In children with asymptomatic potential celiac disease (PCD), a panel of seven serum proteomic biomarkers can predict which individuals will go on to develop villous atrophy (VA), according to investigators.

Given that PCD patients present with positive serology and intact duodenal architecture, these findings may provide a much-needed tool for identifying patients who are more likely to benefit from early dietary interventions, lead author Renata Auricchio, MD, PhD, of the University of Naples Federico II, Italy, and colleagues reported.

“PCD offers the unique opportunity to observe the progression of gluten-induced tissue damage in celiac disease,” the investigators wrote in Gastroenterology. “These patients recognize gluten and produce specific autoantibodies, but have not developed intestinal damage.”

The study included 31 children with asymptomatic PCD who were eating a gluten-containing diet. Serum samples from each child were analyzed for the relative abundance of 92 inflammation-linked proteins using a proximity extension immunoassay. Statistical analyses, including partial least squares discriminant and linear discriminant analyses, were then applied to identify which proteins were associated with the development of VA.

After a mean follow-up period of 5.85 years, 14 participants developed VA (ie, celiac disease), while the remaining 17 remained asymptomatic.

Panel analysis revealed that specific inflammatory proteins, including interleukin (IL)–20, IL-2, sirtuin 2 (SIRT2), leukemia inhibitory factor (LIF), IL-22 receptor subunit a1, cystatin D (CST5), IL-17 receptor A, IL-15 receptor subunit a (RA), CUB domain–containing protein 1 (CDCP1), and IL-14, were 1.23- to 1.76-fold higher in children who developed VA. Among these, seven proteins — CDCP1, IL-2, LIF, IL10RA, SIRT2, CST5, and IL-4 — were able to significantly distinguish between symptomatic and asymptomatic cases in a linear discriminant model. This panel of seven proteins achieved a predictive accuracy of 96.8% in identifying children at risk of VA.

Additionally, bioinformatics pathway analysis confirmed that the broader set of proteins is involved in the positive regulation of JAK-STAT signaling (involving IL-22 receptor subunit a1, IL-4, IL-20, IL10RA, LIF, and IL-2), inflammatory responses (IL-4, IL-20, LIF, and IL-2), and processes such as tyrosine phosphorylation, leukocyte differentiation, IgG isotype switching, and protein phosphorylation regulation. These findings suggest that gluten-induced inflammation may already be active in early stages of the disease, including the initial phases of leukocyte differentiation, according to the investigators.

“Over a long follow-up on a gluten-containing diet, only 40% of these patients progressed to VA,” Dr. Auricchio and colleagues wrote. “Notably, 25%-30% of children with PCD even stop producing anti–tissue transglutaminase antibodies, and the others keep on producing autoantibodies but preserve a normal intestinal mucosa. Considering these data, the decision to address a patient with PCD on a gluten-free diet at time of diagnosis is quite critical.”

The researchers noted that this new model, with accuracy exceeding 95%, is well suited for routine use because of its practicality and reliability.

“Our previous model, based mainly on small intestinal mucosa features, moved a step toward the prediction of outcome but still required a mucosal biopsy, and the accuracy of prediction was not greater than 80%, which is somewhat uncertain for a lifelong clinical decision,” they wrote. In contrast, the present model “appears to be sufficient to immediately suggest a gluten-free diet in children with PCD, who are almost certainly committed to developing VA.”

The investigators called for long-term studies to validate their findings in other cohorts, including adult populations.This study was supported by the TIMID project and Inflammation in Human Early Life: Targeting Impacts on Life Course Health (INITIALISE) by the Horizon Europe Program of the European Union. The investigators disclosed no conflicts of interest.

In children with asymptomatic potential celiac disease (PCD), a panel of seven serum proteomic biomarkers can predict which individuals will go on to develop villous atrophy (VA), according to investigators.

Given that PCD patients present with positive serology and intact duodenal architecture, these findings may provide a much-needed tool for identifying patients who are more likely to benefit from early dietary interventions, lead author Renata Auricchio, MD, PhD, of the University of Naples Federico II, Italy, and colleagues reported.

“PCD offers the unique opportunity to observe the progression of gluten-induced tissue damage in celiac disease,” the investigators wrote in Gastroenterology. “These patients recognize gluten and produce specific autoantibodies, but have not developed intestinal damage.”

The study included 31 children with asymptomatic PCD who were eating a gluten-containing diet. Serum samples from each child were analyzed for the relative abundance of 92 inflammation-linked proteins using a proximity extension immunoassay. Statistical analyses, including partial least squares discriminant and linear discriminant analyses, were then applied to identify which proteins were associated with the development of VA.

After a mean follow-up period of 5.85 years, 14 participants developed VA (ie, celiac disease), while the remaining 17 remained asymptomatic.

Panel analysis revealed that specific inflammatory proteins, including interleukin (IL)–20, IL-2, sirtuin 2 (SIRT2), leukemia inhibitory factor (LIF), IL-22 receptor subunit a1, cystatin D (CST5), IL-17 receptor A, IL-15 receptor subunit a (RA), CUB domain–containing protein 1 (CDCP1), and IL-14, were 1.23- to 1.76-fold higher in children who developed VA. Among these, seven proteins — CDCP1, IL-2, LIF, IL10RA, SIRT2, CST5, and IL-4 — were able to significantly distinguish between symptomatic and asymptomatic cases in a linear discriminant model. This panel of seven proteins achieved a predictive accuracy of 96.8% in identifying children at risk of VA.

Additionally, bioinformatics pathway analysis confirmed that the broader set of proteins is involved in the positive regulation of JAK-STAT signaling (involving IL-22 receptor subunit a1, IL-4, IL-20, IL10RA, LIF, and IL-2), inflammatory responses (IL-4, IL-20, LIF, and IL-2), and processes such as tyrosine phosphorylation, leukocyte differentiation, IgG isotype switching, and protein phosphorylation regulation. These findings suggest that gluten-induced inflammation may already be active in early stages of the disease, including the initial phases of leukocyte differentiation, according to the investigators.

“Over a long follow-up on a gluten-containing diet, only 40% of these patients progressed to VA,” Dr. Auricchio and colleagues wrote. “Notably, 25%-30% of children with PCD even stop producing anti–tissue transglutaminase antibodies, and the others keep on producing autoantibodies but preserve a normal intestinal mucosa. Considering these data, the decision to address a patient with PCD on a gluten-free diet at time of diagnosis is quite critical.”

The researchers noted that this new model, with accuracy exceeding 95%, is well suited for routine use because of its practicality and reliability.

“Our previous model, based mainly on small intestinal mucosa features, moved a step toward the prediction of outcome but still required a mucosal biopsy, and the accuracy of prediction was not greater than 80%, which is somewhat uncertain for a lifelong clinical decision,” they wrote. In contrast, the present model “appears to be sufficient to immediately suggest a gluten-free diet in children with PCD, who are almost certainly committed to developing VA.”

The investigators called for long-term studies to validate their findings in other cohorts, including adult populations.This study was supported by the TIMID project and Inflammation in Human Early Life: Targeting Impacts on Life Course Health (INITIALISE) by the Horizon Europe Program of the European Union. The investigators disclosed no conflicts of interest.

In children with asymptomatic potential celiac disease (PCD), a panel of seven serum proteomic biomarkers can predict which individuals will go on to develop villous atrophy (VA), according to investigators.

Given that PCD patients present with positive serology and intact duodenal architecture, these findings may provide a much-needed tool for identifying patients who are more likely to benefit from early dietary interventions, lead author Renata Auricchio, MD, PhD, of the University of Naples Federico II, Italy, and colleagues reported.

