucocorticoids for the treatment of ipilimumab‐induced hypophysitis is associated with reduced survival in patients with melanoma - Faje - 2018 - Cancer - Wiley Online Library [Internet]. [cited 2022 Aug 17]. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.31629
Seven patients were treated with UDCA alone in our cohort and these patients were mainly with cholestatic or mixed patterns. The indication of UDCA for treatment of CHILI is not defined and recommendations are only based on severity according to CTCAE and do not consider the hepatitis pattern
European Association for the Study of the Liver Electronic address: [email protected], European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis.
We report 15.3% of patients (n=18) requiring second-line treatment. MMF was administered mainly in second-line treatment with a mean delay of 14.1 weeks for hepatitis resolution. MMF is a purine antagonist that inhibits the proliferation of lymphocytes infiltrating the liver and is considered as a first-line treatment option for corticosteroid-resistant CHILI in clinical guidelines (without randomized trial evidence).
Different second-line treatments have been reported (azathioprine, tacrolimus, ciclosporin, infliximab, rituximab) but there is no consensus. Only a few cases of steroid-resistant hepatitis requiring second-line immunosuppression have been reported in the literature.
Our study highlights the possibility of ICI rechallenge. We report ICI rechallenge in 43.6% of patients and this was mostly with anti PD(L)-1 monotherapy (96.1%). Incriminated treatment rechallenge is generally contraindicated in DILI given the recurrence risk of severe forms.
European Association for the Study of the Liver Electronic address: [email protected], Clinical Practice Guideline Panel: Chair:, Panel members, EASL Governing Board representative: EASL Clinical Practice Guidelines: Drug-induced liver injury.
With ICI there is a potential risk of severe hepatitis in case of recurrence, however in the oncological context, the benefit is often in favor of resuming ICI. Here, recurrence after rechallenge did not appear to be systematic; 23.5% of patients developed recurrent CHILI with ranging severity. Moreover, ICI rechallenge was even possible after severe hepatitis (CTCAE grade 3–4) among 31.6% of patients without an increased rate of CHILI recurrence. International guidelines recommend permanent ICI discontinuation for CTCAE ≥ grade 3 hepatitis.
Yet, many of these patients could in fact benefit from ICI maintenance. These data are consistent with previous studies reporting between 25.8% and 35% of hepatitis recurrence after ICI rechallenge
In our study, only one patient (2%) presented a different and non-hepatic irAE after ICI rechallenge; this is inconsistent with literature reporting up to 65.2% of different irAEs after ICI rechallenge.
This difference could be explained by the collection of data on irAEs after ICI rechallenge in our study, which was only collected in patients with CHILI recurrence and perhaps during a shorter follow-up time. In our study, treatment with steroids or UDCA was still ongoing at the time of rechallenge in 68.6% of patients. Finally, neither the type of previous CHILI treatment nor the continuation of CHILI treatment after rechallenge affected the likelihood of CHILI recurrence.
We acknowledge some limitations to our study. Firstly, this is a retrospective study with the known biases related to this type of study. Secondly, the pathologists were different among the three different centers with no centralized tissue slide reading. To limit this bias, liver biopsy interpretation guidelines were validated by pathologists especially for this study (table S7). Moreover, none of the patients included had a history of autoimmune disease prior to initiation of immunotherapy and there were no cases of liver metastasis after inclusion; two factors which would have increased the risk of recurrence. Finally, there is likely an over-representation of CTCAE grade ≥ 3 CHILI compared to grade 1 and 2 given patient recruitment was based on discussions requiring multidisciplinary meetings.
Despite these limitations inherent to the retrospective design of our study, this work highlights the importance of separating CHILI into two different but equally frequent patterns (i.e. cholestatic and hepatocellular) with different outcomes. Characterization of the hepatitis pattern could also guide the treatment of CHILI: steroids +/- UDCA or UDCA alone. Further randomized studies should prospectively validate these findings and clarify the place of UDCA in cholestatic CHILI. Moreover, the possibility of a spontaneous favorable evolution in approximately 15% of patients and the feasibility of ICI rechallenge even after CTCAE grade ≥ 3 hepatitis are of particular value. Some patients with high-grade hepatitis may only have a favorable course by discontinuing ICI; immune-like inflammation is often transient without triggering a genuine autoimmune disease, in contradiction to what has been demonstrated by arthromuscular irAEs.
EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.
Future studies should focus on identifying the predictive factors of spontaneous recovery.
In conclusion, we report the first large study showing different clinical pattern of CHILI. The cholestatic pattern was as frequent as the hepatocellular pattern and this should lead to the consideration of remodeling current CHILI treatment recommendations. We also confirm that ICI rechallenge can be successful without having yet identified the predictive factors for recurrence.
Appendix A. Supplementary data
The following is/are the supplementary data to this article:
Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries.
Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: Case reports with positive rechallenge.
High‐dose glucocorticoids for the treatment of ipilimumab‐induced hypophysitis is associated with reduced survival in patients with melanoma - Faje - 2018 - Cancer - Wiley Online Library [Internet]. [cited 2022 Aug 17]. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.31629
Electronic address: [email protected], European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis.
EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.
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