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. 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. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibroinflammatory damage to the biliary tree.1Karlsen T.H. Folseraas T. Thorburn D. et al.Primary sclerosing cholangitis – a comprehensive review.J Hepatol. 2017; 67: 1298-1323Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar PSC can present in pediatric and adult populations, both men and women, and typically is associated with inflammatory bowel disease (IBD). Complications include progressive biliary fibrosis leading to cirrhosis, liver failure, and cholangiocarcinoma (CCA). Despite improvements in the understanding of pathogenesis (Figure 1), and the recent development of risk-stratification tools, progress to fundamentally alter the course of the disease has been lacking and no effective medical therapy exists. This review discusses relevant topics in the current understanding and management of patients with PSC through the lens of unmet therapeutic need and highlights the state of currently studied interventions and future directions for therapy. The understanding of PSC is challenged by heterogeneous clinical findings that vary between patients: some patients have progressive liver fibrosis and eventual cirrhosis while others have mild fibrosis but nonetheless suffer from recurrent complications such as biliary obstruction, acute bacterial cholangitis, and pruritus. Recently proposed definitions have provided clarity to patients, providers, industry, and regulators.2Ponsioen C.Y. Assis D.N. Boberg K.M. et al.Defining primary sclerosing cholangitis: results from an International Primary Sclerosing Cholangitis Study Group consensus process.Gastroenterology. 2021; 161: 1764-1775Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar The term PSC itself implies the absence of secondary causes of fibrotic biliary strictures. Secondary causes include those identified previously (eg, ischemic biliopathy, IgG4 sclerosing cholangitis) as well as newer considerations such as immune checkpoint inhibitor toxicity. In addition, mutations in the ABCB4 and other genes responsible for progressive familial intrahepatic cholestasis may be confused with PSC. Indeed, the role of genetic testing has been highlighted in recent society guidance documents.3Bowlus C.L. Arrive L. Bergquist A. et al.AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma.Hepatology. 2023; 77: 659-702Crossref PubMed Scopus (31) Google Scholar The ongoing addition of specific causes of secondary sclerosing cholangitis may further refine the characterization of true primary (idiopathic) sclerosing cholangitis. The standard PSC phenotype is defined as large-duct fibrotic strictures of the biliary tree detected on cholangiography by magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). Although most patients have a cholestatic pattern of injury on liver tests such as alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT), this is not always found and levels can fluctuate over time. Given that 70% to 80% of patients with PSC have IBD, specifically a particular right-sided colitis in many patients, PSC with IBD should be viewed as the standard phenotype of a disease manifested in two organs. The impact of PSC therapies on IBD activity, and IBD activity on PSC, is critical in the assessment of specific interventions. A minority of patients (5%–10%) have small-duct PSC, defined as a recent (<1 year) normal high-quality ERCP or MRCP, with histologic features typical of PSC or with both concurrent overt or histologic features of IBD and increased ALP levels (GGT in pediatric cases).2Ponsioen C.Y. Assis D.N. Boberg K.M. et al.Defining primary sclerosing cholangitis: results from an International Primary Sclerosing Cholangitis Study Group consensus process.Gastroenterology. 2021; 161: 1764-1775Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Although the clinical course of small-duct PSC typically is benign and such patients have a much lower risk of CCA or progressive liver fibrosis, a subset of such patients will progress over time to the large-duct phenotype and become susceptible to its complications.4Ringe K.I. Bergquist A. Lenzen H. et al.Clinical features and MRI progression of small duct primary sclerosing cholangitis (PSC).Eur J Radiol. 2020; 129109101Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Another small percentage of patients (5%) have PSC overlapping with autoimmune hepatitis (AIH),5Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatol. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar which is identified more frequently in pediatric populations. For these patients, prognosis is most affected by complications derived from large-duct strictures of PSC rather than AIH itself. The common practice of excluding patients with less-common phenotypes (eg, small-duct PSC, overlapping PSC and AIH) from clinical trials to focus on the standard phenotype (large-duct PSC with IBD) is understandable. However, a significant minority of patients therefore are ineligible for therapeutic trials, which also reduces the pool of available patients for enrollment. The incidence (1–1.5 per 100,000 person-years) and prevalence (6–16 per 100,000 person-years)6Bambha K. Kim W.R. Talwalkar J. et al.Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community.Gastroenterology. 2003; 125: 1364-1369Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar,7Boberg K.M. Aadland E. Jahnsen J. et al.Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population.Scand J Gastroenterol. 1998; 33: 99-103Crossref PubMed Scopus (453) Google Scholar of PSC vary significantly across the world and may be increasing over time, but this may be unrelated to the true increase in disease burden. Until the 1980s, the initial clinical presentation of PSC was entirely symptomatic, often at advanced stages.8Helzberg J.H. Petersen J.M. Boyer J.L. Improved survival with primary sclerosing cholangitis. A review of clinicopathological features and comparison of symptomatic and asymptomatic patients.Gastroenterology. 1987; 92: 1869-1875Crossref PubMed Scopus (168) Google Scholar A decade later, close to 50% of patients still presented with symptoms (pruritus, abdominal pain, fatigue), with close to a quarter subsequently developing symptoms within 5 years.9Broome U. Olsson R. Loof L. et al.Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.Gut. 1996; 38: 610-615Crossref PubMed Scopus (709) Google Scholar In contemporary times with widespread access to MRCP, patients increasingly are diagnosed at early stages and often asymptomatic. Epidemiologic studies in the United States have been challenging both because of limitations of medical databases and because of the lack of International Classification of Diseases codes specific to PSC, which until 2018 consisted only of the generic term cholangitis (K83). The introduction of a PSC-specific code (K83.01), through dedicated advocacy by clinicians and patient organizations such as PSC Partners Seeking a Cure, has opened the opportunity for better population-based studies in the future. Patients of all racial and ethnic backgrounds are at risk of PSC. Recent studies have shown that the frequency of PSC among African Americans is similar to their share of the general population.10Bowlus C.L. Li C.S. Karlsen T.H. et al.Primary sclerosing cholangitis in genetically diverse populations listed for liver transplantation: unique clinical and human leukocyte antigen associations.Liver Transpl. 2010; 16: 1324-1330Crossref PubMed Scopus (61) Google Scholar,11Goldberg D.S. Levy C. Yimam K. et al.Primary sclerosing cholangitis is not rare among blacks in a multicenter North American consortium.Clin Gastroenterol Hepatol. 2018; 16: 591-593Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar The traditional understanding of PSC as a male-predominant disease6Bambha K. Kim W.R. Talwalkar J. et al.Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community.Gastroenterology. 2003; 125: 1364-1369Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar is balanced by trends showing an increasing proportion of females with PSC and IBD,12Lunder A.K. Hov J.R. Borthne A. et al.Prevalence of sclerosing cholangitis detected by magnetic resonance cholangiography in patients with long-term inflammatory bowel disease.Gastroenterology. 2016; 151: 660-669Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar although males appear to have a higher risk of disease progression.13Weismüller T. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar Among pediatric cohorts, multicenter studies from the Pediatric PSC Consortium highlight a 33% concurrence of AIH and a median survival with native liver of 3.5 years in patients who develop biliary complications.14Deneau M.R. El-Matary W. Valentino P.L. et al.The natural history of primary sclerosing cholangitis in 781 children: a multicenter, international collaboration.Hepatology. 