“PCD offers the unique opportunity to observe the progression of gluten-induced tissue damage in celiac disease,” the investigators wrote in Gastroenterology. “These patients recognize gluten and produce specific autoantibodies, but have not developed intestinal damage.”

The study included 31 children with asymptomatic PCD who were eating a gluten-containing diet. Serum samples from each child were analyzed for the relative abundance of 92 inflammation-linked proteins using a proximity extension immunoassay. Statistical analyses, including partial least squares discriminant and linear discriminant analyses, were then applied to identify which proteins were associated with the development of VA.

After a mean follow-up period of 5.85 years, 14 participants developed VA (ie, celiac disease), while the remaining 17 remained asymptomatic.

Panel analysis revealed that specific inflammatory proteins, including interleukin (IL)–20, IL-2, sirtuin 2 (SIRT2), leukemia inhibitory factor (LIF), IL-22 receptor subunit a1, cystatin D (CST5), IL-17 receptor A, IL-15 receptor subunit a (RA), CUB domain–containing protein 1 (CDCP1), and IL-14, were 1.23- to 1.76-fold higher in children who developed VA. Among these, seven proteins — CDCP1, IL-2, LIF, IL10RA, SIRT2, CST5, and IL-4 — were able to significantly distinguish between symptomatic and asymptomatic cases in a linear discriminant model. This panel of seven proteins achieved a predictive accuracy of 96.8% in identifying children at risk of VA.

Additionally, bioinformatics pathway analysis confirmed that the broader set of proteins is involved in the positive regulation of JAK-STAT signaling (involving IL-22 receptor subunit a1, IL-4, IL-20, IL10RA, LIF, and IL-2), inflammatory responses (IL-4, IL-20, LIF, and IL-2), and processes such as tyrosine phosphorylation, leukocyte differentiation, IgG isotype switching, and protein phosphorylation regulation. These findings suggest that gluten-induced inflammation may already be active in early stages of the disease, including the initial phases of leukocyte differentiation, according to the investigators.

“Over a long follow-up on a gluten-containing diet, only 40% of these patients progressed to VA,” Dr. Auricchio and colleagues wrote. “Notably, 25%-30% of children with PCD even stop producing anti–tissue transglutaminase antibodies, and the others keep on producing autoantibodies but preserve a normal intestinal mucosa. Considering these data, the decision to address a patient with PCD on a gluten-free diet at time of diagnosis is quite critical.”

The researchers noted that this new model, with accuracy exceeding 95%, is well suited for routine use because of its practicality and reliability.

“Our previous model, based mainly on small intestinal mucosa features, moved a step toward the prediction of outcome but still required a mucosal biopsy, and the accuracy of prediction was not greater than 80%, which is somewhat uncertain for a lifelong clinical decision,” they wrote. In contrast, the present model “appears to be sufficient to immediately suggest a gluten-free diet in children with PCD, who are almost certainly committed to developing VA.”

The investigators called for long-term studies to validate their findings in other cohorts, including adult populations.This study was supported by the TIMID project and Inflammation in Human Early Life: Targeting Impacts on Life Course Health (INITIALISE) by the Horizon Europe Program of the European Union. The investigators disclosed no conflicts of interest.

Primary sclerosing cholangitis (PSC) is a rare, chronic, and progressive cholestatic liver disorder.¹ Commonly associated with pruritus, an intense itch that significantly impacts patients’ lives, PSC is characterized by inflammation, fibrosis, and stricturing of the intrahepatic and/or extrahepatic bile ducts.^1,2 The natural history of PSC is highly variable, but disease progression frequently leads to end-stage liver disease, with liver transplantation as the only currently available treatment option.^1,2 PSC has a close association with inflammatory bowel disease (IBD), with approximately 60% to 80% of patients with PSC having a diagnosis of either ulcerative colitis or Crohn’s disease.^1,3 Although the exact pathogenesis of PSC is still under investigation, evidence suggests a complex interplay of genetic susceptibility, immune dysregulation, and environmental factors may be responsible.⁴

PSC is considered a rare disease, with an estimated global median incidence of 0.7 to 0.8 per 100,000 and estimated prevalence of 10 cases per 100,000.⁵ PSC is more common in men (60% to 70%), with men having a 2-fold higher risk of developing PSC than women.^2,6,7 The majority of patients are diagnosed between the ages of 30 to 40 years, with a median survival time after diagnosis without a liver transplant of 10 to 20 years.^2,7-9

Signs and Symptoms of PSC

Approximately 50% of patients with PSC are asymptomatic when persistently abnormal liver function tests trigger further evaluation.^1,2,10 Patients may complain of pruritus, which may be episodic; right upper quadrant pain; fatigue; and jaundice.^2,7 Fevers, chills, and night sweats may also be present at the time of diagnosis.²  

Pruritus and fatigue are common symptoms of PSC and can have a significant impact on the lives of patients.⁵ The pathogenesis of pruritus is complex and not completely understood but is believed to be caused by a toxic buildup of bile acids due to a decrease in bile flow related to inflammation, fibrosis, and stricturing resulting from PSC.^11,12

Pruritus has been shown to have a substantial impact on patients’ health-related quality of life (QoL), with greater impairment seen with increased severity of pruritus.¹³ Specifically, patients with pruritus report physical limitations on QoL-specific questionnaires, as well as an impact on emotional, bodily pain, vitality, energy, and physical mobility measures.¹⁴

From a multinational survey on the impact of pruritus in PSC patients, 96% of respondents indicated that their itch was worst in the evening, with 58% indicating mood changes, including anxiety, irritability, and feelings of hopelessness due to their itch. Further, respondents reported that their pruritus disrupted their day-to-day responsibilities and that this disruption lasted 1 month or more.¹⁵

The psychological impact of living with PSC has not been well studied, although it has been found that individuals living with the disease demonstrated a greater number of depressive symptoms and poorer well-being, often coinciding with their stage of liver disease and comorbidity with IBD.¹⁶

In those living with PSC, mental health-related QoL has been shown to be influenced by liver disease, pruritus, social isolation, and depression. In one study, nearly 75% of patients expressed existential anxiety regarding disease progression and shortened life expectancy, with 25% disclosing social isolation.¹³

Diagnosing PSC

PSC should be considered in patients with a cholestatic pattern of liver test abnormalities, especially in those with underlying IBD. Abnormalities that may be detected on physical examination include jaundice, hepatomegaly, splenomegaly, and excoriations from scratching.^3,5 PSC and autoimmune hepatitis (AIH) may coexist, particularly in younger patients, with serum biochemical tests and autoantibodies suggestive of AIH.² Most patients demonstrate elevated serum alkaline phosphatase levels, as well as modest elevation of transaminases.² Bilirubin and albumin levels may be normal at the time of diagnosis, although they may become increasingly abnormal as the disease progresses.² A subset of patients (10%) may have elevated levels of immunoglobulin G4 (IgG4) and tend to progress more rapidly in the absence of treatment.² Autoantibodies, which are characteristic of primary biliary cholangitis (PBC)—another rare, chronic, and progressive liver disease—are usually absent in PSC. When present, autoantibodies are of unknown clinical significance.^2,17

Imaging, including cross-sectional imaging, particularly magnetic resonance cholangiopancreatography, is often used to the biliary tree in patients with persistently abnormal cholestatic tests.² A diagnosis of PSC is typically established by the demonstration of characteristic multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts on cholangiography.⁵ The diagnosis of PSC is occasionally made on liver biopsy, which may reveal characteristic features of “onion skin fibrosis” and fibro-obliterative cholangitis when cholangiography is normal. In this circumstance, it is classified as “small-duct PSC.”^5,18

