Emma L. Culver

Background and Aims: Primary sclerosing cholangitis (PSC) is a rare, progressive cholangiopathy for which diagnosis remains challenging because of the absence of disease‐specific markers and the presence of secondary causes of sclerosing cholangitis (SSC) that closely mimic its clinical presentation. Diagnostic uncertainty can delay appropriate management and add to the psychological burden experienced by patients. This study aimed to identify clinical parameters that support the early and accurate differentiation of PSC from SSC. Methods: We conducted a multicentre retrospective study of adults with an established diagnosis of PSC or SSC. Independent predictors of PSC were identified using multivariable logistic regression and externally validated in an independent cohort. Results: In the derivation cohort ( n = 234, 155 PSC, 79 SSC), six variables were independently associated with PSC diagnosis, including younger age at presentation ( p < 0.0001), presence of IBD ( p < 0.0001), absence of prior hepato‐pancreato‐biliary surgery ( p < 0.0001), autoimmune comorbidities ( p = 0.0038), family history of autoimmune diseases ( p = 0.0086), and absence of pancreatic abnormalities ( p = 0.0338). These variables were used to develop the PSC diagnostic model (PSC‐DM). In the external validation cohort ( n = 142, 98 PSC, 44 SSC), the AUROC of PSC‐DM was 0.95 (95% CI 0.91–0.98). In an exploratory analysis, PSC‐DM significantly improved non‐expert diagnostic accuracy (94.3% versus 78.6%, p = 0.0023). Conclusions: PSC‐DM is a simple, externally validated clinical prediction model that accurately distinguishes PSC from SSC using routinely available clinical variables. It may support initial diagnostic assessment in non‐specialist settings, facilitate timely referral to expert centres and improve patient selection for clinical trials.

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease that can progress from persistent inflammation to intrahepatic ductopenia, fibrosis, and ultimately end‑stage biliary cirrhosis if inadequately treated. Although many patients are asymptomatic at diagnosis, fatigue and pruritus frequently develop and can severely impact quality of life, irrespective of disease stage. Diagnosis relies on cholestatic liver enzyme patterns, particularly raised alkaline phosphatase (ALP), alongside antimitochondrial antibodies (AMA). Failure to normalise ALP and bilirubin correlates with ongoing inflammation and future liver‑related complications. While ursodeoxycholic acid (UDCA) remains the established first‑line therapy, around 40% of patients show an inadequate biochemical response, leaving patients at continued risk of progression. EMJ spoke to PBC experts Emma Culver, Department of Hepatology, John Radcliffe Hospital, Oxford, UK; and David Jones, Department of Hepatology, Freeman Hospital, Newcastle, UK, who emphasise that optimal outcomes depend on timely access to second‑line therapies, targeted symptom management, and a broader clinical appreciation of the disease’s full impact. They highlight that normalising biochemical markers, addressing symptoms proactively, and intervening early are key to preventing disease progression and improving patients’ quality of life.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory immune-mediated condition. The Pancreato-Hepato-Biliary subtype is the most frequent phenotype. The subtype encompasses immunoglobulin G4 (IgG4)-related pancreatitis (autoimmune pancreatitis type 1), IgG4-related cholangitis, IgG4-related hepatopathy and IgG4-related cholecystitis. The condition is characterised by multi-organ involvement and unpredictable recurrent disease flares, which lead to organ damage and failure in the absence of early recognition and adequate treatment. It is associated with a 2-fold increase in mortality and higher incidences of malignancies, such as solid-organ tumours and lymphoma. Diagnostic delays result from the lack of awareness and the absence of a single diagnostic test, leading to multiple generalist and specialist visits prior to the initiation of therapy. There have been major advances in the management of IgG4-RD to include a move to more targeted therapies. This includes the novel cluster of differentiation 19 (CD19)-depletion therapy inebilizumab, which has been approved in the United States, Europe and Japan for the treatment of IgG4-RD. This review highlights crucial diagnostic clues and emerging therapeutic advances in the evolving field of the Pancreato-Hepato-Biliary subtype of IgG4-RD.