2017; 66: 518-527Crossref PubMed Scopus (125) Google Scholar Approximately 5% of patients with IBD have concomitant PSC, suggesting that screening this population is beneficial, although how best to screen is uncertain. Testing of liver biochemistries in a cohort of IBD patients found that serum GGT was the only independent factor predicting the diagnosis of PSC (odds ratio, 1.8; 95% CI, 1.3–2.5).15Belle A. Laurent V. Pouillon L. et al.Systematic screening for primary sclerosing cholangitis with magnetic resonance cholangiography in inflammatory bowel disease.Dig Liver Dis. 2018; 50: 1012-1018Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Although some patients with PSC have normal liver biochemistry values, 75% have persistent or fluctuating ALP and GGT levels, suggesting that repeated screening may be needed.12Lunder A.K. Hov J.R. Borthne A. et al.Prevalence of sclerosing cholangitis detected by magnetic resonance cholangiography in patients with long-term inflammatory bowel disease.Gastroenterology. 2016; 151: 660-669Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Screening of 322 IBD patients with MRCP in Norway identified 17 new cases of PSC who had no symptoms and no abnormal liver biochemistry values, for a final prevalence of 8.1%.12Lunder A.K. Hov J.R. Borthne A. et al.Prevalence of sclerosing cholangitis detected by magnetic resonance cholangiography in patients with long-term inflammatory bowel disease.Gastroenterology. 2016; 151: 660-669Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Whether these isolated cholangiographic changes should be termed an early clinical, or even a pre-clinical, phase of PSC is unclear. Although a recent meta-analysis reported a lower prevalence than the study earlier described above,16Barberio B. Massimi D. Cazzagon N. et al.Prevalence of primary sclerosing cholangitis in patients with inflammatory bowel disease: a systematic review and meta-analysis.Gastroenterology. 2021; 161: 1865-1877Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar the literature is limited by inconsistent methodology for ascertaining PSC in IBD cohorts. The rate at which patients with pre-clinical PSC develop symptoms or more overt clinical manifestations is unknown and therefore routine MRCP screening of IBD patients purely for screening purposes is debatable. However, consideration should be given to this early phase for emerging therapeutic interventions aimed at preventing disease progression. Recent guidance on PSC highlights the centrality of magnetic resonance imaging (MRI) in the diagnosis of PSC.3Bowlus C.L. Arrive L. Bergquist A. et al.AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma.Hepatology. 2023; 77: 659-702Crossref PubMed Scopus (31) Google Scholar A high-quality MRI/MRCP is required and is defined by a minimum 1.5-T field with 3-dimensional reconstruction that is T2 weighted.17Schramm C. Eaton J. Ringe K.I. et al.Recommendations on the used of magnetic resonance imaging in PSC-a position statement from the International PSC Study Group.Hepatology. 2017; 66: 1675-1688Crossref PubMed Scopus (87) Google Scholar Repeated imaging with interpretation at an experienced center is recommended for patients with equivocal findings. In the absence of large-duct strictures, histologic evaluation for small-duct PSC should be performed. Histologic findings include typical features of sclerosing cholangitis such as periductal fibrosis and fibro-obliterative duct lesions, or compatible features including bile duct loss, ductular reaction, a biliary pattern of interface activity, and cholate stasis.2Ponsioen C.Y. Assis D.N. Boberg K.M. et al.Defining primary sclerosing cholangitis: results from an International Primary Sclerosing Cholangitis Study Group consensus process.Gastroenterology. 2021; 161: 1764-1775Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar In the setting of IBD and typical histologic features, a diagnosis of small-duct PSC can be made. Otherwise, testing for genetic mutations in ABCB4 and other genes associated with inherited forms of cholestasis should be performed, particularly in the absence of IBD.18Hakim A. Zhang X. DeLisle A. et al.Clinical utility of genomic analysis in adults with idiopathic liver disease.J Hepatol. 2019; 70: 1214-1221Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar In the absence of known IBD, patients with newly diagnosed PSC should receive an ileocolonoscopy with random biopsies to exclude colitis. This is especially important because of the increased risk of colorectal cancer in patients with PSC and IBD.19Trivedi P.J. Crothers H. Mytton J. et al.Effects of primary sclerosing cholangitis on risks of cancer and death in people with inflammatory bowel disease, based on sex, race, and age.Gastroenterology. 