Autoimmune hepatitis: Brighton Collaboration case definition and guidelines for data collection, analysis, and presentation of immunisation safety data.

This report introduces a Brighton Collaboration (BC) case definition for autoimmune hepatitis (AIH), which has been classified as a priority adverse event of special interest (AESI), as there were possible cases seen following COVID-19 vaccination. The case definition was developed by a group of subject matter and BC process experts to facilitate safety data comparability across pre- and post-licensure clinical trials, as well as pharmacovigilance activities in multiple settings with diverse resources and healthcare access. The usual BC case definition development process was followed in an expedited manner, and took two months to complete, including finalising the manuscript for publication, instead of the usual 1 year development time. It includes a systematic review of the literature and an expert consensus to define levels of diagnostic certainty for AIH, and provides specific guidelines for data collection and analysis. Histology, serological and biochemical tests and exclusion of alternate diagnosis were considered necessary to define the levels of certainty (definitive, probable and possible). AEFI reports of suspected AIH were independently classified by the WG members to test its useability and these classifications were used to finalise the case definition. The document underwent peer review by external AIH experts and a Reference Group of vaccine safety stakeholders in high-, low- and middle-income countries to ensure case definition useability, applicability, and scientific integrity. The expedited process can be replicated for development of other standardised case definitions for priority AESIs for endemics and epidemics. While applicable to cases reported following immunisation, the case definition is independent of lapsed time following vaccination and, as such, can also be used to determine background incidence for vaccinated and unvaccinated control groups in studies of causal association. While use of this case definition is also appropriate for the study of safety of other products including drugs, it is not meant to guide clinical case management.

African American race does not confer an increased risk of clinical events in patients with primary sclerosing cholangitis.

BACKGROUND: The natural history of primary sclerosing cholangitis (PSC) among African Americans (AA) is not well understood. METHODS: Transplant-free survival and hepatic decompensation-free survival were assessed using a retrospective research registry from 16 centers throughout North America. Patients with PSC alive without liver transplantation after 2008 were included. Diagnostic delay was defined from the first abnormal liver test to the first abnormal cholangiogram/liver biopsy. Socioeconomic status was imputed by the Zip code. RESULTS: Among 850 patients, 661 (77.8%) were non-Hispanic Whites (NHWs), and 85 (10.0%) were AA. There were no significant differences by race in age at diagnosis, sex, or PSC type. Inflammatory bowel disease was more common in NHWs (75.8% vs. 51.8% p=0.0001). The baseline (median, IQR) Amsterdam-Oxford Model score was lower in NHWs (14.3, 13.4-15.2 vs. 15.1, 14.1-15.7, p=0.002), but Mayo risk score (0.03, -0.8 to 1.1 vs. 0.02, -0.7 to 1.0, p=0.83), Model for End-stage Liver Disease (5.9, 2.8-10.7 vs. 6.4, 2.6-10.4, p=0.95), and cirrhosis (27.4% vs. 27.1%, p=0.95) did not differ. Race was not associated with hepatic decompensation, and after adjusting for clinical variables, neither race nor socioeconomic status was associated with transplant-free survival. Variables independently associated with death/liver transplant (HR, 95% CI) included age at diagnosis (1.04, 1.02-1.06, p<0.0001), total bilirubin (1.06, 1.04-1.08, p<0.0001), and albumin (0.44, 0.33-0.61, p<0.0001). AA race did not affect the performance of prognostic models. CONCLUSIONS: AA patients with PSC have a lower rate of inflammatory bowel disease but similar progression to hepatic decompensation and liver transplant/death compared to NHWs.

Cystic fibrosis screening, evaluation and management of hepatobiliary disease consensus recommendations.

