A pharmacovigilance study of immune checkpoint inhibitor-associated cholangitis using the Food and Drug Administration adverse event reporting system

A pharmacovigilance study of immune checkpoint inhibitor-associated cholangitis using the Food and Drug Administration adverse event reporting system | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A pharmacovigilance study of immune checkpoint inhibitor-associated cholangitis using the Food and Drug Administration adverse event reporting system Haowen Tan, Xuan Ou, Ying Chen, Weiwei Lan, Luping Luo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7185162/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Immune checkpoint inhibitor (ICI)-associated cholangitis is a rare immune-related adverse event (irAE). However, large-scale clinical studies specifically investigating this toxicity are still lacking. This study aimed to describe ICI-associated cholangitis reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Methods Reports of irAEs were extracted from the FAERS database (Q1 2011 to Q4 2024). Cases of ICI-associated cholangitis were identified using the following Preferred Terms from the Medical Dictionary for Regulatory Activities (version 27.1): “cholangitis”, “sclerosing cholangitis”, and “immune-mediated cholangitis”. Reporting odds ratio (ROR) method was performed to evaluate the association between cholangitis and different ICI therapies. Additionally, the clinical features of ICI-associated cholangitis were characterized, and the time-to-onset (TTO) of ICI-associated cholangitis was assessed. Results A total of 1,102 patients with ICI-associated cholangitis were identified. Male patients (n = 628, 56.99%) outnumbered females (n = 334, 30.31%). Most patients were aged ≥ 65 years (n = 540, 49.00%) and from Japan (n = 817, 74.14%). Hospitalization (n = 454, 41.20%) was the most frequent clinical outcome. Programmed cell death protein 1 inhibitors showed the strongest risk association (ROR = 24.65, 95% confidence interval [CI]: 22.84–26.59), followed by programmed death-ligand 1 inhibitors (ROR = 19.03, 95% CI: 16.41–22.08). In contrast, cytotoxic T-lymphocyte-associated protein 4 inhibitors demonstrated no significant association (ROR = 2.08, 95% CI: 0.93–4.64). The median TTO was 77 days (interquartile range: 31–164 days). Conclusion ICI-associated cholangitis represents a rare but clinically significant irAE. This study elucidates distinct risk profiles across ICI classes and characterizes the clinical features of this toxicity, providing unique insights to inform clinical management. cholangitis data mining FAERS immune checkpoint inhibitors pharmacovigilance Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Immune checkpoint inhibitors (ICIs), representing a revolutionary breakthrough in cancer therapeutics, have emerged as a critical pillar of modern oncology. By blocking immune checkpoints, these agents disrupt inhibitory signals of T-cell activation, thereby allowing tumor-reactive T cells to overcome immune suppression and elicit an effective antitumor immune response.[ 1 , 2 , 3 ] Since the initial approval of the first ICI in 2011, the United States Food and Drug Administration (FDA) has subsequently authorized multiple classes of ICIs, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) inhibitors, and programmed death-ligand 1 (PD-L1) inhibitors. These agents have exhibited remarkable clinical efficacy across multiple malignancies, including melanoma, non-small cell lung cancer, and renal cell carcinoma, demonstrating not only significant improvements in overall survival outcomes but also sustained clinical benefits for patients. [ 4 , 5 , 6 ] However, while ICIs augment antitumor immunity, they may also induce immune-mediated attacks on self-tissues, resulting in immune-associated adverse events (irAEs). IrAEs can affect multiple organ systems, including the gastrointestinal, endocrine, respiratory, nervous, integumentary, and cardiovascular systems.[ 7 , 8 ] The liver is also one of the primary target organs frequently affected by immune dysregulation during ICIs therapy, with reported hepatotoxicity incidence rates ranging from 5–30%.[ 9 ] Historically, ICI-induced hepatotoxicity primarily manifested as immune-mediated hepatitis. However, recent studies have identified the intrahepatic and extrahepatic bile ducts as additional targets of immune attack, leading to immune-mediated cholangitis. This phenomenon poses significant challenges for clinical diagnosis and treatment. Previous studies on ICI-associated cholangitis have been largely confined to case reports and small single-center analyses, [ 10 , 11 , 12 , 13 ] and large-scale clinical studies specifically investigating this immune-mediated biliary toxicity are still lacking. Consequently, urgent investigation is needed to address this knowledge gap and inform clinical decision-making. The FDA Adverse Event Reporting System (FAERS), an international pharmacovigilance database, has amassed more than 10 million spontaneous reports of medication-related adverse events (AEs), serving as a vital resource for drug safety research. In recent years, many studies have utilized this database to investigate irAEs, with particular progress achieved in identifying and characterizing rare irAEs. [ 14 , 15 , 16 ] This study aimed to investigate ICI-associated cholangitis through systematic analysis of case reports from the FAERS database. The objectives of this study were threefold: (1) to characterize the epidemiology of this rare irAE, (2) to quantify differential risk associations among distinct ICI classes, and (3) to analyze time-to-onset (TTO) of this irAE. Materials and Methods Data collection and processing The FAERS database is updated quarterly and is publicly accessible at: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. This study utilized 56 quarterly ASCII-formatted data files spanning Q1 2011 through Q4 2024. The data files comprise seven distinct subfiles: DEMO (demographic characteristics), DRUG (drug usage information), REAC (adverse events), OUTC (clinical outcomes), RPSR (reporting sources), THER (treatment start and end dates), and INDI (indications for drugs). The AE report data across seven subfiles are interlinked through identifiers such as CASEID, FDA_DT and PRIMARYID, establishing a complete relational data structure in the FAERS database architecture. Following the FDA-recommended deduplication procedures, only the record with the most recent FDA_DT value is retained for reports sharing identical CASEIDs. When both CASEID and FDA_DT values are identical, the record with the highest PRIMARYID is selected as the final entry. Data processing was performed using R software (https:// www.r-project.org/, version 4.3.1). This study did not require institutional review board approval because it met the Department of Health and Human Services regulations exemption from the Office for Protection from Research Risks [17]. Data mining The target drugs in this study were ten FDA-approved ICIs: pembrolizumab, nivolumab, cemiplimab, dostarlimab, toripalimab, atezolizumab, durvalumab, avelumab, ipilimumab, and tremelimumab. A search was conducted in DrugBank (https://go.drugbank.com/) to identify all brand and generic names of the target ICIs. Data were then extracted from the FAERS database using all relevant search terms, including both generic and brand names for these 10 agents (see Supplementary Table 1 for details). Meanwhile, the Medical Dictionary for Regulatory Activities, Version 27.1 (https://www.meddra.org/) was consulted to select three Preferred Terms (PTs) for defining the target AE-cholangitis, including: “cholangitis” (PT code 10008604), “sclerosing cholangitis” (PT code 10008609), and “immune-mediated cholangitis” (PT code 10083406). Additionally, to avoid potential confounding effects from biliary tract malignancies on study outcomes, patients with these indications were excluded (see Supplementary Table 2 for details). Per FAERS reporting standards, drugs are classified as “primary suspect (PS)”, “secondary suspect”, “concomitant”, or “interacting”. To strengthen the causal association between the target drugs and the target AE, only PS drugs were included in this study. Moreover, monotherapy was defined as administration of a single ICI designated as PS, with no other ICIs reported in the same case. Combination therapy was defined as concurrent administration of CTLA-4 and PD-1 or PD-L1 inhibitors, with one agent designated as PS and the other as secondary suspect, concomitant, or