Treatment and Management of PSC

Despite advances in our understanding of PSC, there are currently no approved drug therapies for PSC and no approved treatments for PSC-associated pruritus. The American Association for the Study of Liver Diseases (AASLD) published the most recent practice guidance for the treatment and management of PSC in 2022.⁷

Ursodeoxycholic acid (UDCA) has been widely studied as a potential PSC treatment. While UDCA demonstrates improvements in biochemical measures, there has been a lack of evidence demonstrating clinical improvement.¹⁹

 The role of UDCA in the treatment of PSC is unclear and, at this time, is not supported by the American College of Gastroenterology or AASLD.^2,7 Additional treatments, including immunosuppressive medications (methotrexate, tacrolimus), corticosteroids (prednisolone), and antibiotics (minocycline, vancomycin) have been explored but have not shown definitive clinical benefit.²

UDCA, if used, should not be prescribed at doses in excess of 20 mg/kg/day since high-dose UDCA (28-30 mg/kg) was associated with adverse liver outcomes.²

Although there are no therapies approved specifically to manage PSC-associated pruritus, cholestyramine and rifampin have been shown to be beneficial in relieving itch in some patients.²² In a survey of PSC patients, one in three reported suffering from pruritus during the previous week. It is possible that the prevalence and severity of pruritus in PSC may be under-recognized compared with PBC, given that patients and physicians may be focused on the many other medical issues that are often prioritized over symptoms, such as concern about cancer risk and need for frequent surveillance procedures.^15,23 Discussions between patients and physicians are important to deepen our understanding of the prevalence of pruritus and its burden on the lives of patients.

Novel therapies for PSC and PSC-associated pruritus, including a selective inhibitor of the ileal bile acid transporter (IBAT), are currently being explored in clinical trials. Research suggests that the inhibition of IBAT blocks the recycling  of bile acids, which reduces bile acids systemically and in the liver. Early clinical studies demonstrated on-target fecal bile acid excretion, a pharmacodynamic marker of IBAT inhibition, in addition to decreases in low-density lipoprotein cholesterol and increases in 7αC4, which are markers of bile acid synthesis.²⁴

To learn more about ongoing clinical trials, please visit https://www.mirumclinicaltrials.com.

References

1. Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis – a comprehensive review. J Hepatol. 2017;67(6):1298-1323. doi:10.1016/j.jhep.2017.07.022

2. Lindor KD, Kowdley KV, Harrison EM. ACG clinical guideline: primary sclerosing cholangitis. Am. J. Gastroenterol. 110, 646–659 (2015).

3. Chapman R, Fevery J, Kalloo A, et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51(2):660-678. doi:10.1002/hep.23294

4. Jiang X, Karlsen TH. Genetics of primary sclerosing cholangitis and pathophysiological implications. Nat Rev Gastroenterol Hepatol. 2017;14(5):279-295. doi:10.1038/nrgastro.2016.154

5. Sohal A, Kayani S, Kowdley KV. Primary sclerosing cholangitis: epidemiology, diagnosis, and presentation. Clin Liver Dis. 2024;28(1):129-141. doi:10.1016/j.cld.2023.07.005

6. Molodecky NA, Kareemi H, Parab R, et al. Incidence of primary sclerosing cholangitis: a systematic review and meta-analysis. Hepatology. 2011;53(5):1590-1599. doi:10.1002/hep.24247

7. Bowlus CL, Arrivé L, Bergquist A, et al. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology. 2023;77(2):659-702. doi:10.1002/hep.32771

8. Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet. 2013;382(9904):1587-1599.

9. Trivedi PJ, Bowlus CL, Yimam KK, Razavi H, Estes C. Epidemiology, natural history, and outcomes of primary sclerosing cholangitis: a systematic review of population-based studies. Clin Gastroenterol Hepatol. 2022;20(8):1687-1700.e4. doi:10.1016/j.cgh.2021.08.039

10. Tischendorf JJ, Hecker H, Krüger M, Manns MP, Meier PN. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol. 2007;102(1):107-114. doi:10.1111/j.1572-0241.2006.00872.x

11. Sanjel B, Shim WS. Recent advances in understanding the molecular mechanisms of cholestatic pruritus: a review. Biochim Biophys Acta Mol Basis Dis. 2020;1866(12):165958. doi:10.1016/j.bbadis.2020.16595

12. Patel SP, Vasavda C, Ho B, Meixiong J, Dong X, Kwatra SG. Cholestatic pruritus: emerging mechanisms and therapeutics. J Am Acad Dermatol. 2019;81(6):1371-1378. doi:10.1016/j.jaad.2019.04.035

13. Cheung AC, Patel H, Meza-Cardona J, Cino M, Sockalingam S, Hirschfield GM. Factors that influence health-related quality of life in patients with primary sclerosing cholangitis. Dig Dis Sci. 2016;61(6):1692-9. doi:10.1007/s10620-015-4013-1

14. Jin XY, Khan TM. Quality of life among patients suffering from cholestatic liver disease-induced pruritus: a systematic review. J Formos Med Assoc. 2016;115(9):689-702. doi:10.1016/j.jfma.2016.05.006

15. Kowdley K, et al. Impact of pruritus in primary sclerosing cholangitis (PSC): a multinational survey. J. Hepatol. 2022;(1)77:S312-S313.

16. Ranieri V, Kennedy E, Walmsley M, Thorburn D, McKay K. The Primary Sclerosing Cholangitis (PSC) Wellbeing Study: understanding psychological distress in those living with PSC and those who support them. PLoS One. 2020;15(7):e0234624.:10.1371/journal.pone.0234624

17. Hov JR, Boberg KM, Karlsen TH. Autoantibodies in primary sclerosing cholangitis. World J Gastroenterol. 2008;14(24):3781-91. doi:10.3748/wjg.14.3781

18. Cazzagon N, Sarcognato S, Catanzaro E, Bonaiuto E, Peviani M, Pezzato F, Motta R. Primary Sclerosing Cholangitis: Diagnostic Criteria. Tomography. 2024;10(1):47-65. doi:10.3390/tomography10010005

19. Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med. 1997;336(10):691-695. doi:10.1056/NEJM199703063361003

20. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med. 1995;332(14):924-33. doi:10.1056/NEJM199504063321406

21. Said K, Glaumann H, Bergquist A. Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol. 2008;48(4):598-605. doi:10.1016/j.jhep.2007.11.01

22. Basic PSC facts: basic facts. PSC Partners Seeking a Cure. Accessed October 14, 2024. https://pscpartners.org/about/the-disease/basic-facts.html

23. PSC support: patient insights report. Accessed October 14, 2024. https://pscsupport.org.uk/surveys/insights-living-with-psc/

24. Key C, McKibben A, Chien E. A phase 1 dose-ranging study assessing fecal bile acid excretion by volixibat, an apical sodium‑dependent bile acid transporter inhibitor, and coadministration with loperamide. Poster presented at The Liver Meeting Digital Experience™ (TLMdX), American Association for the Study of Liver Diseases (AASLD); November 13-16, 2020.

US-DS-2400079 December 2024

Neither of the editors of GI & Hepatology News^® nor the Editorial Advisory Board nor the reporting staff contributed to this content.

Faculty Disclosure: Dr. Kowdley has been paid consulting fees by Mirum.