2020; 159: 915-928Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar If IBD is not found, a colonoscopy with biopsies should be repeated every 5 years for screening or at the time of new clinical suspicion. After diagnosis, staging and prognostication should be performed to identify high-risk groups. All patients with PSC should have baseline assessment of liver fibrosis. Although histology remains the gold standard, and is best evaluated using the Nakanuma criteria,20De Vries E.M.G. Verheij J. Hubscher S.G. et al.Applicability and prognostic value of histologic scoring systems in primary sclerosing cholangitis.J Hepatol. 2015; 63: 1212-1219Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar,21De Vries E.M.G. de Krijger M. Farkkila M. et al.Validation of the prognostic value of histologic scoring systems in primary sclerosing cholangitis: an international cohort study.Hepatology. 2017; 65: 907-919Crossref PubMed Scopus (72) Google Scholar the invasive nature of the biopsy and the heterogeneity of biliary findings and fibrosis in PSC make this unadvisable for routine care. However, the Food and Drug Administration requirement of histologic assessment for clinical trials highlights the current need to include biopsies in phase 3 therapeutic studies.22Ponsioen C.Y. Chapman R.W. Chazouilleres O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (123) Google Scholar Noninvasive measurement of fibrosis is recommended and can be performed with liver stiffness measurement (LSM) modalities such as transient elastography (TE) and magnetic resonance elastography. A retrospective study of TE in a French cohort reported a cut-off value of 14.4 kPa for stage 4 fibrosis, with 0.88 diagnostic accuracy.23Corpechot C. Gaouar F. El Naggar A. et al.Baseline values and changes in liver stiffness measured by transient elastography are associated with severity of fibrosis and outcomes of patients with primary sclerosing cholangitis.Gastroenterology. 2014; 146: 970-979Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar An annual increase of more than 1.3 kPa/y was associated with reduced transplant-free survival. A prospective study (FICUS) organized through the International PSC Study Group aims to validate these findings and determine the optimal frequency of TE testing in PSC. Limitations of TE in PSC include increased stiffness resulting from transient biliary obstruction and the patchy nature of biliary strictures. Magnetic resonance elastography stiffness of greater than 4.32 kPa is associated with a significant risk of hepatic decompensation, as is an increase of greater than 0.34 kPa/y.24Eaton J.E. Sen A. Hoodeshenas S. et al.Changes in liver stiffness, measured by magnetic resonance elastography, associated with hepatic decompensation in patients with primary sclerosing cholangitis.Clin Gastroenterol Hepatol. 2020; 18: 1576-1583Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar No therapeutic clinical trial to date has shown a reduction of fibrosis as measured by LSM. Serum-based measures of fibrosis, particularly the enhanced liver fibrosis (ELF) score, quantitating serum tissue inhibitor of metalloproteinase 1, procollagen III amino terminal peptide, and hyaluronic acid, increasingly are regarded as clinically and prognostically useful in the setting of PSC.25Vesterhus M. Hov J.R. Holm A. et al.Enhanced liver fibrosis score predicts transplant-free survival in primary sclerosing cholangitis.Hepatology. 2015; 62: 188-197Crossref PubMed Scopus (97) Google Scholar Analysis of ELF score and paired liver biopsy specimens collected 96 weeks apart during a phase 2b clinical trial of simtuzumab revealed that the baseline ELF score was associated with the risk of an increase in fibrosis by 1 or more stages.26Trivedi P.J. Muir A.J. Levy C. et al.Inter- and intra-individual variation, and limited prognostic utility, of serum alkaline phosphatase in a trial of patients with primary sclerosing cholangitis.Clin Gastroenterol Hepatol. 2021; 19: 1248-1257Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar The recent availability of serum ELF for clinical use in nonalcoholic fatty liver disease may lead to more routine testing in the clinic, and the interpretation of these results for individual patients with PSC should be studied further. The utility of prognostic scores based on imaging features of PSC is receiving renewed attention. The Amsterdam criteria originally were proposed based on ERCP images and had prognostic value,27Ponsioen C.Y. Vrouenraets S.M.E. Prawirodirdjo W. et al.Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population.Gut. 2002; 51: 562-566Crossref PubMed Scopus (234) Google Scholar but the replacement of diagnostic ERCP with MRCP lessened interest in this system. The ANALI score integrates biliary stricture burden with liver parenchymal abnormalities including hepatic dysmorphy and radiographic evidence of portal hypertension on MRI and can predict hepatic decompensation or survival without liver transplantation with a C-statistic of 0.89 (with gadolinium) and 0.75 (without gadolinium).28Lemoinne S. Cazzagon N. El Mouhadi S. et al.Simple magnetic resonance scores associated with outcomes of patients with primary sclerosing cholangitis.Clin Gastroenterol Hepatol. 2019; 17: 2785-2792Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Scores such as the ANALI could be combined with LSM to further improve accuracy. Other recently published imaging-based tools requiring multicenter validation include the DiStrict score29Grigoriadis A. Ringe K.I. Bengtsson J. et al.Development of a prognostic MRCP-score (DiStrict) for individuals with large-duct primary sclerosing cholangitis.JHEP Rep. 2022; 4100595PubMed Google Scholar and a machine learning approach.30Singh Y. Jons W.A. Eaton J.E. et al.Algebraic topology-based machine learning using MRI predicts outcomes in primary sclerosing cholangitis.Eur Radiol Exp. 2022; 6: 58Crossref PubMed Scopus (3) Google Scholar Quantitative biliary imaging (MRCP+) is now approved for use in the United States and several studies have shown some ability to predict clinical outcomes.31Cristoferi L. Porta M. Bernasconi D.P. et al.A quantitative MRCP-derived score for medium-term outcome prediction in primary sclerosing cholangitis.Dig Liver Dis. 2023; 55: 373-380Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar,32Cazzagon N. El Mouhadi S. Vanderbecq Q. et al.Quantitative magnetic resonance cholangiopancreatography metrics are associated with disease severity and outcomes in people with primary sclerosing cholangitis.JHEP Rep. 2022; 4100577PubMed Google Scholar These approaches to biliary tree assessment in PSC require further study as candidate clinical trial end points. Prediction tools based on clinical and laboratory features also may hold value in the clinical care and prognostication of patients with PSC. The Revised Mayo Risk Score is the most-studied prediction tool, particularly for short-term outcomes,33Kim W.R. Therneau T.M. Wiesner R.H. et al.A revised natural history model for primary sclerosing cholangitis.Mayo Clin Proc. 2000; 75: 688-694Abstract Full Text Full Text PDF PubMed Google Scholar however, it has not been found adequate for clinical trial purposes, particularly outside mortality endpoints, and cannot account for variant phenotypes.34Lindor K.D. Kowdley K.V. Luketic V.A. et al.High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.Hepatology. 2009; 50: 808-814Crossref PubMed Scopus (570) Google Scholar Newer models, including the Amsterdam-Oxford,35De Vries E.M. Wang J. Williamson K.D. et al.A novel prognostic model for transplant-free survival in primary sclerosing cholangitis.Gut. 2018; 67: 1864-1869Crossref PubMed Scopus (74) Google Scholar,36Goet J.C. Floreani A. Verhelst X. et al.Validation, clinical utility, and limitations of the Amsterdam-Oxford model for primary sclerosing cholangitis.J Hepatol. 2019; 71: 992-999Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar UK-PSC,37Goode E.C. Clark A.B. Mells G.F. et al.Factors associated with outcomes of patients with primary sclerosing cholangitis and development and validation of a risk scoring system.Hepatology. 2019; 69: 2120-2135Crossref PubMed Scopus (47) Google Scholar Sclerosing Cholangitis Outcomes in PEdiatrics,38Deneau M.R. Mack C. Perito E.R. et al.The sclerosing cholangitis outcomes in pediatrics (SCOPE) index: a prognostic tool for children.Hepatology. 2021; 73: 1074-1087Crossref PubMed Scopus (18) Google Scholar and PReSTo,39Eaton J.E. Vesterhus M. McCauley B.M. et al.Primary sclerosing cholangitis risk estimate tool (PREsTo) predicts outcomes of the disease: a derivation and validation study using machine learning.Hepatology. 