interacting. Disproportionality analysis Disproportionality analysis based on 2×2 contingency table (Supplementary Table 3) is routinely used in pharmacovigilance studies to assess potential safety signals between drugs and AEs. In this study, the reporting odds ratio (ROR) [18] from this disproportionality analysis method was employed to evaluate potential risks between ICI therapies and cholangitis. ROR=(a/c)(b/d)=ad/bc, and 95% confidence interval (CI)= . A potential risk signal is considered significant when the number of cases (a) exceeds 3, and the lower limit of the 95% CI for the ROR is greater than 1. Furthermore, higher ROR values indicate stronger associations between the target drug and the target AE. TTO analysis of the occurrence of ICI-associated cholangitis TTO was defined as the interval between the initiation date of ICIs and the occurrence of cholangitis. To ensure data accuracy, only reports with complete TTO information were analyzed. Considering ICI-associated cholangitis resulted from immune system activation (a process requiring several days for effector T-cell expansion [19]), a plausible temporal sequence was defined as >7 days following initiation of an ICI in this study. This definition aligned with established evidence that irAEs typically emerged within weeks to months after treatment initiation. [7] TTO characteristics were evaluated using median values, interquartile ranges (IQR), and the shape parameter β of the Weibull distribution. [20,21] When the shape parameter β was <1 and its 95% CI was lower than 1, the hazard was considered to have decreased over time (early failure type); when the shape parameter β was equal to or nearly 1 and its 95% CI included the value 1, the hazard was estimated to constantly occur over time (random failure type); and when the shape parameter β was >1 and its 95% CI excluded the value 1, the hazard was considered to increase over time (wear-out failure type). [22] The Kaplan–Meier method was used to estimate the event-free probabilities for the TTO of ICI-associated cholangitis. Mann-Whitney U test was employed to compare the median TTO across demographic subgroups (age, gender). Additionally, immune-mediated hepatitis (PT code: 10078962) was selectedas a control group to further investigate the TTO characteristics of ICI-associated cholangitis. A statistically significant difference was shown when P was lower than 0.05. Results Results of data mining for ICI-associated cholangitis in the FAERS database From the FAERS database, a total of 19,348,490 records spanning Q1 2011 through Q4 2024 were extracted. After deduplication, 16,564,754 records remained, including 456,846 documented irAEs involving 171,483 unique patients. Based on predefined inclusion and exclusion criteria, 1,102 cases of ICI-associated cholangitis were ultimately retained. The procedure of data mining and processing for ICI-associated cholangitis is illustrated in Fig. 1 . An overview of the total number of ICI-associated cholangitis cases is presented in Fig. 2 . Since 2012, the FAERS database has documented cases of ICI-associated cholangitis. With expanding clinical use of ICIs, reported cases progressively increased, peaking in 2024. Although ICI-associated cholangitis represents a relatively small proportion (6.90%) of all hepatobiliary AEs, it remains a clinically significant irAE that warrants attention. Clinical characteristics of ICI-associated cholangitis After excluding cases with unspecified gender (n = 140), male patients (n = 628, 56.99%) outnumbered female patients (n = 334, 30.31%). Among patients with available age data, those aged ≥ 65 years constituted the majority (n = 540, 49.00%). The most frequent indications for ICI therapy were lung cancer (n = 444), followed by renal cell carcinoma (n = 90), and skin cancer (n = 88). Hospitalization was the most frequent clinical outcome (n = 454, 41.20%), while death represented an important clinical outcome (n = 188, 17.06%). Additionally, the majority of reports in this study originated from Japan (n = 817, 74.14%). Healthcare professionals constituted the primary reporting source, accounting for 989 cases (89.75%). Figure 3 provides further details on the clinical characteristics of ICI-associated cholangitis. Disproportionality analysis of ICI-associated cholangitis under various treatment strategies The findings showed differential risk associations for developing cholangitis among different ICI therapeutic strategies. Among monotherapy regimens, PD-1 inhibitors showed the strongest risk association (ROR = 24.65, 95% CI: 22.84–26.59), followed by PD-L1 inhibitors (ROR = 19.03, 95% CI: 16.41–22.08). In contrast, CTLA-4 inhibitors demonstrated no significant association (ROR = 2.08, 95% CI: 0.93–4.64). Specifically, three PD-1 inhibitor monotherapies (nivolumab, pembrolizumab, and cemiplimab) and three PD-L1 inhibitor monotherapies (atezolizumab, durvalumab, and avelumab) demonstrated significant risk signals. Among these, nivolumab (ROR = 28.17, 95% CI: 25.52–31.10) and atezolizumab (ROR = 22.22, 95% CI: 18.85–26.19) exhibited the highest risk associations within their respective inhibitor classes. Among combination therapies, three distinct ICI regimens generated significant risk signals. The durvalumab-tremelimumab combination demonstrated the strongest association (ROR = 37.22, 95%CI: 23.97–57.79). Figure 4 illustrates the comparative risk association profiles across all treatment strategies. TTO for ICI-associated cholangitis Meeting inclusion criteria, 395 patients with ICI-associated cholangitis were identified for TTO analysis. The median TTO was 77 days (IQR: 31–164 days). The Weibull distribution shape parameter (β) was 0.96 (95% CI: 0.89–1.02), indicating a random failure type in the TTO of ICI-associated cholangitis. Subgroup analysis revealed significantly longer median TTO in patients aged ≥ 65 years compared to those aged 18–<65 years (P = 0.026). No statistically significant difference in TTO was observed between male and female patients (P = 0.62). Additionally, TTO data were collected from 257 cases of ICI-mediated hepatitis. Comparative analysis showed that ICI-associated cholangitis had significantly delayed onset versus ICI-mediated hepatitis (P < 0.001). Figure 5 provides additional detailed information on the TTO of ICI-associated cholangitis. Discussion Since ICI-associated cholangitis is a rare irAE, its low incidence presents significant challenges for systematic investigation. The current study systematically evaluates ICI-associated cholangitis using the FAERS database, assembling the largest global case series and generating essential new insights into this toxicity. This study revealed that the first reported case of ICI-associated cholangitis was documented in the FAERS database in 2012, demonstrating the system’s capacity for the early safety signal detection and its critical role in global pharmacovigilance. Since 2017, there has been a marked increase in reports of ICI-associated cholangitis, with an overall upward trend in case numbers year over year. This observed trend may be primarily attributed to two key factors. First, since 2017, published case reports [10,11,23] have documented ICI-associated cholangitis, significantly improving clinical recognition of this condition. This enhanced awareness has facilitated identification and reporting of cases that might otherwise have been missed. Second, the expanding clinical indications for ICIs have led to their broader therapeutic application, resulting in a substantially larger patient population receiving these agents. Consequently, the increased exposure is associated with higher absolute numbers of reported cholangitis cases Current study found that among patients with ICI-associated cholangitis, males (56.99%) were more commonly affected than females (30.31%). This sex disparity reflects established oncological trends.[24] The higher cancer burden in males leads to greater ICI use and, consequently, more reported cases. Additionally, this study showed that ICI-associated cholangitis occurred most frequently in patients aged ≥65 years. This age distribution was similar to that reported in previous cases of nivolumab-induced cholangitis, with a median age of 69 years.[25] These findings underscore the need for enhanced vigilance in monitoring for ICI-associated cholangitis among elderly patients receiving ICIs, particularly those aged ≥65 years. Prior pharmacovigilance research using the FAERS database identified Japan as the most frequent reporting country for ICI-associated hepatitis.