Primary sclerosing cholangitis (PSC) is a rare, chronic, and progressive cholestatic liver disorder.¹ Commonly associated with pruritus, an intense itch that significantly impacts patients’ lives, PSC is characterized by inflammation, fibrosis, and stricturing of the intrahepatic and/or extrahepatic bile ducts.^1,2 The natural history of PSC is highly variable, but disease progression frequently leads to end-stage liver disease, with liver transplantation as the only currently available treatment option.^1,2 PSC has a close association with inflammatory bowel disease (IBD), with approximately 60% to 80% of patients with PSC having a diagnosis of either ulcerative colitis or Crohn’s disease.^1,3 Although the exact pathogenesis of PSC is still under investigation, evidence suggests a complex interplay of genetic susceptibility, immune dysregulation, and environmental factors may be responsible.⁴

PSC is considered a rare disease, with an estimated global median incidence of 0.7 to 0.8 per 100,000 and estimated prevalence of 10 cases per 100,000.⁵ PSC is more common in men (60% to 70%), with men having a 2-fold higher risk of developing PSC than women.^2,6,7 The majority of patients are diagnosed between the ages of 30 to 40 years, with a median survival time after diagnosis without a liver transplant of 10 to 20 years.^2,7-9

Signs and Symptoms of PSC

Approximately 50% of patients with PSC are asymptomatic when persistently abnormal liver function tests trigger further evaluation.^1,2,10 Patients may complain of pruritus, which may be episodic; right upper quadrant pain; fatigue; and jaundice.^2,7 Fevers, chills, and night sweats may also be present at the time of diagnosis.²  

Pruritus and fatigue are common symptoms of PSC and can have a significant impact on the lives of patients.⁵ The pathogenesis of pruritus is complex and not completely understood but is believed to be caused by a toxic buildup of bile acids due to a decrease in bile flow related to inflammation, fibrosis, and stricturing resulting from PSC.^11,12

Pruritus has been shown to have a substantial impact on patients’ health-related quality of life (QoL), with greater impairment seen with increased severity of pruritus.¹³ Specifically, patients with pruritus report physical limitations on QoL-specific questionnaires, as well as an impact on emotional, bodily pain, vitality, energy, and physical mobility measures.¹⁴

From a multinational survey on the impact of pruritus in PSC patients, 96% of respondents indicated that their itch was worst in the evening, with 58% indicating mood changes, including anxiety, irritability, and feelings of hopelessness due to their itch. Further, respondents reported that their pruritus disrupted their day-to-day responsibilities and that this disruption lasted 1 month or more.¹⁵

The psychological impact of living with PSC has not been well studied, although it has been found that individuals living with the disease demonstrated a greater number of depressive symptoms and poorer well-being, often coinciding with their stage of liver disease and comorbidity with IBD.¹⁶

In those living with PSC, mental health-related QoL has been shown to be influenced by liver disease, pruritus, social isolation, and depression. In one study, nearly 75% of patients expressed existential anxiety regarding disease progression and shortened life expectancy, with 25% disclosing social isolation.¹³

Diagnosing PSC

PSC should be considered in patients with a cholestatic pattern of liver test abnormalities, especially in those with underlying IBD. Abnormalities that may be detected on physical examination include jaundice, hepatomegaly, splenomegaly, and excoriations from scratching.^3,5 PSC and autoimmune hepatitis (AIH) may coexist, particularly in younger patients, with serum biochemical tests and autoantibodies suggestive of AIH.² Most patients demonstrate elevated serum alkaline phosphatase levels, as well as modest elevation of transaminases.² Bilirubin and albumin levels may be normal at the time of diagnosis, although they may become increasingly abnormal as the disease progresses.² A subset of patients (10%) may have elevated levels of immunoglobulin G4 (IgG4) and tend to progress more rapidly in the absence of treatment.² Autoantibodies, which are characteristic of primary biliary cholangitis (PBC)—another rare, chronic, and progressive liver disease—are usually absent in PSC. When present, autoantibodies are of unknown clinical significance.^2,17

Imaging, including cross-sectional imaging, particularly magnetic resonance cholangiopancreatography, is often used to the biliary tree in patients with persistently abnormal cholestatic tests.² A diagnosis of PSC is typically established by the demonstration of characteristic multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts on cholangiography.⁵ The diagnosis of PSC is occasionally made on liver biopsy, which may reveal characteristic features of “onion skin fibrosis” and fibro-obliterative cholangitis when cholangiography is normal. In this circumstance, it is classified as “small-duct PSC.”^5,18

Treatment and Management of PSC

Despite advances in our understanding of PSC, there are currently no approved drug therapies for PSC and no approved treatments for PSC-associated pruritus. The American Association for the Study of Liver Diseases (AASLD) published the most recent practice guidance for the treatment and management of PSC in 2022.⁷

Ursodeoxycholic acid (UDCA) has been widely studied as a potential PSC treatment. While UDCA demonstrates improvements in biochemical measures, there has been a lack of evidence demonstrating clinical improvement.¹⁹

 The role of UDCA in the treatment of PSC is unclear and, at this time, is not supported by the American College of Gastroenterology or AASLD.^2,7 Additional treatments, including immunosuppressive medications (methotrexate, tacrolimus), corticosteroids (prednisolone), and antibiotics (minocycline, vancomycin) have been explored but have not shown definitive clinical benefit.²

UDCA, if used, should not be prescribed at doses in excess of 20 mg/kg/day since high-dose UDCA (28-30 mg/kg) was associated with adverse liver outcomes.²

Although there are no therapies approved specifically to manage PSC-associated pruritus, cholestyramine and rifampin have been shown to be beneficial in relieving itch in some patients.²² In a survey of PSC patients, one in three reported suffering from pruritus during the previous week. It is possible that the prevalence and severity of pruritus in PSC may be under-recognized compared with PBC, given that patients and physicians may be focused on the many other medical issues that are often prioritized over symptoms, such as concern about cancer risk and need for frequent surveillance procedures.^15,23 Discussions between patients and physicians are important to deepen our understanding of the prevalence of pruritus and its burden on the lives of patients.

Novel therapies for PSC and PSC-associated pruritus, including a selective inhibitor of the ileal bile acid transporter (IBAT), are currently being explored in clinical trials. Research suggests that the inhibition of IBAT blocks the recycling  of bile acids, which reduces bile acids systemically and in the liver. Early clinical studies demonstrated on-target fecal bile acid excretion, a pharmacodynamic marker of IBAT inhibition, in addition to decreases in low-density lipoprotein cholesterol and increases in 7αC4, which are markers of bile acid synthesis.²⁴

To learn more about ongoing clinical trials, please visit https://www.mirumclinicaltrials.com.

References

1. Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis – a comprehensive review. J Hepatol. 2017;67(6):1298-1323. doi:10.1016/j.jhep.2017.07.022

2. Lindor KD, Kowdley KV, Harrison EM. ACG clinical guideline: primary sclerosing cholangitis. Am. J. Gastroenterol. 110, 646–659 (2015).

3. Chapman R, Fevery J, Kalloo A, et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51(2):660-678. doi:10.1002/hep.23294

4. Jiang X, Karlsen TH. Genetics of primary sclerosing cholangitis and pathophysiological implications. Nat Rev Gastroenterol Hepatol. 2017;14(5):279-295. doi:10.1038/nrgastro.2016.154

5. Sohal A, Kayani S, Kowdley KV. Primary sclerosing cholangitis: epidemiology, diagnosis, and presentation. Clin Liver Dis. 2024;28(1):129-141. doi:10.1016/j.cld.2023.07.005

6. Molodecky NA, Kareemi H, Parab R, et al. Incidence of primary sclerosing cholangitis: a systematic review and meta-analysis. Hepatology. 2011;53(5):1590-1599. doi:10.1002/hep.24247

7. Bowlus CL, Arrivé L, Bergquist A, et al. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology. 2023;77(2):659-702. doi:10.1002/hep.32771

8. Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet. 2013;382(9904):1587-1599.