Background and Aims Cystic fibrosis (CF) may cause a spectrum of hepatobiliary complications, including portal hypertension, multilobular cirrhosis, and liver failure. Current guidelines on the detection and monitoring of hepatobiliary complications in CF were published in 1999. The CF Foundation assembled a committee to evaluate research advances and formulate revised guidelines for CF-associated liver disease. Approach A committee of hepatologists, gastroenterologists, pulmonologists, pharmacist, nurse, dietitian, individual with CF, and parent of a child with CF devised "population, intervention, comparison, and outcome" (PICO) questions regarding hepatobiliary disease in CF. PubMed literature searches were performed for each PICO question. Recommendations were voted on with 80% agreement required to approve a recommendation. Public comment on initial recommendations was solicited prior to formulation of final recommendations. Results 31 PICO questions were assembled, 6,401 manuscripts were title screened for relevance, with 1,053 manuscripts undergoing detailed full text review. Seven recommendations were approved for screening, 13 for monitoring of existing disease, and 14 for treatment of CF-associated hepatobiliary involvement or advanced liver disease. One recommendation on liver biopsy did not meet the 80% threshold. One recommendation on screening ultrasound was revised and re-voted on. Conclusions Through a multidisciplinary committee and public engagement, we have assembled updated recommendations and guidance on screening, monitoring and treatment of CF-associated hepatobiliary involvement and advanced liver disease. While research gaps remain, we anticipate that these recommendations will lead to improvements in CF outcomes through earlier detection and increased evidence-based approaches to monitoring and treatment.

Advancing diagnosis and management of liver disease in adults through exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) is an effective tool for diagnosis in patients who remain undiagnosed despite a comprehensive clinical work-up. While WES is being used increasingly in pediatrics and oncology, it remains underutilized in non-oncological adult medicine, including in patients with liver disease, in part based on the faulty premise that adults are unlikely to harbor rare genetic variants with large effect size. Here, we aim to assess the burden of rare genetic variants underlying liver disease in adults at two major tertiary referral academic medical centers. METHODS: WES analysis paired with comprehensive clinical evaluation was performed in fifty-two adult patients with liver disease of unknown etiology evaluated at two US tertiary academic health care centers. FINDINGS: Exome analysis uncovered a definitive or presumed diagnosis in 33% of patients (17/52) providing insight into their disease pathogenesis, with most of these patients (12/17) not having a known family history of liver disease. Our data shows that over two-thirds of undiagnosed liver disease patients attaining a genetic diagnosis were being evaluated for cholestasis or hepatic steatosis of unknown etiology. INTERPRETATION: This study reveals an underappreciated incidence and spectrum of genetic diseases presenting in adulthood and underscores the clinical value of incorporating exome sequencing in the evaluation and management of adults with liver disease of unknown etiology. FUNDING: S.V. is supported by the NIH/NIDDK (K08 DK113109 and R01 DK131033-01A1) and the Doris Duke Charitable Foundation Grant #2019081. This work was supported in part by NIH-funded Yale Liver Center, P30 DK34989.

Recent Advances in the Management of Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibroinflammatory damage to the biliary tree, typically in the setting of inflammatory bowel disease, with an increased risk of liver failure and cholangiocarcinoma. A complex pathophysiology, heterogeneity in clinical features, and the rare nature of the disease have contributed to the lack of effective therapy to date. However, recent innovations in the characterization and prognostication of patients with PSC, in addition to new tools for medical management and emerging pharmacologic agents, give rise to the potential for meaningful progress in the next several years. This review summarizes current concepts in PSC and highlights particular areas in need of further study.

Research gaps and opportunities in autoimmune hepatitis-Results of the international autoimmune hepatitis group research workshop 2022.

Autoimmune hepatitis (AIH) is a rare autoimmune liver disease that is characterised by a chronic inflammatory immune reaction directed against hepatocytes. The disease results in a substantial reduction in quality of life and potentially leads to liver-related complications or death. The International Autoimmune Hepatitis Group (IAIHG) initiated a series of research workshops to uncover the scientific gaps and opportunities in AIH. This review summarises the results of the latest workshop in Maastricht in 2022 and reviews the current challenges in adult AIH, particularly in relation to four important aspects of AIH: diagnostics; new immunomodulatory therapies; clinical trial design; and unmet clinical needs. This review also summarises the progress made since the AIH workshop in 2017. Patients and patient representatives were actively involved in the parallel working groups alongside clinicians and researchers. Despite 40 years of experience with diagnosing and treating AIH, false diagnoses occur and treatment is still based on nonselective immunosuppression. In addition to the need for more specific diagnostic tests, prognostic markers and tailor-based treatments, a major unmet clinical need was identified in areas of care delivery and health-related quality of life.