[26] ICI-associated cholangitis, as a distinct form of immune-mediated hepatotoxicity, exhibited similar geographic distribution patterns in current study, with 74.1% (817/1,102) of cases reported from Japan. This finding was similar to the study from He et al., in which 63.2% (24/38) of nivolumab-induced cholangitis cases were from Japan.[25] There are two potential factors explaining this phenomenon. First, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) has explicitly listed sclerosing cholangitis as a clinically significant adverse reaction to PD-1/PD-L1 inhibitors, including pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab. In contrast, the FDA’s prescribing information on sclerosing cholangitis as an adverse reaction remains limited to nivolumab and durvalumab among PD-1/PD-L1 inhibitors. PMDA’s stringent and detailed regulatory policies may have increased awareness and reporting vigilance for this rare irAE among Japanese medical practitioners. Second, from a pharmacogenetic perspective, the Japanese population may have unique susceptibility to ICI-associated cholangitis. However, the possibility that the observed geographic differences arise from reporting biases cannot be excluded. Therefore, this hypothesis requires further validation through multicenter, multiethnic studies. Previous studies showed that ICI-associated cholangitis occurs most commonly with PD-1/PD-L1 inhibitors monotherapy, less commonly with combination therapy (PD-1/PD-L1 plus CTLA-4 inhibitors), and least commonly with CTLA-4 inhibitor monotherapy. [13,27,28,29,30] The findings of the current study were consistent with prior studies, demonstrating the same case distribution pattern. Furthermore, through disproportionality analysis, a hierarchical risk association profile was identified: PD-1 inhibitors (ROR=24.65, 95% CI:22.84-26.59) > PD-L1 inhibitors (ROR=19.03, 95% CI: 16.41-22.08) ≫ CTLA-4 inhibitors (ROR=2.08, 95% CI 0.93-4.64). These findings carry important clinical implications. When cholangitis develops during PD-1/PD-L1 plus CTLA-4 combination therapy, attributing causality to a specific agent has been clinically challenging. Current findings provide actionable insights for identifying the primary contributor to ICI-associated cholangitis, thereby guiding therapeutic decision-making. However, the pharmacological mechanisms underlying ICI-associated cholangitis remain incompletely understood, potentially involving dysregulated T-cell responses. Further studies are needed to elucidate the pathophysiological and pharmacodynamic mechanisms of ICI-associated cholangitis. Understanding the TTO is critical for the timely identification and diagnosis of ICI-associated cholangitis. Current study showed that, compared with ICI-mediated hepatitis, the onset of ICI-associated cholangitis occurred significantly later, suggesting a prolonged latent period. Previous studies have shown wide variations in the onset of ICI-associated cholangitis. Onoyama et al. reported a median of 5.5 treatment cycles (range: 1-27) until onset of PD-1 inhibitor-associated sclerosing cholangitis.[31] In contrast, Cho et al. described a case of delayed-onset cholecystitis with concurrent cholangitis in a non-small cell lung cancer patient after 12 months of avelumab therapy.[32] Furthermore, a French pharmacovigilance database study of 48 ICI-associated cholangitis cases found a median TTO of 5.7 months (range: 3-28.8 months).[27] In this study, the median TTO was 77 days with the broad temporal range (8-1,160 days) covering all previously reported intervals. These findings collectively underscore the wide variability in TTO for this irAE. Further analysis based on the Weibull distribution demonstrated that the TTO of ICI-associated cholangitis followed a random failure type, indicating that this irAE may occur continuously over time during ICI therapy. Given these findings, clinicians should maintain vigilance for potential symptoms of ICI-associated cholangitis (including fever, jaundice, and right upper quadrant pain) throughout the entire course of ICI therapy to enable early detection and prompt management. Suzuki et al. reported a case of a 63-year-old female patient with non-squamous cell carcinoma who developed sclerosing cholangitis after treatment with pembrolizumab.[33] Despite receiving multiple therapies, the patient experienced recurrent episodes of acute cholangitis and ultimately died 24 weeks after the onset of sclerosing cholangitis. In this study, 188 patients (17.1%) with ICI-associated cholangitis ultimately died. Although tumor progression may have contributed to some fatalities given the complexity of cancer patients' conditions, the potential severity of this rare irAE remains a significant concern. Additionally, this study found hospitalization to be the most common clinical outcome of ICI-associated cholangitis (454 cases, 41.2%). Consequently, effective management of this immune-mediated toxicity is crucial for optimizing patient outcomes. Prompt referral to a hepatologist is essential for the diagnosis and management of patients with suspected ICI-associated cholangitis. It was reported that this immune-mediated toxicity appeared to respond poorly to corticosteroids. [31] The current European Society for Medical Oncology guidelines recommend ursodeoxycholic acid for the treatment of immune-related cholangitis.[9] However, optimal treatment strategies for ICI-associated cholangitis remain unclear. Additional clinical experience is needed to establish optimal management strategies for this irAE. The FAERS database offers distinct advantages for monitoring rare AEs. However, several limitations of this study must be acknowledged. First, the FAERS database accepts AE reports submitted by healthcare professionals, consumers, and manufacturers. However, this reporting mechanism is inherently susceptible to bias, since reports from non-healthcare professionals may affect data reliability. Second, as the FAERS database relies on voluntary reporting, submitted reports often contain incomplete information, making it difficult to control for confounding factors such as patients’ baseline medical conditions and complex concomitant medications. Third, the FAERS database lacks detailed clinical documentation of AEs, preventing comprehensive characterization of ICI-associated cholangitis features including clinical manifestations, laboratory findings, and imaging features. Fourth, incidence rates of ICI-associated cholangitis cannot be derived from the FAERS database because this system relies on reported events rather than actual occurrences. The true incidence requires further investigation. Despite these limitations, this study reveals both the risk profile and clinical characteristics of ICI-associated cholangitis, advancing understanding of this rare irAE and providing critical leads for future safety investigations. In Conclusion, ICI-associated cholangitis represents a rare irAE. Current pharmacovigilance study elucidated different risk association profiles across ICI classes and characterized key clinical features, providing clinicians with helpful information for improved recognition and management of this toxicity. Nevertheless, critical knowledge gaps remain regarding the pathophysiological mechanisms, racial disparities in susceptibility, and evidence-based management approaches for ICI-associated cholangitis, necessitating further investigation. Declarations Acknowledgments The FAERS database, which was made available by the FDA, was used to conduct this study. Competing Interests The authors declare that they have no conflict of interest. Data Availability There is data available from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html). Ethics approval statement Ethics approval was not considered necessary for this study because of the nature of the study, which is a retrospective analysis of reports registered in the FAERS. Author Contributions Haowen Tan contributed to the conceptualization and design of the study and wrote the original manuscript. Xuan Ou and Ying Chen took responsibility for the collection, integrity, and accuracy of the data. Weiwei Lan contributed to data curation. Luping Luo oversaw the review and editing of the manuscript. All authors contributed to the manuscript’s revision and read and approved the submitted version. References Sharma P, Allison JP (2015) The future of immune checkpoint therapy. 