9. Trivedi PJ, Bowlus CL, Yimam KK, Razavi H, Estes C. Epidemiology, natural history, and outcomes of primary sclerosing cholangitis: a systematic review of population-based studies. Clin Gastroenterol Hepatol. 2022;20(8):1687-1700.e4. doi:10.1016/j.cgh.2021.08.039

10. Tischendorf JJ, Hecker H, Krüger M, Manns MP, Meier PN. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol. 2007;102(1):107-114. doi:10.1111/j.1572-0241.2006.00872.x

11. Sanjel B, Shim WS. Recent advances in understanding the molecular mechanisms of cholestatic pruritus: a review. Biochim Biophys Acta Mol Basis Dis. 2020;1866(12):165958. doi:10.1016/j.bbadis.2020.16595

12. Patel SP, Vasavda C, Ho B, Meixiong J, Dong X, Kwatra SG. Cholestatic pruritus: emerging mechanisms and therapeutics. J Am Acad Dermatol. 2019;81(6):1371-1378. doi:10.1016/j.jaad.2019.04.035

13. Cheung AC, Patel H, Meza-Cardona J, Cino M, Sockalingam S, Hirschfield GM. Factors that influence health-related quality of life in patients with primary sclerosing cholangitis. Dig Dis Sci. 2016;61(6):1692-9. doi:10.1007/s10620-015-4013-1

14. Jin XY, Khan TM. Quality of life among patients suffering from cholestatic liver disease-induced pruritus: a systematic review. J Formos Med Assoc. 2016;115(9):689-702. doi:10.1016/j.jfma.2016.05.006

15. Kowdley K, et al. Impact of pruritus in primary sclerosing cholangitis (PSC): a multinational survey. J. Hepatol. 2022;(1)77:S312-S313.

16. Ranieri V, Kennedy E, Walmsley M, Thorburn D, McKay K. The Primary Sclerosing Cholangitis (PSC) Wellbeing Study: understanding psychological distress in those living with PSC and those who support them. PLoS One. 2020;15(7):e0234624.:10.1371/journal.pone.0234624

17. Hov JR, Boberg KM, Karlsen TH. Autoantibodies in primary sclerosing cholangitis. World J Gastroenterol. 2008;14(24):3781-91. doi:10.3748/wjg.14.3781

18. Cazzagon N, Sarcognato S, Catanzaro E, Bonaiuto E, Peviani M, Pezzato F, Motta R. Primary Sclerosing Cholangitis: Diagnostic Criteria. Tomography. 2024;10(1):47-65. doi:10.3390/tomography10010005

19. Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med. 1997;336(10):691-695. doi:10.1056/NEJM199703063361003

20. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med. 1995;332(14):924-33. doi:10.1056/NEJM199504063321406

21. Said K, Glaumann H, Bergquist A. Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol. 2008;48(4):598-605. doi:10.1016/j.jhep.2007.11.01

22. Basic PSC facts: basic facts. PSC Partners Seeking a Cure. Accessed October 14, 2024. https://pscpartners.org/about/the-disease/basic-facts.html

23. PSC support: patient insights report. Accessed October 14, 2024. https://pscsupport.org.uk/surveys/insights-living-with-psc/

24. Key C, McKibben A, Chien E. A phase 1 dose-ranging study assessing fecal bile acid excretion by volixibat, an apical sodium‑dependent bile acid transporter inhibitor, and coadministration with loperamide. Poster presented at The Liver Meeting Digital Experience™ (TLMdX), American Association for the Study of Liver Diseases (AASLD); November 13-16, 2020.

US-DS-2400079 December 2024

Neither of the editors of GI & Hepatology News^® nor the Editorial Advisory Board nor the reporting staff contributed to this content.

Faculty Disclosure: Dr. Kowdley has been paid consulting fees by Mirum.

Primary sclerosing cholangitis (PSC) is a rare, chronic, and progressive cholestatic liver disorder.¹ Commonly associated with pruritus, an intense itch that significantly impacts patients’ lives, PSC is characterized by inflammation, fibrosis, and stricturing of the intrahepatic and/or extrahepatic bile ducts.^1,2 The natural history of PSC is highly variable, but disease progression frequently leads to end-stage liver disease, with liver transplantation as the only currently available treatment option.^1,2 PSC has a close association with inflammatory bowel disease (IBD), with approximately 60% to 80% of patients with PSC having a diagnosis of either ulcerative colitis or Crohn’s disease.^1,3 Although the exact pathogenesis of PSC is still under investigation, evidence suggests a complex interplay of genetic susceptibility, immune dysregulation, and environmental factors may be responsible.⁴

PSC is considered a rare disease, with an estimated global median incidence of 0.7 to 0.8 per 100,000 and estimated prevalence of 10 cases per 100,000.⁵ PSC is more common in men (60% to 70%), with men having a 2-fold higher risk of developing PSC than women.^2,6,7 The majority of patients are diagnosed between the ages of 30 to 40 years, with a median survival time after diagnosis without a liver transplant of 10 to 20 years.^2,7-9

Signs and Symptoms of PSC

Approximately 50% of patients with PSC are asymptomatic when persistently abnormal liver function tests trigger further evaluation.^1,2,10 Patients may complain of pruritus, which may be episodic; right upper quadrant pain; fatigue; and jaundice.^2,7 Fevers, chills, and night sweats may also be present at the time of diagnosis.²  

Pruritus and fatigue are common symptoms of PSC and can have a significant impact on the lives of patients.⁵ The pathogenesis of pruritus is complex and not completely understood but is believed to be caused by a toxic buildup of bile acids due to a decrease in bile flow related to inflammation, fibrosis, and stricturing resulting from PSC.^11,12

Pruritus has been shown to have a substantial impact on patients’ health-related quality of life (QoL), with greater impairment seen with increased severity of pruritus.¹³ Specifically, patients with pruritus report physical limitations on QoL-specific questionnaires, as well as an impact on emotional, bodily pain, vitality, energy, and physical mobility measures.¹⁴

From a multinational survey on the impact of pruritus in PSC patients, 96% of respondents indicated that their itch was worst in the evening, with 58% indicating mood changes, including anxiety, irritability, and feelings of hopelessness due to their itch. Further, respondents reported that their pruritus disrupted their day-to-day responsibilities and that this disruption lasted 1 month or more.¹⁵

The psychological impact of living with PSC has not been well studied, although it has been found that individuals living with the disease demonstrated a greater number of depressive symptoms and poorer well-being, often coinciding with their stage of liver disease and comorbidity with IBD.¹⁶

In those living with PSC, mental health-related QoL has been shown to be influenced by liver disease, pruritus, social isolation, and depression. In one study, nearly 75% of patients expressed existential anxiety regarding disease progression and shortened life expectancy, with 25% disclosing social isolation.¹³

Diagnosing PSC

PSC should be considered in patients with a cholestatic pattern of liver test abnormalities, especially in those with underlying IBD. Abnormalities that may be detected on physical examination include jaundice, hepatomegaly, splenomegaly, and excoriations from scratching.^3,5 PSC and autoimmune hepatitis (AIH) may coexist, particularly in younger patients, with serum biochemical tests and autoantibodies suggestive of AIH.² Most patients demonstrate elevated serum alkaline phosphatase levels, as well as modest elevation of transaminases.² Bilirubin and albumin levels may be normal at the time of diagnosis, although they may become increasingly abnormal as the disease progresses.² A subset of patients (10%) may have elevated levels of immunoglobulin G4 (IgG4) and tend to progress more rapidly in the absence of treatment.² Autoantibodies, which are characteristic of primary biliary cholangitis (PBC)—another rare, chronic, and progressive liver disease—are usually absent in PSC. When present, autoantibodies are of unknown clinical significance.^2,17