Unique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis.

Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2+ACE2+ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2+ACE2+ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27+ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2+ACE2+ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2+ACE2+ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

Outcomes of immunomodulator and advanced therapies for primary sclerosing cholangitis-associated inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) coexists in up to 80% of patients with primary sclerosing cholangitis (PSC). The aim of this study is to investigate the outcomes of immunomodulator (IMM)/advanced therapies for the treatment of PSC-IBD. METHODS: This was a single-center, retrospective study of patients with PSC from 1 January 2012 to 1 April 2021. Adult patients (age ≥ 18 years) with PSC-IBD were included. Primary outcomes were rates and predictors of IMM/advanced therapies to treat PSC-IBD. Secondary outcomes included rates of cholangitis, PSC-IBD clinical remission, and endoscopic healing. RESULTS: A total of 106 patients with PSC were reviewed and 72 (68%) with confirmed PSC-IBD were included in the study. The median age was 48 years (IQR, 33-59.5) and 69.4% were male. Overall, 28 patients (38.9%) required IMM/advanced therapies to treat PSC-IBD (22 biologic/small molecule therapy and six thiopurine monotherapy). Patients in the IMM/advanced therapies group were more likely to have small bowel involvement (32.1% vs. 4.6%; P = 0.002). In the IMM/advanced therapies group, clinical remission was achieved in 78.6% but endoscopic healing in only 50%. The rate of acute ascending cholangitis was 42.9% in the IMM/advanced therapies group compared with 31.8% in the non-IMM/advanced therapies group (P = 0.34). CONCLUSION: In our cohort, up to a third of patients with PSC-IBD required IMM/advanced therapies with only 50% of these patients achieving endoscopic healing. The use of IMM/advanced therapies was not associated with a higher risk of cholangitis, but larger studies are needed to investigate the risk with different classes of advanced therapies.

Update in Advancing the Gastrointestinal Frontier in Cystic Fibrosis.

Clinical complications of cystic fibrosis (CF) include a variety of gastrointestinal (GI) and hepatobiliary manifestations. Recent years have witnessed several advances in the understanding and management of these complications, in addition to opportunities for therapeutic innovations. Herein we review the current understanding of these disorders and also discuss the management of the GI and hepatobiliary complications experienced by persons with CF.

Fenofibrate Downregulates NF-κB Signaling to Inhibit Pro-inflammatory Cytokine Secretion in Human THP-1 Macrophages and During Primary Biliary Cholangitis.

Chronic liver diseases, e.g., cholestasis, are negatively impacted by inflammation, which further aggravates liver injury. Pharmacotherapy targeting the peroxisome proliferator-activated receptor alpha (PPARα), e.g., fenofibrate, has recently become an off-label therapeutic option for patients with refractory cholestasis. Clinical studies show that fibrates can reduce some pro-inflammatory cytokines in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC); however, its anti-inflammatory mechanisms have not been established. Numerous cytokines are regulated by the transcription factor nuclear receptor kappa B (NF-κB), and PPARα has been shown to interfere with NF-κB signaling. This study investigates the anti-inflammatory mechanism of fenofibrate by inhibiting NF-κB signaling in human macrophages and clinical outcomes in patients with PBC. For adult patients with PBC and an incomplete biochemical response to ursodiol (13-15 mg/kg/day), the addition of fenofibrate (145-160 mg/day) reduced serum levels of TNF-α, IL-17A, IL-1ß, IL-6, IL-8, and MCP-1 and increased IL-10. In THP-1 cells, pretreatment with fenofibrate (125 µM) reduced LPS-stimulated peak concentrations of IL-1ß (- 63%), TNF-α (- 88%), and IL-8 (- 54%), in a PPARα-dependent manner. Treatment with fenofibrate prior to LPS significantly decreased nuclear NF-κB p50 and p65 subunit binding by 49% and 31%, respectively. Additionally, fenofibrate decreased nuclear NF-κB p50 and p65 protein expression by 66% and 55% and increased cytoplasmic levels by 53% and 54% versus LPS alone, respectively. Lastly, fenofibrate increased IκBα levels by 2.7-fold (p < 0.001) vs. LPS. These data demonstrate that fenofibrate reduces pro-inflammatory cytokines section by inhibiting in NF-κB signaling, which likely contribute to its anti-inflammatory effects during chronic liver diseases.

Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a rare disease of unclear etiology characterized by loss of self-tolerance that can lead to liver injury, cirrhosis, and acute liver failure. First-line treatment consists of systemic corticosteroids, or budesonide, and azathioprine, to which most patients are initially responsive, although predictors of response are lacking. Relapses are very common, correlate with histological activity despite normal serum transaminases, and increase hepatic fibrosis. Furthermore, current regimens lead to adverse effects and reduced quality of life, whereas medication titration is imprecise. Biomarkers that can predict the clinical course of disease, identify patients at elevated risk for relapse, and improve monitoring and medication dosing beyond current practice would have high clinical value. Herein, we review novel candidate biomarkers in adult and pediatric AIH based on prespecified criteria, including gene expression profiles, proteins, metabolites, and immune cell phenotypes in different stages of AIH. We also discuss biomarkers relevant to AIH from other immune diseases. We conclude with proposed future directions in which biomarker implementation into clinical practice could lead to advances in personalized therapeutic management of AIH.

Mindfulness-based stress reduction may decrease stress, disease activity, and inflammatory cytokine levels in patients with autoimmune hepatitis.

Background & Aims: Psychological and life stressors may impact autoimmune hepatitis (AIH) disease activity and increase relapse risk. Mindfulness-based stress reduction (MBSR) is a validated course that reduces stress reactivity, and improves stress and emotion regulation. This single-arm exploratory pilot study of adult patients with AIH aimed to define the impact of an 8-week MBSR program on quality of life, disease activity, and cytokine mediators. Methods: The perceived stress survey-10 (PSS) and the brief self-control scale (BSCS) measured subjective distress and self-control. Serum alanine aminotransferase (ALT) and cytokine levels were measured, and immunosuppressant doses recorded. Results: Seventeen patients completed the MBSR program. Post-MBSR, 71% (n = 12) showed PSS score improvement at 8 weeks vs. baseline (median 15 vs. 21, p = 0.02). At 12 months, PSS improvement persisted vs. baseline (median 15 vs. 21, p = 0.02). Post-MBSR, 71% (n = 12) showed BSCS score improvement at 8 weeks vs. baseline (median 4.1 vs. 3.8, p = 0.03). At 12 months, the median BSCS score remained significant (3.9 vs. 3.8, p = 0.03). After the 8-week MBSR, the 35% of patients with ALT >34 U/L had a median ALT reduction (44.5 vs. 71.5 U/L, p = 0.06), whereas the 71% of patients on prednisone had significant dose reductions (5.75 vs. 10 mg, p = 0.02) which persisted at 12 months vs. baseline (3.75 vs. 10 mg, p = 0.02) without a compensatory increase in steroid-sparing dosing. Significant improvement was noted in peripheral blood cytokine levels (IL-6, IL-8, IL-10, IL-17, IL-23, and sCD74/MIF ratio) from baseline to 8 weeks. Conclusions: MBSR significantly improved perceived stress and self-control scores while decreasing ALT levels, steroid requirements, and inflammatory cytokine levels in this pilot study in adult AIH. Stress modification may impact quality of life and disease activity, and should be further evaluated as an intervention in AIH. Clinical Trials registration: This study is registered at ClinicalTrials.gov (NCT02950077). Lay summary: Autoimmune hepatitis can reduce quality of life and mental health, while stress may impact autoimmune hepatitis itself. We piloted mindfulness-based stress reduction as a strategy to reduce stress in adult patients with autoimmune hepatitis and found that the intervention reduced perceived stress and may have also impacted the disease by improving inflammation and medication needs. Stress reduction should be further studied to improve quality of life and possibly to impact disease activity in autoimmune hepatitis.