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Liver Int 45:e16163. https://doi.org/10.1111/liv.16163 Onoyama T, Takeda Y, Yamashita T, et al (2020) Programmed cell death-1 inhibitor-related sclerosing cholangitis: A systematic review. World J Gastroenterol 26:353-365. https://doi.org/10.3748/wjg.v26.i3.353 Cho JH, Sun JM, Lee SH, et al (2018) Late-Onset Cholecystitis with Cholangitis after Avelumab Treatment in Non-Small Cell Lung Cancer. J Thorac Oncol 13:e34-e36. https://doi.org/10.1016/j.jtho.2017.10.007 Suzuki N, Ikeda Y, Ono M, et al (2022) Gastrointestinal: Immune-related sclerosing cholangitis with pembrolizumab: Imaging and histological features. J Gastroenterol Hepatol 37:1652. https://doi.org/10.1111/jgh.15797 Supplementary Files SupplementaryTables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7185162","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":492325771,"identity":"d8156f76-2996-44d9-9823-73ed8711777c","order_by":0,"name":"Haowen Tan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYBACAygtxyZ/+MCBDz+I12JgzC/BlnhwZg8JWhJnzuAxPszBRoQWc/bDxyQ+7viTuOF2z4fDDDwM8vxiB/BrsexJS5OcecbAeMOdsxsOF1gwGM6cnUDAYQdyzG7zthnIbjiQu+HwDB6GBIPbhLScf2N2+2+bAeOGAzkPDvOwEaPlBtAWxjYDxZkzchiI1fIs/Wdvm7ExP88xA2AgSxDhl/PJhw1+tsnJsbE3P/7w4YeNPL80AS3oQII05aNgFIyCUTAKsAMAufxLtxsxK1IAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0007-0754-3373","institution":"Wuzhou Red Cross Hospital","correspondingAuthor":true,"prefix":"","firstName":"Haowen","middleName":"","lastName":"Tan","suffix":""},{"id":492325772,"identity":"57fa3687-bcc2-4cc8-bb54-c7c565843500","order_by":1,"name":"Xuan Ou","email":"","orcid":"","institution":"Wuzhou Red Cross Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xuan","middleName":"","lastName":"Ou","suffix":""},{"id":492325773,"identity":"8d687eb8-caf6-459e-96e9-cd6b1afe1584","order_by":2,"name":"Ying Chen","email":"","orcid":"","institution":"Wuzhou Red Cross Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Chen","suffix":""},{"id":492325774,"identity":"b835a135-870a-4ab4-9803-870800d2d42c","order_by":3,"name":"Weiwei Lan","email":"","orcid":"","institution":"Wuzhou Red Cross Hospital","correspondingAuthor":false,"prefix":"","firstName":"Weiwei","middleName":"","lastName":"Lan","suffix":""},{"id":492325775,"identity":"dd0691c5-20c3-4c85-9550-bcfec8d733ae","order_by":4,"name":"Luping Luo","email":"","orcid":"https://orcid.org/0009-0001-4641-2874","institution":"Wuzhou Red Cross Hospital","correspondingAuthor":false,"prefix":"","firstName":"Luping","middleName":"","lastName":"Luo","suffix":""}],"badges":[],"createdAt":"2025-07-22 09:23:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7185162/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7185162/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88003628,"identity":"6f91a23e-c30a-45c6-9069-42b53580b3c3","added_by":"auto","created_at":"2025-07-31 10:33:04","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":111258,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the process for data mining on ICI-associated cholangitis\u003c/p\u003e\n\u003cp\u003eFootnotes:\u003c/p\u003e\n\u003cp\u003eAE: adverse events; CTLA-4: cytotoxic T-lymphocyte-associated protein; DEMO: demographic characteristics; DRUG: drug usage information; FAERS: Food and Drug Administration adverse event reporting system; ICI: immune checkpoint inhibitor; PD-1: programmed cell death 1; PD-L1: programmed cell death ligand 1; REAC: adverse events\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7185162/v1/f4df243afe01672771641127.jpg"},{"id":88003619,"identity":"3c660f81-82a9-4eb7-be5b-436917e981df","added_by":"auto","created_at":"2025-07-31 10:33:04","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":67068,"visible":true,"origin":"","legend":"\u003cp\u003eStatistical data on the occurrence of ICI-associated cholangitis from the FAERS database\u003c/p\u003e\n\u003cp\u003eFootnotes:\u003c/p\u003e\n\u003cp\u003eFAERS: Food and Drug Administration Adverse Event Reporting System; ICI: immune checkpoint inhibitor\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7185162/v1/e1ebc3b168863225e23f8e06.jpg"},{"id":88003622,"identity":"4bad3c9a-3cfd-4151-87b6-b0301a21aded","added_by":"auto","created_at":"2025-07-31 10:33:04","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":156258,"visible":true,"origin":"","legend":"\u003cp\u003eDescriptive analysis of patients with ICI-associated cholangitis\u003c/p\u003e\n\u003cp\u003eFootnotes:\u003c/p\u003e\n\u003cp\u003eICI: immune checkpoint inhibitor\u003c/p\u003e\n\u003cp\u003e(a) Distribution of patients’ sex. (b) Distribution of patients’ age. (c) Distribution of patients’ clinical outcome. (d) Distribution of cancer types among patients. The anatomical diagram on the left shows the patient’s original cancer site and the total number of cases. A darker color indicates a higher incidence of this type of tumor. The bar plot on the right shows the detailed number of cases for the patient’s original cancer sites. (e) Distribution of the reporters. (f) Distribution of cases reported by the top 5 countries.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7185162/v1/0595bd83d3eafeb997b535b4.jpg"},{"id":88005769,"identity":"afe5a22a-70fe-4135-b6e9-d234923b8972","added_by":"auto","created_at":"2025-07-31 10:49:04","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":101081,"visible":true,"origin":"","legend":"\u003cp\u003eThe results of disproportionality analysis for ICI-associated cholangitis under various treatment strategies in the FAERS database\u003c/p\u003e\n\u003cp\u003eFootnotes:\u003c/p\u003e\n\u003cp\u003eCTLA-4: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); FAERS: Food and Drug Administration Adverse Event Reporting System;ICI: immune checkpoint inhibitor; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1\u003c/p\u003e\n\u003cp\u003e† The data on PD-1 inhibitors included monotherapy results for five agents:nivolumab, pembrolizumab, cemiplimab, dostarlimab, and toripalimab.\u003c/p\u003e\n\u003cp\u003e‡ Disproportionality analysis was not performed for treatment strategies with fewer than 3 cases.\u003c/p\u003e\n\u003cp\u003e§ The data on PD-L1 inhibitors included monotherapy results for three agents: atezolizumab, durvalumab, and avelumab.\u003c/p\u003e\n\u003cp\u003e¶ The data on CTLA-4 inhibitors included monotherapy results for two agents: ipilimumab and tremelimumab.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7185162/v1/d25aa2a658c7032ca4c0a8f9.jpg"},{"id":88003623,"identity":"46bca59c-69fb-4e81-8149-d21167ce25fa","added_by":"auto","created_at":"2025-07-31 10:33:04","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":123559,"visible":true,"origin":"","legend":"\u003cp\u003eTime-to-onset analysis for ICI-associated cholangitis\u003c/p\u003e\n\u003cp\u003eFootnotes:\u003c/p\u003e\n\u003cp\u003eICI: immune checkpoint inhibitor; TTO: time-to-onset\u003c/p\u003e\n\u003cp\u003e(a) Histograms, boxplots and Weibull distribution depict the TTO distribution of ICI-associated cholangitis. (b-c) The cumulative distribution curves show the TTO of ICI-associated cholangitis in different subgroups (age and gender). Statistical tests were conducted using the nonparametric Wilcoxon rank sum test. (d)The cumulative distribution curves demonstrate the TTO for ICI­associated cholangitis versus ICI- mediated hepatitis.Statistical tests were conducted using the nonparametric Wilcoxon rank sum test.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7185162/v1/13e56bb65bf0ccb5bf658bb9.jpg"},{"id":90226956,"identity":"b0131522-3088-46cd-9f35-da50122a3e14","added_by":"auto","created_at":"2025-08-30 12:05:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1145646,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7185162/v1/1f1d28a1-8541-45d6-aca5-ccee230dc136.pdf"},{"id":88005406,"identity":"b1eef96c-0ecb-4b18-94f3-910f6b53d0ba","added_by":"auto","created_at":"2025-07-31 10:41:04","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":28169,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7185162/v1/e3dd1b716703f550d20353c2.docx"}],"financialInterests":"","formattedTitle":"A pharmacovigilance study of immune checkpoint inhibitor-associated cholangitis using the Food and Drug Administration adverse event reporting system","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmune checkpoint inhibitors (ICIs), representing a revolutionary breakthrough in cancer therapeutics, have emerged as a critical pillar of modern oncology. By blocking immune checkpoints, these agents disrupt inhibitory signals of T-cell activation, thereby allowing tumor-reactive T cells to overcome immune suppression and elicit an effective antitumor immune response.