Imaging, including cross-sectional imaging, particularly magnetic resonance cholangiopancreatography, is often used to the biliary tree in patients with persistently abnormal cholestatic tests.² A diagnosis of PSC is typically established by the demonstration of characteristic multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts on cholangiography.⁵ The diagnosis of PSC is occasionally made on liver biopsy, which may reveal characteristic features of “onion skin fibrosis” and fibro-obliterative cholangitis when cholangiography is normal. In this circumstance, it is classified as “small-duct PSC.”^5,18

Treatment and Management of PSC

Despite advances in our understanding of PSC, there are currently no approved drug therapies for PSC and no approved treatments for PSC-associated pruritus. The American Association for the Study of Liver Diseases (AASLD) published the most recent practice guidance for the treatment and management of PSC in 2022.⁷

Ursodeoxycholic acid (UDCA) has been widely studied as a potential PSC treatment. While UDCA demonstrates improvements in biochemical measures, there has been a lack of evidence demonstrating clinical improvement.¹⁹

 The role of UDCA in the treatment of PSC is unclear and, at this time, is not supported by the American College of Gastroenterology or AASLD.^2,7 Additional treatments, including immunosuppressive medications (methotrexate, tacrolimus), corticosteroids (prednisolone), and antibiotics (minocycline, vancomycin) have been explored but have not shown definitive clinical benefit.²

UDCA, if used, should not be prescribed at doses in excess of 20 mg/kg/day since high-dose UDCA (28-30 mg/kg) was associated with adverse liver outcomes.²

Although there are no therapies approved specifically to manage PSC-associated pruritus, cholestyramine and rifampin have been shown to be beneficial in relieving itch in some patients.²² In a survey of PSC patients, one in three reported suffering from pruritus during the previous week. It is possible that the prevalence and severity of pruritus in PSC may be under-recognized compared with PBC, given that patients and physicians may be focused on the many other medical issues that are often prioritized over symptoms, such as concern about cancer risk and need for frequent surveillance procedures.^15,23 Discussions between patients and physicians are important to deepen our understanding of the prevalence of pruritus and its burden on the lives of patients.

Novel therapies for PSC and PSC-associated pruritus, including a selective inhibitor of the ileal bile acid transporter (IBAT), are currently being explored in clinical trials. Research suggests that the inhibition of IBAT blocks the recycling  of bile acids, which reduces bile acids systemically and in the liver. Early clinical studies demonstrated on-target fecal bile acid excretion, a pharmacodynamic marker of IBAT inhibition, in addition to decreases in low-density lipoprotein cholesterol and increases in 7αC4, which are markers of bile acid synthesis.²⁴

To learn more about ongoing clinical trials, please visit https://www.mirumclinicaltrials.com.

References

1. Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis – a comprehensive review. J Hepatol. 2017;67(6):1298-1323. doi:10.1016/j.jhep.2017.07.022

2. Lindor KD, Kowdley KV, Harrison EM. ACG clinical guideline: primary sclerosing cholangitis. Am. J. Gastroenterol. 110, 646–659 (2015).

3. Chapman R, Fevery J, Kalloo A, et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51(2):660-678. doi:10.1002/hep.23294

4. Jiang X, Karlsen TH. Genetics of primary sclerosing cholangitis and pathophysiological implications. Nat Rev Gastroenterol Hepatol. 2017;14(5):279-295. doi:10.1038/nrgastro.2016.154

5. Sohal A, Kayani S, Kowdley KV. Primary sclerosing cholangitis: epidemiology, diagnosis, and presentation. Clin Liver Dis. 2024;28(1):129-141. doi:10.1016/j.cld.2023.07.005

6. Molodecky NA, Kareemi H, Parab R, et al. Incidence of primary sclerosing cholangitis: a systematic review and meta-analysis. Hepatology. 2011;53(5):1590-1599. doi:10.1002/hep.24247

7. Bowlus CL, Arrivé L, Bergquist A, et al. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology. 2023;77(2):659-702. doi:10.1002/hep.32771

8. Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet. 2013;382(9904):1587-1599.

9. Trivedi PJ, Bowlus CL, Yimam KK, Razavi H, Estes C. Epidemiology, natural history, and outcomes of primary sclerosing cholangitis: a systematic review of population-based studies. Clin Gastroenterol Hepatol. 2022;20(8):1687-1700.e4. doi:10.1016/j.cgh.2021.08.039

10. Tischendorf JJ, Hecker H, Krüger M, Manns MP, Meier PN. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol. 2007;102(1):107-114. doi:10.1111/j.1572-0241.2006.00872.x

11. Sanjel B, Shim WS. Recent advances in understanding the molecular mechanisms of cholestatic pruritus: a review. Biochim Biophys Acta Mol Basis Dis. 2020;1866(12):165958. doi:10.1016/j.bbadis.2020.16595

12. Patel SP, Vasavda C, Ho B, Meixiong J, Dong X, Kwatra SG. Cholestatic pruritus: emerging mechanisms and therapeutics. J Am Acad Dermatol. 2019;81(6):1371-1378. doi:10.1016/j.jaad.2019.04.035

13. Cheung AC, Patel H, Meza-Cardona J, Cino M, Sockalingam S, Hirschfield GM. Factors that influence health-related quality of life in patients with primary sclerosing cholangitis. Dig Dis Sci. 2016;61(6):1692-9. doi:10.1007/s10620-015-4013-1

14. Jin XY, Khan TM. Quality of life among patients suffering from cholestatic liver disease-induced pruritus: a systematic review. J Formos Med Assoc. 2016;115(9):689-702. doi:10.1016/j.jfma.2016.05.006

15. Kowdley K, et al. Impact of pruritus in primary sclerosing cholangitis (PSC): a multinational survey. J. Hepatol. 2022;(1)77:S312-S313.

16. Ranieri V, Kennedy E, Walmsley M, Thorburn D, McKay K. The Primary Sclerosing Cholangitis (PSC) Wellbeing Study: understanding psychological distress in those living with PSC and those who support them. PLoS One. 2020;15(7):e0234624.:10.1371/journal.pone.0234624

17. Hov JR, Boberg KM, Karlsen TH. Autoantibodies in primary sclerosing cholangitis. World J Gastroenterol. 2008;14(24):3781-91. doi:10.3748/wjg.14.3781

18. Cazzagon N, Sarcognato S, Catanzaro E, Bonaiuto E, Peviani M, Pezzato F, Motta R. Primary Sclerosing Cholangitis: Diagnostic Criteria. Tomography. 2024;10(1):47-65. doi:10.3390/tomography10010005

19. Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med. 1997;336(10):691-695. doi:10.1056/NEJM199703063361003

20. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med. 1995;332(14):924-33. doi:10.1056/NEJM199504063321406

21. Said K, Glaumann H, Bergquist A. Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol. 2008;48(4):598-605. doi:10.1016/j.jhep.2007.11.01

22. Basic PSC facts: basic facts. PSC Partners Seeking a Cure. Accessed October 14, 2024. https://pscpartners.org/about/the-disease/basic-facts.html

23. PSC support: patient insights report. Accessed October 14, 2024. https://pscsupport.org.uk/surveys/insights-living-with-psc/

24. Key C, McKibben A, Chien E. A phase 1 dose-ranging study assessing fecal bile acid excretion by volixibat, an apical sodium‑dependent bile acid transporter inhibitor, and coadministration with loperamide. Poster presented at The Liver Meeting Digital Experience™ (TLMdX), American Association for the Study of Liver Diseases (AASLD); November 13-16, 2020.