2020; 71: 214-224Crossref PubMed Scopus (73) Google Scholar represent a significant advance and can address short-term and long-term outcomes. Each score outperformed the Revised Mayo Risk Score, and several are applicable to specific populations such as pediatrics (Sclerosing Cholangitis Outcomes in PEdiatrics), overlapping PSC and AIH (Amsterdam-Oxford), and small-duct PSC (UK-PSC and Amsterdam-Oxford). PReSTo is a notable advance in prognostication given that it was developed using machine learning, resulting in the highest C-statistic for any tool to date (0.90; 95% CI, 0.84–0.95).39Eaton J.E. Vesterhus M. McCauley B.M. et al.Primary sclerosing cholangitis risk estimate tool (PREsTo) predicts outcomes of the disease: a derivation and validation study using machine learning.Hepatology. 2020; 71: 214-224Crossref PubMed Scopus (73) Google Scholar The use of these tools should be considered in light of the stage of the disease, the patient population, and the end point (transplant-free survival vs decompensated cirrhosis).40Trivedi P.J. Risk stratification in primary sclerosing cholangitis: it's time to move on from replicating imperfection and break the glass ceiling.J Hepatol. 2019; 71: 867-870Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar This is relevant for therapeutic trials, for which these models can help identify patients most likely to benefit from a drug's mechanism(s) of action. The lack of effective medical therapy for PSC is a glaring unmet need and stands in stark contrast to progress made in other chronic liver disorders in recent decades. In the absence of a therapy proven to improve the clinical course of disease, patients and clinicians often rely on suboptimal data to make management decisions. All patients with PSC should be highly encouraged to seek out and consider participation in clinical trials at experienced centers. Although effective treatment is lacking for many symptoms of PSC, including fatigue, current and emerging therapies for management of cholestatic pruritus are summarized in Table 1.Table 1Current and Emerging Pharmacotherapy for Cholestatic Pruritus in PSCCategoryAgentDosingCommentCurrent therapies NonpharmacologicEmollients, heat avoidanceAs neededSufficient for mild pruritus AntihistamineHydroxyzine25 mg q8hDrowsiness Bile acid sequestrantsCholestyramine4–6 g/taken 20 minutes before mealsFrequent GI intolerance SSRISertraline100 mg/dLimited efficacy μ-opioid antagonistNaltrexone50–100 mg/dLimited efficacy PXR agonistRifampin150–300 mg/dMay cause hepatotoxicity, AKI, hemolytic anemia PPAR agonistsFenofibrate, Bezafibrate160 mg/d400 mg/dSignificant improvement in pruritus in FITCH study (bezafibrate) Systemic therapiesPlasmapheresis, ultraviolet phototherapy5–10 sessions or until effectVariable efficacyPotential future therapies G-protein–coupled–receptor 5MAS-related GPR family member X4 EP547NCT05525520 Ileal sodium–bile acid cotransporter inhibitor (ASBTi)Frequent adverse effect: drug-induced diarrheaVolixibatMaralixibat (LUM001)Odevixibat (A4250)A3907NCT04663308NCT02061540NCT05642468AKI, acute kidney injury; ASBTi, ileal sodium-dependent bile acid transporter inhibitors; FITCH, fibrates for cholestatic ITCH; GI, gastrointestinal; GPR, G protein coupled receptor; MAS, mastocyte; PPAR, peroxisome proliferator-activated receptor; PSC, primary sclerosing cholangitis; PXR, pregnane X receptor; q8h, every 8 hours; SSRI, selective serotonin reuptake inhibitor. Open table in a new tab AKI, acute kidney injury; ASBTi, ileal sodium-dependent bile acid transporter inhibitors; FITCH, fibrates for cholestatic ITCH; GI, gastrointestinal; GPR, G protein coupled receptor; MAS, mastocyte; PPAR, peroxisome proliferator-activated receptor; PSC, primary sclerosing cholangitis; PXR, pregnane X receptor; q8h, every 8 hours; SSRI, selective serotonin reuptake inhibitor. Ursodeoxycholic acid (UDCA), a bile acid that renders the bile pool more hydrophilic, has been widely used in PSC. Although safe at doses less than 25 mg/kg/d, the benefit of UDCA remains uncertain. A randomized, placebo-controlled trial of 105 patients treated with 13 to 15 mg/kg/d UDCA vs placebo revealed a meaningful reduction in serum ALP level, but no change in histologic progression or transplantation.41Lindor K.D. Ursodiol for primary sclerosing cholangitis. Mayo primary sclerosing cholangitis-ursodeoxycholic acid study group.N Engl J Med. 1997; 336: 691-695Crossref PubMed Scopus (558) Google Scholar A larger study with 198 patients randomized to 17 to 23 mg/kg/d UDCA or placebo showed a tendency to improved survival in the UDCA-treated patients, but there was no statistical significance at the studied dose.42Olsson R. Boberg K.M. de Muckadell O.S. et al.High-do