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Since the initial approval of the first ICI in 2011, the United States Food and Drug Administration (FDA) has subsequently authorized multiple classes of ICIs, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) inhibitors, and programmed death-ligand 1 (PD-L1) inhibitors. These agents have exhibited remarkable clinical efficacy across multiple malignancies, including melanoma, non-small cell lung cancer, and renal cell carcinoma, demonstrating not only significant improvements in overall survival outcomes but also sustained clinical benefits for patients. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] However, while ICIs augment antitumor immunity, they may also induce immune-mediated attacks on self-tissues, resulting in immune-associated adverse events (irAEs).\u003c/p\u003e\u003cp\u003eIrAEs can affect multiple organ systems, including the gastrointestinal, endocrine, respiratory, nervous, integumentary, and cardiovascular systems.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] The liver is also one of the primary target organs frequently affected by immune dysregulation during ICIs therapy, with reported hepatotoxicity incidence rates ranging from 5\u0026ndash;30%.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Historically, ICI-induced hepatotoxicity primarily manifested as immune-mediated hepatitis. However, recent studies have identified the intrahepatic and extrahepatic bile ducts as additional targets of immune attack, leading to immune-mediated cholangitis. This phenomenon poses significant challenges for clinical diagnosis and treatment. Previous studies on ICI-associated cholangitis have been largely confined to case reports and small single-center analyses, [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and large-scale clinical studies specifically investigating this immune-mediated biliary toxicity are still lacking. Consequently, urgent investigation is needed to address this knowledge gap and inform clinical decision-making.\u003c/p\u003e\u003cp\u003eThe FDA Adverse Event Reporting System (FAERS), an international pharmacovigilance database, has amassed more than 10\u0026nbsp;million spontaneous reports of medication-related adverse events (AEs), serving as a vital resource for drug safety research. In recent years, many studies have utilized this database to investigate irAEs, with particular progress achieved in identifying and characterizing rare irAEs. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] This study aimed to investigate ICI-associated cholangitis through systematic analysis of case reports from the FAERS database. The objectives of this study were threefold: (1) to characterize the epidemiology of this rare irAE, (2) to quantify differential risk associations among distinct ICI classes, and (3) to analyze time-to-onset (TTO) of this irAE.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003eData collection and processing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe FAERS database is updated quarterly and is publicly accessible at: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. This study utilized 56 quarterly ASCII-formatted data files spanning Q1 2011 through Q4 2024. The data files comprise seven distinct subfiles: DEMO (demographic characteristics), DRUG (drug usage information), REAC (adverse events), OUTC (clinical outcomes), RPSR (reporting sources), THER (treatment start and end dates), and INDI (indications for drugs). The AE report data across seven subfiles are interlinked through identifiers such as CASEID, FDA_DT and PRIMARYID, establishing a complete relational data structure in the FAERS database architecture. Following the FDA-recommended deduplication procedures, only the record with the most recent FDA_DT value is retained for reports sharing identical CASEIDs. When both CASEID and FDA_DT values are identical, the record with the highest PRIMARYID is selected as the final entry. Data processing was performed using R software (https:// www.r-project.org/, version 4.3.1). This study did not require institutional review board approval because it met the Department of Health and Human Services regulations exemption from the Office for Protection from Research Risks [17].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData mining\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe target drugs in this study were ten FDA-approved ICIs: pembrolizumab, nivolumab, cemiplimab, dostarlimab, toripalimab, atezolizumab, durvalumab, avelumab, ipilimumab, and tremelimumab. A search was conducted in DrugBank (https://go.drugbank.com/) to identify all brand and generic names of the target ICIs. Data were then extracted from the FAERS database using all relevant search terms, including both generic and brand names for these 10 agents (see Supplementary Table 1 for details). Meanwhile, the Medical Dictionary for Regulatory Activities, Version 27.1 (https://www.meddra.org/) was consulted to select three Preferred Terms (PTs) for defining the target AE-cholangitis, including: \u0026ldquo;cholangitis\u0026rdquo; (PT code 10008604), \u0026ldquo;sclerosing cholangitis\u0026rdquo; (PT code 10008609), and \u0026ldquo;immune-mediated cholangitis\u0026rdquo; (PT code 10083406). Additionally, to avoid potential confounding effects from biliary tract malignancies on study outcomes, patients with these indications were excluded (see Supplementary Table 2 for details).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePer FAERS reporting standards, drugs are classified as \u0026ldquo;primary suspect (PS)\u0026rdquo;, \u0026ldquo;secondary suspect\u0026rdquo;, \u0026ldquo;concomitant\u0026rdquo;, or \u0026ldquo;interacting\u0026rdquo;. To strengthen the causal association between the target drugs and the target AE, only PS drugs were included in this study. Moreover, monotherapy was defined as administration of a single ICI designated as PS, with no other ICIs reported in the same case. Combination therapy was defined as concurrent administration of CTLA-4 and PD-1 or PD-L1 inhibitors, with one agent designated as PS and the other as secondary suspect, concomitant, or interacting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisproportionality analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDisproportionality analysis based on 2\u0026times;2 contingency table (Supplementary Table 3) is routinely used in pharmacovigilance studies to assess potential safety signals between drugs and AEs. In this study, \u0026nbsp;the reporting odds ratio (ROR) [18] from this disproportionality analysis method was employed to evaluate potential risks between ICI therapies and cholangitis. ROR=(a/c)(b/d)=ad/bc, and 95% confidence interval (CI)=\u003cimg width=\"96\" height=\"35\" src=\"data:image/wmf;base64,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\" alt=\"image\"\u003e. A potential risk signal is considered significant when the number of cases (a) exceeds 3, and the lower limit of the 95% CI for the ROR is greater than 1. Furthermore, higher ROR values indicate stronger associations between the target drug and the target AE.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTTO analysis of the occurrence of ICI-associated cholangitis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTTO was defined as the interval between the initiation date of ICIs and the occurrence of cholangitis. To ensure data accuracy, only reports with complete TTO information were analyzed. Considering ICI-associated cholangitis resulted from immune system activation (a process requiring several days for effector T-cell expansion [19]), a plausible temporal sequence was defined as \u0026gt;7 days following initiation of an ICI in this study. This definition aligned with established evidence that irAEs typically emerged within weeks to months after treatment initiation. [7] TTO characteristics were evaluated using median values, interquartile ranges (IQR), and the shape parameter \u0026beta; of the Weibull distribution. [20,21] When the shape parameter \u0026beta; was \u0026lt;1 and its 95% CI was lower than 1, the hazard was considered to have decreased over time (early failure type); when the shape parameter \u0026beta; was equal to or nearly 1 and its 95% CI included the value 1, the hazard was estimated to constantly occur over time (random failure type); and when the shape parameter \u0026beta; was \u0026gt;1 and its 95% CI excluded the value 1, the hazard