IgG4-related disease (IgG4-RD) is a chronic, multiorgan fibroinflammatory condition characterized by recurring flares that can lead to progressive organ damage and failure, impaired quality of life, and death. Glucocorticoids (GCs) remain the primary therapy despite their significant toxicity. Obexelimab is a humanized, bifunctional, monoclonal antibody designed to inhibit B cells by co-engaging CD19 and FcγRIIb (CD32b), mimicking natural inhibitory signaling triggered by antigen-antibody complexes. Following promising phase 2 results that demonstrated clinical improvement in 93% of patients with IgG4-RD, the phase 3 INDIGO trial was initiated. INDIGO is a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of obexelimab in patients with IgG4-RD. The trial has enrolled adult patients ≥ 18 years old with active IgG4-RD meeting the 2019 ACR/EULAR classification criteria (score ≥ 20). Following standardized GC induction, patients are randomized 1:1 to weekly subcutaneous obexelimab 250 mg or placebo for 52 weeks. An independent adjudication committee (AC) ensures consistent application of IgG4-RD classification and organ-specific flare criteria developed for the trial. The primary endpoint is time to first IgG4-RD flare requiring initiation of rescue therapy as determined by both the investigator and AC. Key secondary endpoints are time to first investigator-determined flare requiring rescue therapy, number of investigator- and AC-determined flares requiring rescue therapy, proportion of patients achieving complete remission, and cumulative dose of GC rescue therapy for active IgG4-RD through Week 52. The INDIGO trial achieved its global enrollment goal with 194 patients, making it the largest phase 3 trial in IgG4-RD to date and providing 90% power to detect a clinically meaningful reduction in flare risk. This trial will provide critical evidence on B-cell inhibition as a treatment strategy for IgG4-RD and assess obexelimab as a potential steroid-sparing option to address significant unmet needs of this patient population. NCT05662241.

Introduction Primary biliary cholangitis (PBC) is a rare chronic cholestatic disease that despite current therapy has significant ongoing unmet needs, including risks of cirrhosis and life-impairing symptoms. The current treatment approach is a step-up model, wherein first-line therapy, ursodeoxycholic acid (UDCA), is given for a minimum of 12 months before the addition of second-line therapy is considered for non-responding patients. This ‘waiting to fail’ approach, focused on the needs of low-risk patients, allows, we postulate, a key process of biliary epithelial cell (BEC) senescence to become established, driving accelerated bile duct loss and aggressive disease. Preclinical mouse modelling has shown that early use of the farnesoid X receptor agonist obeticholic acid (OCA), currently only used as second-line therapy following UDCA failure, reverses BEC senescence, changing the clinical course of disease. Here, we describe the design of the Optimising Primary thErapy in pRimAry biliary cholangitis (OPERA) trial. The aim of OPERA is to explore a new paradigm for disease-modifying treatment of PBC: risk-informed early treatment stratification, with patients at increased risk offered UDCA and OCA combination with the goal of complete biochemical remission. Methods and analysis OPERA is a multicentre, randomised, double-blind, placebo-controlled trial of OCA in combination with UDCA, as first-line treatment for high-risk PBC. This is a multicentre trial in England, which will be undertaken in specialist clinics in secondary/tertiary referral centres (or as per local set up). These centres will be specialists in the area of PBC management and will manage patients from across their local region. OPERA will recruit and randomise 106 adults, within 6 months of PBC diagnosis, who are at an enhanced risk of non-response to standard first-line therapy, between either: (1) UDCA and OCA or (2) UDCA and matched placebo in a 1:1 ratio. The primary efficacy outcome measure is the percentage of participants showing normalisation of serum alkaline phosphatase and total bilirubin values at 26 weeks (disease remission). Ethics and dissemination Favourable ethical opinion was received from London – Riverside Research Ethics Committee (reference: 22/LO/0878). Potential participants will be fully informed of their rights and the benefits and harms of the trial by the research team before giving informed consent to participate in the trial. Results will be disseminated in peer-reviewed publications, at national and international conferences, in peer-reviewed journals and to participants and the public (using lay language). Trial registration number ISRCTN17176388.

Background: Magnetic resonance cholangiopancreatography (MRCP) is used in the diagnosis and management of primary sclerosing cholangitis (PSC). However, MRCP is subjective, and guidelines state that there is insufficient evidence to recommend MRCP as a prognostic tool. EASL-PSC guidelines have identified quantitative MRCP (MRCP+) as having promising utility for risk assessment and prediction of clinical outcomes. We conducted a systematic review to determine the clinical utility of MRCP+ metrics for the management of patients with PSC. Methods: We systematically searched PubMed and MEDLINE for cohort studies reporting on MRCP+ metrics associated with risk prediction, clinical outcomes, and disease progression published between January 2019 and May 2024. Studies reporting on adults with diagnosed PSC with paired MRCP were selected. There were no limitations on the type of study (retrospective/prospective). Studies reporting on only qualitative assessment of MRCP were excluded. Results: Six manuscripts with 512 subjects met the study criteria. For risk prediction and disease progression, 4 articles reported 21 unique MRCP+ metrics, which were significantly associated with the Amsterdam-Oxford model and the MAYO risk score. MRCP+ metrics had AUC ranging 0.65 to 0.87 and hazard ratios ranging 0.96 to 17.79 for the prediction of adverse outcomes, including liver transplantation, death, hepatic decompensation, biliary complications, and cholangiocarcinoma. Associations between biochemical markers of liver function (alkaline phosphatase, bilirubin, aspartate aminotransferase, gamma glutamyl transferase, and albumin) ranged -0.42≤ R ≤0.48. Conclusion: MRCP+ metrics have clinical utility to support patient management alongside addressing key gaps, including standardising MRCP assessment, early detection of disease, and quantification of risk.