US-DS-2400079 December 2024

Neither of the editors of GI & Hepatology News^® nor the Editorial Advisory Board nor the reporting staff contributed to this content.

Faculty Disclosure: Dr. Kowdley has been paid consulting fees by Mirum.

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In a rapidly expanding therapeutic landscape, the American Gastroenterological Association (AGA) has issued updated practice guidelines for the pharmacological management of moderate to severe ulcerative colitis (UC) in adult outpatients.

“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.

 

Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.

“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.

 

The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”

One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated. 

“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.

The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.

 

Specifics

Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.

The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.

The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.

Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:

• Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
• Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
• Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
• For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
• In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
• The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
• The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
• Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
• The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
• For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
• For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.

According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.

However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”

Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”

 

The Future

The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.

The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.

They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.

The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.

These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.

A version of this article appeared on Medscape.com.

In a rapidly expanding therapeutic landscape, the American Gastroenterological Association (AGA) has issued updated practice guidelines for the pharmacological management of moderate to severe ulcerative colitis (UC) in adult outpatients.

“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.

 

Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.

“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.

 

The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”

One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated. 

“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.

The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.

 

Specifics

Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.

The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.

The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.

Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:

• Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
• Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
• Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
• For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
• In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
• The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
• The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
• Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
• The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
• For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
• For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.

According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.

However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”

Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”

 

The Future

The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.

The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.

They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.

The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.

These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.

A version of this article appeared on Medscape.com.

In a rapidly expanding therapeutic landscape, the American Gastroenterological Association (AGA) has issued updated practice guidelines for the pharmacological management of moderate to severe ulcerative colitis (UC) in adult outpatients.

“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.

 

Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.

“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.

 

The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”

One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated. 

“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.

The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.

 

Specifics

Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.

The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.

The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.

Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:

• Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
• Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
• Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
• For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
• In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
• The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
• The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
• Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
• The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
• For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
• For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.

According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.

However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”

Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”

 

The Future

The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.

The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.

They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.

The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.

These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.

A version of this article appeared on Medscape.com.

SAN DIEGO — An Air Force pharmacist urged colleagues in the military to advocate for the gold standard of quadruple therapy in patients with heart failure with reduced ejection fraction (HFrEF). “When possible, initiate and optimize quadruple therapy before discharge; don’t leave it for a primary care manager (PCM) to handle,” said Maj. Elizabeth Tesch, PharmD, of Maxwell Air Force Base, Montgomery, Ala., in a presentation here at the Joint Federal Pharmacy Seminar. Tesch also cautioned colleagues about the proper use of IV inotropes and vasodilators in congestive heart failure and warned of the dangers of polypharmacy.

“It’s just as important to use medications that provide a mortality benefit in these patients as it is to remove things that are either harmful or lack trial benefit data,” Tesch said. 

In patients with acute heart failure and systolic blood pressure < 90 mmHg, guidelines recommend using both an inotrope and a vasopressor. “There tends to be better data about 2 of them together vs just cranking up a vasoconstrictor, which we tend to sometimes to do when a patient’s blood pressure is bottoming out,” Tesch explained. “But in these patients specifically, that tends to lead to increased afterload, difficulty with cardiac output, and then increased risk of ischemia. So it tends to be better to use both.”

Ideally, Tesch said, patients stabilize within a couple days. In cases of HFrEF, this is when quadruple therapy can enter the picture. 

Quadruple therapy consists of the “4 pillars”: a sodium-glucose co-transporter 2 inhibitor (SGLT2i), a β blocker, a mineralocorticoid receptor antagonist (MRA), and either an angiotensin receptor neprilysin inhibitor (ARNI), an angiotensin‐converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB). 

Tesch noted that the need for titration varies by drug. β blockers typically will need the most up-titration, often in several steps, followed by ARNIs. MRAs may require only one titration or even not at all, and SGLT2 inhibitors do not require titration. 

“[Clinicians] are most comfortable giving ACE inhibitors, ARBs, and β blockers to patients, she said. But new research suggests there is a 10.3% jump in mortality risk (absolute risk difference) compared to ACEi/ β blocker/ARB therapy. Additionally, a 2022 systematic review linked quadruple therapy to a gain of 5 years of life (ranging from 2.5 to7.5 years) for 70-year-old patients compared to no therapy. 

“I don't know how many times I've had a conversation along the lines of, ‘Hey, can we go ahead and start an SGLT2 on this patient?’ only to hear, ‘We'll give that to the PCM [primary care manager]. That sounds like a PCM thing. You just want to get them out of here, it’s a PCM problem.’”

But quick initiation of treatment is crucial. “We're seeing very real mortality benefit data very quickly in these patients,” Tesch said. 

As for polypharmacy, Tesch highlighted the importance of reducing mediation load when possible. “If they have nothing else wrong, these patients will walk out the door on quadruple therapy and perhaps a diuretic, but they probably have a lot more going on,” she said. “All of us in this room are fully aware of what polypharmacy can do to these patients: increased drug interactions, side effects, higher cost, and decreased patient compliance. This is a problem for the heart failure population that really translates into readmissions and increased mortality. We've got to be able to peel off things that are either harmful or not helping.”

Statins, for example, have questionable benefit in HFrEF without coronary artery disease or hyperlipidemia, she said. Oral iron and vitamin D supplementation also have uncertain benefits in the HFrEF population.

Tesch highlighted a pair of reports – one from 2024 and the other from 2022 – that recommended certain therapies  in heart failure, including the antidepressant citalopram (Celexa), the hypertension/urinary retention drug doxazosin (Cardura), and DPP-4 inhibitors (eg, diabetes/weight-loss drugs such as liraglutide [Saxenda]).

Tesch has no disclosures. 

SAN DIEGO — An Air Force pharmacist urged colleagues in the military to advocate for the gold standard of quadruple therapy in patients with heart failure with reduced ejection fraction (HFrEF). “When possible, initiate and optimize quadruple therapy before discharge; don’t leave it for a primary care manager (PCM) to handle,” said Maj. Elizabeth Tesch, PharmD, of Maxwell Air Force Base, Montgomery, Ala., in a presentation here at the Joint Federal Pharmacy Seminar. Tesch also cautioned colleagues about the proper use of IV inotropes and vasodilators in congestive heart failure and warned of the dangers of polypharmacy.

“It’s just as important to use medications that provide a mortality benefit in these patients as it is to remove things that are either harmful or lack trial benefit data,” Tesch said. 

In patients with acute heart failure and systolic blood pressure < 90 mmHg, guidelines recommend using both an inotrope and a vasopressor. “There tends to be better data about 2 of them together vs just cranking up a vasoconstrictor, which we tend to sometimes to do when a patient’s blood pressure is bottoming out,” Tesch explained. “But in these patients specifically, that tends to lead to increased afterload, difficulty with cardiac output, and then increased risk of ischemia. So it tends to be better to use both.”

Ideally, Tesch said, patients stabilize within a couple days. In cases of HFrEF, this is when quadruple therapy can enter the picture. 

Quadruple therapy consists of the “4 pillars”: a sodium-glucose co-transporter 2 inhibitor (SGLT2i), a β blocker, a mineralocorticoid receptor antagonist (MRA), and either an angiotensin receptor neprilysin inhibitor (ARNI), an angiotensin‐converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB). 