was considered to increase over time (wear-out failure type). [22] The Kaplan\u0026ndash;Meier method was used to estimate the event-free probabilities for the TTO of ICI-associated cholangitis. Mann-Whitney U test was employed to compare the median TTO across demographic subgroups (age, gender). Additionally, immune-mediated hepatitis (PT code: 10078962) was selectedas a control group to further investigate the TTO characteristics of ICI-associated cholangitis. A statistically significant difference was shown when P was lower than 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eResults of data mining for ICI-associated cholangitis in the FAERS database\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFrom the FAERS database, a total of 19,348,490 records spanning Q1 2011 through Q4 2024 were extracted. After deduplication, 16,564,754 records remained, including 456,846 documented irAEs involving 171,483 unique patients. Based on predefined inclusion and exclusion criteria, 1,102 cases of ICI-associated cholangitis were ultimately retained. The procedure of data mining and processing for ICI-associated cholangitis is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. An overview of the total number of ICI-associated cholangitis cases is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Since 2012, the FAERS database has documented cases of ICI-associated cholangitis. With expanding clinical use of ICIs, reported cases progressively increased, peaking in 2024. Although ICI-associated cholangitis represents a relatively small proportion (6.90%) of all hepatobiliary AEs, it remains a clinically significant irAE that warrants attention.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical characteristics of ICI-associated cholangitis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAfter excluding cases with unspecified gender (n\u0026thinsp;=\u0026thinsp;140), male patients (n\u0026thinsp;=\u0026thinsp;628, 56.99%) outnumbered female patients (n\u0026thinsp;=\u0026thinsp;334, 30.31%). Among patients with available age data, those aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years constituted the majority (n\u0026thinsp;=\u0026thinsp;540, 49.00%). The most frequent indications for ICI therapy were lung cancer (n\u0026thinsp;=\u0026thinsp;444), followed by renal cell carcinoma (n\u0026thinsp;=\u0026thinsp;90), and skin cancer (n\u0026thinsp;=\u0026thinsp;88). Hospitalization was the most frequent clinical outcome (n\u0026thinsp;=\u0026thinsp;454, 41.20%), while death represented an important clinical outcome (n\u0026thinsp;=\u0026thinsp;188, 17.06%). Additionally, the majority of reports in this study originated from Japan (n\u0026thinsp;=\u0026thinsp;817, 74.14%). Healthcare professionals constituted the primary reporting source, accounting for 989 cases (89.75%). Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e provides further details on the clinical characteristics of ICI-associated cholangitis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eDisproportionality analysis of ICI-associated cholangitis under various treatment strategies\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe findings showed differential risk associations for developing cholangitis among different ICI therapeutic strategies. Among monotherapy regimens, PD-1 inhibitors showed the strongest risk association (ROR\u0026thinsp;=\u0026thinsp;24.65, 95% CI: 22.84\u0026ndash;26.59), followed by PD-L1 inhibitors (ROR\u0026thinsp;=\u0026thinsp;19.03, 95% CI: 16.41\u0026ndash;22.08). In contrast, CTLA-4 inhibitors demonstrated no significant association (ROR\u0026thinsp;=\u0026thinsp;2.08, 95% CI: 0.93\u0026ndash;4.64). Specifically, three PD-1 inhibitor monotherapies (nivolumab, pembrolizumab, and cemiplimab) and three PD-L1 inhibitor monotherapies (atezolizumab, durvalumab, and avelumab) demonstrated significant risk signals. Among these, nivolumab (ROR\u0026thinsp;=\u0026thinsp;28.17, 95% CI: 25.52\u0026ndash;31.10) and atezolizumab (ROR\u0026thinsp;=\u0026thinsp;22.22, 95% CI: 18.85\u0026ndash;26.19) exhibited the highest risk associations within their respective inhibitor classes. Among combination therapies, three distinct ICI regimens generated significant risk signals. The durvalumab-tremelimumab combination demonstrated the strongest association (ROR\u0026thinsp;=\u0026thinsp;37.22, 95%CI: 23.97\u0026ndash;57.79). Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e illustrates the comparative risk association profiles across all treatment strategies.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTTO for ICI-associated cholangitis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMeeting inclusion criteria, 395 patients with ICI-associated cholangitis were identified for TTO analysis. The median TTO was 77 days (IQR: 31\u0026ndash;164 days). The Weibull distribution shape parameter (β) was 0.96 (95% CI: 0.89\u0026ndash;1.02), indicating a random failure type in the TTO of ICI-associated cholangitis. Subgroup analysis revealed significantly longer median TTO in patients aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years compared to those aged 18\u0026ndash;\u0026lt;65 years (P\u0026thinsp;=\u0026thinsp;0.026). No statistically significant difference in TTO was observed between male and female patients (P\u0026thinsp;=\u0026thinsp;0.62). Additionally, TTO data were collected from 257 cases of ICI-mediated hepatitis. Comparative analysis showed that ICI-associated cholangitis had significantly delayed onset versus ICI-mediated hepatitis (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Figure\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e provides additional detailed information on the TTO of ICI-associated cholangitis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSince ICI-associated cholangitis is a rare irAE, its low incidence presents significant challenges for systematic investigation. The current study systematically evaluates ICI-associated cholangitis using the FAERS database, assembling the largest global case series and generating essential new insights into this toxicity.\u003c/p\u003e\n\u003cp\u003eThis study revealed that the first reported case of ICI-associated cholangitis was documented in the FAERS database in 2012, demonstrating the system\u0026rsquo;s capacity for the early safety signal detection and its critical role in global pharmacovigilance. Since 2017, there has been a marked increase in reports of ICI-associated cholangitis, with an overall upward trend in case numbers year over year. This observed trend may be primarily attributed to two key factors. First, since 2017, published case reports [10,11,23] have documented ICI-associated cholangitis, significantly improving clinical recognition of this condition. This enhanced awareness has facilitated identification and reporting of cases that might otherwise have been missed. Second, the expanding clinical indications for ICIs have led to their broader therapeutic application, resulting in a substantially larger patient population receiving these agents. Consequently, the increased exposure is associated with higher absolute numbers of reported cholangitis cases\u003c/p\u003e\n\u003cp\u003eCurrent study found that among patients with ICI-associated cholangitis, males (56.99%) were more commonly affected than females (30.31%). This sex disparity reflects established oncological trends.[24] The higher cancer burden in males leads to greater ICI use and, consequently, more reported cases. Additionally, this study showed that ICI-associated cholangitis occurred most frequently in patients aged \u0026ge;65 years. This age distribution was similar to that reported in previous cases of nivolumab-induced cholangitis, with a median age of 69 years.[25] These findings underscore the need for enhanced vigilance in monitoring for ICI-associated cholangitis among elderly patients receiving ICIs, particularly those aged \u0026ge;65 years.\u003c/p\u003e\n\u003cp\u003ePrior pharmacovigilance research using the FAERS database identified Japan as the most frequent reporting country for ICI-associated hepatitis.[26] ICI-associated cholangitis, as a distinct form of immune-mediated hepatotoxicity, exhibited similar geographic distribution patterns in current study, with 74.1% (817/1,102) of cases reported from Japan. This finding was similar to the study from He et al., in which 63.2% (24/38) of nivolumab-induced cholangitis cases were from Japan.