Background and Aims: Drug development in primary sclerosing cholangitis (PSC) is challenging, giving orphan disease status and variable rates of disease progression. A potential route for new therapies is through attenuation of symptoms. However, the epidemiology of symptomatic presentations and how they inherently fluctuate over time is not known. We conducted a prospective, multicenter study (trial registration: ISRCTN:15518794) to quantify the prevalence, intensity, and variability of pruritus in PSC. Approach and Results: Participants underwent face-to-face symptom assessment through the itch numerical rating scale (NRS) and 5D-itch tool. Clinical, radiological, and biochemical factors associated with pruritus intensity were determined, alongside the impact on health-related quality-of-life [EQ-5D-5L and chronic liver disease questionnaires (CLDQ)] over 12-week intervals (up to 48±4 weeks). In all, 220 patients participated, of whom n=116 reported pruritus, with n=56 scoring NRS worst itch ≥4. Median 5D-itch was greater in people with cirrhosis (11.0 vs. 8.0), transient elastography readings >8.0 kPa (9.5 vs. 5.0), and a history of ascending cholangitis (11.0 vs. 7.0) ( p <0.01; all). 5D-itch correlated positively with serum bilirubin, ALP, ALT, and AST; and negatively with CLDQ and EQ-5D-5L. In patients scoring NRS ≥4, 61.5% reported persistent pruritus intensity over 48 weeks. Reciprocally, 46.2% experienced a spontaneous ≥2 point reduction in NRS without the addition of a new anti-pruritic agent. Conclusions: One in 4 PSC patients experience moderate-severe pruritus, with greater symptom intensity in those with advanced disease. Our dataset is able to serve as a reference tool to aid future interventional study design, with regard to anti-pruritus therapies in PSC.

Introduction: United European Gastroenterology (UEG) Guidelines on immunoglobulin G4 (IgG4)‐related digestive disease provides evidence‐based recommendations for the diagnosis and management of IgG4‐related digestive disease. The aim of this study is to evaluate the adherence to recommendations of this IgG4 guideline across centers in Europe.Patients and methods: Questionnaire‐based data related to organ involvement, diagnosis, treatment and follow‐up of newly diagnosed patients with IgG4‐related digestive diseases over a 3‐year period, were collected from 14 centers in 11 European countries.Results: One hundred and ninety‐nine patients (76% males) were included. Median age at diagnosis was 64 years. Most of the patients had concomitant pancreatic and biliary tree involvement (46%), followed by isolated pancreatic involvement (33.5%), isolated biliary tree involvement (18.5%), esophageal involvement (1.5%) or bowel (0.5%) involvement. Most of the patients (64%) underwent a combination of computed tomography and magnetic resonance imaging at diagnosis. Among the 158 autoimmune pancreatitis patients with or without concomitant bile duct involvement, treatment was performed according to guidelines in 115 patients (73%; moderate adherence). Follow‐up assessment was performed between 2 and 4 weeks in 75 patients (47%, partial adherence). Among 37 patients with liver‐ or biliary tree involvement, 29 patients were treated according to guidelines (78%; full adherence). In the follow‐up of patients with isolated liver‐ or biliary tree involvement, we observed moderate adherence in 21 (57%). Disease monitoring for activity and damage using the IgG4 responder activity index was utilized in only 3/14 centers (poor adherence).Conclusions: IgG4‐related digestive disease is restricted to the pancreas and bile ducts in the majority of patients. Even in specialist centers with an interest in IgG4‐related digestive disease, UEG guideline treatment adherence was moderate, follow‐up at 2–4 weeks was only partial, and monitoring for disease activity was poor. These findings highlight the need for ongoing education and improved adherence to monitoring among healthcare providers.