Adjunct Fenofibrate Up-regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis.

Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator-activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up-regulate BA-glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n = 32) and primary sclerosing cholangitis (PSC, n = 23), who experienced an incomplete response while receiving ursodiol monotherapy (13-15 mg/kg/day), defined as serum alkaline phosphatase (ALP) ≥ 1.5 times the upper limit of normal, received additional fenofibrate (145-160 mg/day) as standard of care. Serum BA and BA-glucuronide concentrations were measured by liquid chromatography-mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (-76%, P < 0.001), aspartate transaminase, alanine aminotransferase, bilirubin, total serum BAs (-54%), and increased serum BA-glucuronides (+2.1-fold, P < 0.01) versus ursodiol monotherapy. The major serum BA-glucuronides that were favorably altered following adjunct fenofibrate include hyodeoxycholic acid-6G (+3.7-fold, P < 0.01), hyocholic acid-6G (+2.6-fold, P < 0.05), chenodeoxycholic acid (CDCA)-3G (-36%), and lithocholic acid (LCA)-3G (-42%) versus ursodiol monotherapy. Fenofibrate also up-regulated the expression of uridine 5'-diphospho-glucuronosyltransferases and multidrug resistance-associated protein 3 messenger RNA in primary human hepatocytes. Pearson's correlation coefficients identified strong associations between serum ALP and metabolic ratios of CDCA-3G (r2  = 0.62, P < 0.0001), deoxycholic acid (DCA)-3G (r2  = 0.48, P < 0.0001), and LCA-3G (r2  = 0.40, P < 0.001), in ursodiol monotherapy versus control. Receiver operating characteristic analysis identified serum BA-glucuronides as measures of response to therapy. Conclusion: Fenofibrate favorably alters major serum BA-glucuronides, which correlate with reduced serum ALP levels and improved outcomes. A PPARα-mediated anti-cholestatic mechanism is involved in detoxifying serum BAs in patients with PBC and PSC who have an incomplete response on ursodiol monotherapy and receive adjunct fenofibrate. Serum BA-glucuronides may serve as a noninvasive measure of treatment response in PBC and PSC.

Role of Biliary Organoids in Cholestasis Research and Regenerative Medicine.

Translational studies in human cholestatic diseases have for years been hindered by various challenges, including the rarity of the disorders, the difficulty in obtaining biliary tissue from across the spectrum of the disease stage, and the difficulty culturing and maintaining primary cholangiocytes. Organoid technology is increasingly being viewed as a technological breakthrough in translational medicine as it allows the culture and biobanking of self-organizing cells from various sources that facilitate the study of pathophysiology and therapeutics, including from individual patients in a personalized approach. This review describes current research using biliary organoids for the study of human cholestatic diseases and the emerging applications of organoids to regenerative medicine directed at the biliary tree. Challenges and possible solutions to the current hurdles in this emerging field, particularly the need for standardization of terminology and clarity on source materials and techniques, are also discussed.

Treatment of Metastatic Extramammary Paget Disease with Combination Ipilimumab and Nivolumab: A Case Report.

Metastatic primary cutaneous extramammary Paget disease (EMPD) is a rare clinical entity with a 5-year survival <10% and no standard therapy. We report the first case to our knowledge of metastatic EMPD with treatment response to checkpoint inhibitor immunotherapy. The patient had diffusely metastatic disease and previously progressed on cytotoxic chemotherapy and a molecularly targeted agent. Treatment with four cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg resulted in a durable partial response lasting 7 months. Analysis of metastatic tumor tissue failed to identify known predictors of treatment response to immune checkpoint inhibitors, such as high PD-L1 expression, high tumor mutation burden, or microsatellite instability. These findings support further investigation of immune checkpoint inhibition for the management of metastatic EMPD, which currently has an abysmal prognosis and no standard therapies.