[25] There are two potential factors explaining this phenomenon. First, Japan\u0026rsquo;s Pharmaceuticals and Medical Devices Agency (PMDA) has explicitly listed sclerosing cholangitis as a clinically significant adverse reaction to PD-1/PD-L1 inhibitors, including pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab. In contrast, the FDA\u0026rsquo;s prescribing information on sclerosing cholangitis as an adverse reaction remains limited to nivolumab and durvalumab among PD-1/PD-L1 inhibitors. PMDA\u0026rsquo;s stringent and detailed regulatory policies may have increased awareness and reporting vigilance for this rare irAE among Japanese medical practitioners. Second, from a pharmacogenetic perspective, the Japanese population may have unique susceptibility to ICI-associated cholangitis. However, the possibility that the observed geographic differences arise from reporting biases cannot be excluded. Therefore, this hypothesis requires further validation through multicenter, multiethnic studies.\u003c/p\u003e\n\u003cp\u003ePrevious studies showed that ICI-associated cholangitis occurs most commonly with PD-1/PD-L1 inhibitors monotherapy, less commonly with combination therapy (PD-1/PD-L1 plus CTLA-4 inhibitors), and least commonly with CTLA-4 inhibitor monotherapy. [13,27,28,29,30] The findings of the current study were consistent with prior studies, demonstrating the same case distribution pattern. Furthermore, through disproportionality analysis, a hierarchical risk association profile was identified: PD-1 inhibitors (ROR=24.65, 95% CI:22.84-26.59) \u0026gt; PD-L1 inhibitors (ROR=19.03, 95% CI: 16.41-22.08) ≫ CTLA-4 inhibitors (ROR=2.08, 95% CI 0.93-4.64). These findings carry important clinical implications. When cholangitis develops during PD-1/PD-L1 plus CTLA-4 combination therapy, attributing causality to a specific agent has been clinically challenging. Current findings provide actionable insights for identifying the primary contributor to ICI-associated cholangitis, thereby guiding therapeutic decision-making. However, the pharmacological mechanisms underlying ICI-associated cholangitis remain incompletely understood, potentially involving dysregulated T-cell responses. Further studies are needed to elucidate the pathophysiological and pharmacodynamic mechanisms of ICI-associated cholangitis.\u003c/p\u003e\n\u003cp\u003eUnderstanding the TTO is critical for the timely identification and diagnosis of ICI-associated cholangitis. Current study showed that, compared with ICI-mediated hepatitis, the onset of ICI-associated cholangitis occurred significantly later, suggesting a prolonged latent period. Previous studies have shown wide variations in the onset of ICI-associated cholangitis. Onoyama et al. reported a median of 5.5 treatment cycles (range: 1-27) until onset of PD-1 inhibitor-associated sclerosing cholangitis.[31] In contrast, Cho et al. described a case of delayed-onset cholecystitis with concurrent cholangitis in a non-small cell lung cancer patient after 12 months of avelumab therapy.[32] Furthermore, a French pharmacovigilance database study of 48 ICI-associated cholangitis cases found a median TTO of 5.7 months (range: 3-28.8 months).[27] In this study, the median TTO was 77 days with the broad temporal range (8-1,160 days) covering all previously reported intervals. These findings collectively underscore the wide variability in TTO for this irAE. Further analysis based on the Weibull distribution demonstrated that the TTO of ICI-associated cholangitis followed a random failure type, indicating\u0026nbsp;that this irAE may occur continuously over time during ICI therapy. Given these findings, clinicians should maintain vigilance for potential symptoms of ICI-associated cholangitis (including fever, jaundice, and right upper quadrant pain) throughout the entire course of ICI therapy to enable early detection and prompt management.\u003c/p\u003e\n\u003cp\u003eSuzuki et al. reported a case of a 63-year-old female patient with non-squamous cell carcinoma who developed sclerosing cholangitis after treatment with pembrolizumab.[33] Despite receiving multiple therapies, the patient experienced recurrent episodes of acute cholangitis and ultimately died 24 weeks after the onset of sclerosing cholangitis. In this study, 188 patients (17.1%) with ICI-associated cholangitis ultimately died. Although tumor progression may have contributed to some fatalities given the complexity of cancer patients\u0026apos; conditions, the potential severity of this rare irAE remains a significant concern. Additionally, this study found hospitalization to be the most common clinical outcome of ICI-associated cholangitis (454 cases, 41.2%). Consequently, effective management of this immune-mediated toxicity is crucial for optimizing patient outcomes. Prompt referral to a hepatologist is essential for the diagnosis and management of patients with suspected ICI-associated cholangitis. It was reported that this immune-mediated toxicity appeared to respond poorly to corticosteroids. [31] The current European Society for Medical Oncology guidelines recommend ursodeoxycholic acid for the treatment of immune-related cholangitis.[9] However, optimal treatment strategies for ICI-associated cholangitis remain unclear. Additional clinical experience is needed to establish optimal management strategies for this irAE.\u003c/p\u003e\n\u003cp\u003eThe FAERS database offers distinct advantages for monitoring rare AEs. However, several limitations of this study must be acknowledged. First, the FAERS database accepts AE reports submitted by healthcare professionals, consumers, and manufacturers. However, this reporting mechanism is inherently susceptible to bias, since reports from non-healthcare professionals may affect data reliability. Second, as the FAERS database relies on voluntary reporting, submitted reports often contain incomplete information, making it difficult to control for confounding factors such as patients\u0026rsquo; baseline medical conditions and complex concomitant medications. Third, the FAERS database lacks detailed clinical documentation of AEs, preventing comprehensive characterization of ICI-associated cholangitis features including clinical manifestations, laboratory findings, and imaging features. Fourth, incidence rates of ICI-associated cholangitis cannot be derived from the FAERS database because this system relies on reported events rather than actual occurrences. The true incidence requires further investigation. Despite these limitations, this study reveals both the risk profile and clinical characteristics of ICI-associated cholangitis, advancing understanding of this rare irAE and providing critical leads for future safety investigations.\u003c/p\u003e\n\u003cp\u003eIn Conclusion, ICI-associated cholangitis represents a rare irAE. Current pharmacovigilance study elucidated different risk association profiles across ICI classes and characterized key clinical features, providing clinicians with helpful information for improved recognition and management of this toxicity. Nevertheless, critical knowledge gaps remain regarding the pathophysiological mechanisms, racial disparities in susceptibility, and evidence-based management approaches for ICI-associated cholangitis, necessitating further investigation.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe FAERS database, which was made available by the FDA, was used to conduct this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is data available from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was not considered necessary for this study because of the nature of the study, which is a retrospective analysis of reports registered in the FAERS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHaowen Tan contributed to the conceptualization and design of the study and wrote the original manuscript. Xuan Ou and Ying Chen took responsibility for the collection, integrity, and accuracy of the data. Weiwei Lan contributed to data curation. Luping Luo oversaw the review and editing of the manuscript. All authors contributed to the manuscript\u0026rsquo;s revision and read and approved the submitted version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSharma P, Allison JP (2015) The future of immune checkpoint therapy. Science 348:56-61. https://doi.org/10.1126/science.aaa8172\u003c/li\u003e\n\u003cli\u003eTopalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450-461. https://doi.org/10.1016/j.ccell.2015.03.001\u003c/li\u003e\n\u003cli\u003ePardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. 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N Engl J Med 378:158-168. https://doi.org/10.1056/NEJMra1703481\u003c/li\u003e\n\u003cli\u003eMartins F, Sofiya L, Sykiotis GP, et al (2019) Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 16:563-580. https://doi.org/10.1038/s41571-019-0218-0\u003c/li\u003e\n\u003cli\u003eHaanen J, Obeid M, Spain L, et al (2022) Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 33:1217-1238. https://doi.org/10.1016/j.annonc.2022.10.001\u003c/li\u003e\n\u003cli\u003eGelsomino F, Vitale G, D\u0026apos;Errico A, et al (2017) Nivolumab-induced cholangitic liver disease: a novel form of serious liver injury. Ann Oncol 28:671-672. https://doi.org/10.1093/annonc/mdw649\u003c/li\u003e\n\u003cli\u003eKawakami H, Tanizaki J, Tanaka K, et al (2017) Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer. Invest New Drugs 35:529-536. https://doi.org/10.1007/s10637-017-0453-0\u003c/li\u003e\n\u003cli\u003eTahboub Amawi AD, Tremaine WJ, Venkatesh SK (2022) Pembrolizumab-Induced Sclerosing Cholangitis. Clin Gastroenterol Hepatol 20:e18. https://doi.org/10.1016/j.cgh.2020.11.048\u003c/li\u003e\n\u003cli\u003eFouchard M, Jantzem H, Quere G, et al (2019) Three cases of immune cholangitis related to anti-programmed cell death and programmed cell death ligand agents for the treatment of non-small cell lung cancer. Eur J Cancer 115:107-110. https://doi.org/10.1016/j.ejca.2019.04.022\u003c/li\u003e\n\u003cli\u003eAnand K, Sahu G, Burns E, et al (2020) Mycobacterial infections due to PD-1 and PD-L1 checkpoint inhibitors. ESMO Open 5:e000866. https://doi.org/10.1136/esmoopen-2020-000866\u003c/li\u003e\n\u003cli\u003eXia S, Gong H, Zhao Y, et al (2022) Association of Pulmonary Sepsis and Immune Checkpoint Inhibitors: A Pharmacovigilance Study. Cancers (Basel) 15:240. https://doi.org/10.3390/cancers15010240\u003c/li\u003e\n\u003cli\u003eMoore DC, Elmes JB, Arnall JR, et al (2022) Acquired thrombotic thrombocytopenic purpura associated with immune checkpoint inhibitors: A real-world study of the FDA adverse event reporting system. Int Immunopharmacol 110:109015. https://doi.org/10.1016/j.intimp.2022.109015\u003c/li\u003e\n\u003cli\u003eCFR \u0026sect; 600.80\u0026mdash;Postmarketing reporting of adverse experiences. https://www.govinfo.gov/app/details/CFR-2023-title21-vol7/CFR-2023-title21-vol7-sec600-80/context. Accessed 12 July 2025.\u003c/li\u003e\n\u003cli\u003eRothman KJ, Lanes S, Sacks ST (2004) The reporting odds ratio and its advantages over the proportional reporting ratio. Pharmacoepidemiol Drug Saf 13:519-523. https://doi.org/10.1002/pds.1001\u003c/li\u003e\n\u003cli\u003eWei SC, Duffy CR, Allison JP (2018) Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. 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ESMO Open 2:e000268. https://doi.org/10.1136/esmoopen-2017-000268\u003c/li\u003e\n\u003cli\u003eSiegel RL, Miller KD, Wagle NS, et al (2023) Cancer statistics, 2023. CA Cancer J Clin 73:17-48. https://doi.org/10.3322/caac.21763\u003c/li\u003e\n\u003cli\u003eHe Y, Fan Z, Sun W, et al (2024) Clinical features, treatment, and outcome of nivolumab-induced cholangitis. Immunopharmacol Immunotoxico 46:757-762. https://doi.org/10.1080/08923973.2024.2402338\u003c/li\u003e\n\u003cli\u003eLi Z, Zhou Z, Zhang N, et al (2024) Hepatitis associated with immune checkpoint inhibitors-based combinations of other therapies: A real-world pharmacovigilance analysis based on the FDA adverse event reporting system (FAERS) database. Cancer Immunol Immunother 74:25. https://doi.org/10.1007/s00262-024-03858-4\u003c/li\u003e\n\u003cli\u003eMeunier L, Hountondji L, Jantzem H, et al (2024) Cholangitis Induced by Immune Checkpoint Inhibitors: Analysis of Pharmacovigilance Data. Clin Gastroenterol Hepatol 22:1542-1545.e4. https://doi.org/10.1016/j.cgh.2023.12.008\u003c/li\u003e\n\u003cli\u003eJohncilla M, Misdraji J, Pratt DS, et al (2015) Ipilimumab-associated Hepatitis: Clinicopathologic Characterization in a Series of 11 Cases. Am J Surg Pathol 39:1075-1084. https://doi.org/10.1097/PAS.0000000000000453\u003c/li\u003e\n\u003cli\u003eTanaka T, Sakai A, Tsujimae M, et al (2022) Delayed immune-related sclerosing cholangitis after discontinuation of pembrolizumab: A case report. World J Gastroenterol 28:3732-3738. https://doi.org/10.3748/wjg.v28.i28.3732\u003c/li\u003e\n\u003cli\u003eBjornsson ES, Arnedillo D, Bessone F (2025) Secondary Sclerosing Cholangitis due to Drugs With a Special Emphasis on Checkpoint Inhibitors. Liver Int 45:e16163. https://doi.org/10.1111/liv.16163\u003c/li\u003e\n\u003cli\u003eOnoyama T, Takeda Y, Yamashita T, et al (2020) Programmed cell death-1 inhibitor-related sclerosing cholangitis: A systematic review. World J Gastroenterol 26:353-365. https://doi.org/10.3748/wjg.v26.i3.353\u003c/li\u003e\n\u003cli\u003eCho JH, Sun JM, Lee SH, et al (2018) Late-Onset Cholecystitis with Cholangitis after Avelumab Treatment in Non-Small Cell Lung Cancer. J Thorac Oncol 13:e34-e36. https://doi.org/10.1016/j.jtho.2017.10.007\u003c/li\u003e\n\u003cli\u003eSuzuki N, Ikeda Y, Ono M, et al (2022) Gastrointestinal: Immune-related sclerosing cholangitis with pembrolizumab: Imaging and histological features. J Gastroenterol Hepatol 37:1652. https://doi.org/10.1111/jgh.15797\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"cholangitis, data mining, FAERS, immune checkpoint inhibitors, pharmacovigilance","lastPublishedDoi":"10.21203/rs.3.rs-7185162/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7185162/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eImmune checkpoint inhibitor (ICI)-associated cholangitis is a rare immune-related adverse event (irAE). However, large-scale clinical studies specifically investigating this toxicity are still lacking. This study aimed to describe ICI-associated cholangitis reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eReports of irAEs were extracted from the FAERS database (Q1 2011 to Q4 2024). Cases of ICI-associated cholangitis were identified using the following Preferred Terms from the Medical Dictionary for Regulatory Activities (version 27.1): \u0026ldquo;cholangitis\u0026rdquo;, \u0026ldquo;sclerosing cholangitis\u0026rdquo;, and \u0026ldquo;immune-mediated cholangitis\u0026rdquo;. Reporting odds ratio (ROR) method was performed to evaluate the association between cholangitis and different ICI therapies. Additionally, the clinical features of ICI-associated cholangitis were characterized, and the time-to-onset (TTO) of ICI-associated cholangitis was assessed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 1,102 patients with ICI-associated cholangitis were identified. Male patients (n\u0026thinsp;=\u0026thinsp;628, 56.99%) outnumbered females (n\u0026thinsp;=\u0026thinsp;334, 30.31%). Most patients were aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years (n\u0026thinsp;=\u0026thinsp;540, 49.00%) and from Japan (n\u0026thinsp;=\u0026thinsp;817, 74.14%). Hospitalization (n\u0026thinsp;=\u0026thinsp;454, 41.20%) was the most frequent clinical outcome. Programmed cell death protein 1 inhibitors showed the strongest risk association (ROR\u0026thinsp;=\u0026thinsp;24.65, 95% confidence interval [CI]: 22.84\u0026ndash;26.59), followed by programmed death-ligand 1 inhibitors (ROR\u0026thinsp;=\u0026thinsp;19.03, 95% CI: 16.41\u0026ndash;22.08). In contrast, cytotoxic T-lymphocyte-associated protein 4 inhibitors demonstrated no significant association (ROR\u0026thinsp;=\u0026thinsp;2.08, 95% CI: 0.93\u0026ndash;4.64). The median TTO was 77 days (interquartile range: 31\u0026ndash;164 days).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eICI-associated cholangitis represents a rare but clinically significant irAE. This study elucidates distinct risk profiles across ICI classes and characterizes the clinical features of this toxicity, providing unique insights to inform clinical management.\u003c/p\u003e","manuscriptTitle":"A pharmacovigilance study of immune checkpoint inhibitor-associated cholangitis using the Food and Drug Administration adverse event reporting system","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-31 10:32:59","doi":"10.21203/rs.3.rs-7185162/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"676cd8fb-ec32-4243-affb-76b98f4e0d67","owner":[],"postedDate":"July 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-30T11:57:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-31 10:32:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7185162","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7185162","identity":"rs-7185162","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}