Tesch noted that the need for titration varies by drug. β blockers typically will need the most up-titration, often in several steps, followed by ARNIs. MRAs may require only one titration or even not at all, and SGLT2 inhibitors do not require titration. 

“[Clinicians] are most comfortable giving ACE inhibitors, ARBs, and β blockers to patients, she said. But new research suggests there is a 10.3% jump in mortality risk (absolute risk difference) compared to ACEi/ β blocker/ARB therapy. Additionally, a 2022 systematic review linked quadruple therapy to a gain of 5 years of life (ranging from 2.5 to7.5 years) for 70-year-old patients compared to no therapy. 

“I don't know how many times I've had a conversation along the lines of, ‘Hey, can we go ahead and start an SGLT2 on this patient?’ only to hear, ‘We'll give that to the PCM [primary care manager]. That sounds like a PCM thing. You just want to get them out of here, it’s a PCM problem.’”

But quick initiation of treatment is crucial. “We're seeing very real mortality benefit data very quickly in these patients,” Tesch said. 

As for polypharmacy, Tesch highlighted the importance of reducing mediation load when possible. “If they have nothing else wrong, these patients will walk out the door on quadruple therapy and perhaps a diuretic, but they probably have a lot more going on,” she said. “All of us in this room are fully aware of what polypharmacy can do to these patients: increased drug interactions, side effects, higher cost, and decreased patient compliance. This is a problem for the heart failure population that really translates into readmissions and increased mortality. We've got to be able to peel off things that are either harmful or not helping.”

Statins, for example, have questionable benefit in HFrEF without coronary artery disease or hyperlipidemia, she said. Oral iron and vitamin D supplementation also have uncertain benefits in the HFrEF population.

Tesch highlighted a pair of reports – one from 2024 and the other from 2022 – that recommended certain therapies  in heart failure, including the antidepressant citalopram (Celexa), the hypertension/urinary retention drug doxazosin (Cardura), and DPP-4 inhibitors (eg, diabetes/weight-loss drugs such as liraglutide [Saxenda]).

Tesch has no disclosures. 

SAN DIEGO — An Air Force pharmacist urged colleagues in the military to advocate for the gold standard of quadruple therapy in patients with heart failure with reduced ejection fraction (HFrEF). “When possible, initiate and optimize quadruple therapy before discharge; don’t leave it for a primary care manager (PCM) to handle,” said Maj. Elizabeth Tesch, PharmD, of Maxwell Air Force Base, Montgomery, Ala., in a presentation here at the Joint Federal Pharmacy Seminar. Tesch also cautioned colleagues about the proper use of IV inotropes and vasodilators in congestive heart failure and warned of the dangers of polypharmacy.

“It’s just as important to use medications that provide a mortality benefit in these patients as it is to remove things that are either harmful or lack trial benefit data,” Tesch said. 

In patients with acute heart failure and systolic blood pressure < 90 mmHg, guidelines recommend using both an inotrope and a vasopressor. “There tends to be better data about 2 of them together vs just cranking up a vasoconstrictor, which we tend to sometimes to do when a patient’s blood pressure is bottoming out,” Tesch explained. “But in these patients specifically, that tends to lead to increased afterload, difficulty with cardiac output, and then increased risk of ischemia. So it tends to be better to use both.”

Ideally, Tesch said, patients stabilize within a couple days. In cases of HFrEF, this is when quadruple therapy can enter the picture. 

Quadruple therapy consists of the “4 pillars”: a sodium-glucose co-transporter 2 inhibitor (SGLT2i), a β blocker, a mineralocorticoid receptor antagonist (MRA), and either an angiotensin receptor neprilysin inhibitor (ARNI), an angiotensin‐converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB). 

Tesch noted that the need for titration varies by drug. β blockers typically will need the most up-titration, often in several steps, followed by ARNIs. MRAs may require only one titration or even not at all, and SGLT2 inhibitors do not require titration. 

“[Clinicians] are most comfortable giving ACE inhibitors, ARBs, and β blockers to patients, she said. But new research suggests there is a 10.3% jump in mortality risk (absolute risk difference) compared to ACEi/ β blocker/ARB therapy. Additionally, a 2022 systematic review linked quadruple therapy to a gain of 5 years of life (ranging from 2.5 to7.5 years) for 70-year-old patients compared to no therapy. 

“I don't know how many times I've had a conversation along the lines of, ‘Hey, can we go ahead and start an SGLT2 on this patient?’ only to hear, ‘We'll give that to the PCM [primary care manager]. That sounds like a PCM thing. You just want to get them out of here, it’s a PCM problem.’”

But quick initiation of treatment is crucial. “We're seeing very real mortality benefit data very quickly in these patients,” Tesch said. 

As for polypharmacy, Tesch highlighted the importance of reducing mediation load when possible. “If they have nothing else wrong, these patients will walk out the door on quadruple therapy and perhaps a diuretic, but they probably have a lot more going on,” she said. “All of us in this room are fully aware of what polypharmacy can do to these patients: increased drug interactions, side effects, higher cost, and decreased patient compliance. This is a problem for the heart failure population that really translates into readmissions and increased mortality. We've got to be able to peel off things that are either harmful or not helping.”

Statins, for example, have questionable benefit in HFrEF without coronary artery disease or hyperlipidemia, she said. Oral iron and vitamin D supplementation also have uncertain benefits in the HFrEF population.

Tesch highlighted a pair of reports – one from 2024 and the other from 2022 – that recommended certain therapies  in heart failure, including the antidepressant citalopram (Celexa), the hypertension/urinary retention drug doxazosin (Cardura), and DPP-4 inhibitors (eg, diabetes/weight-loss drugs such as liraglutide [Saxenda]).

Tesch has no disclosures. 

SAN DIEGO — An artificial intelligence (AI)–driven algorithm may be able to accurately detect early-stage metabolic dysfunction–associated steatotic liver disease (MASLD) based on imaging findings and other criteria in patient electronic medical records, according to new research.

Among the patients identified by the algorithm as meeting the criteria for MASLD, only a small percentage had an MASLD-associated diagnostic code.

“A significant portion of patients who meet criteria for MASLD go undiagnosed, which can lead to delays in care and progression to advanced liver disease,” said lead author Ariana Stuart, MD, an internal medicine resident at the University of Washington, Seattle, who presented the findings at The Liver Meeting 2024: American Association for the Study of Liver Diseases (AASLD).

“However, people shouldn’t interpret our findings as a lack of primary care training or management,” she said. “Instead, this study indicates that AI can complement physician workflow and address the limitations of traditional clinical practice.”

 

Developing an MASLD Algorithm

Typically, the identification of MASLD has relied on clinician recognition and descriptions in chart notes, Stuart said. Early-stage disease often goes unnoticed, particularly if patients remain asymptomatic, until cirrhosis develops.

To address this, Stuart and colleagues created a machine learning, natural language processing AI algorithm on the basis of MASLD criteria from AASLD: Hepatic steatosis on imaging and at least one metabolic factor (elevated body mass index, hypertension, prediabetes or diabetes, or dyslipidemia). The model was validated by two physicians, who manually reviewed monthly cohorts generated by the algorithm.

Between December 2023 and May 2024, the researchers used the algorithm to analyze an MASLD cohort from medical centers in the Seattle area. The mean age was 51 years, 44% were women, and 68% were White. Those with alcohol-associated liver disease, metastatic malignancy, and autoimmune, genetic, and infectious causes of liver disease were excluded.

The algorithm identified 957 patients with imaging that matched MASLD criteria.

Among those, 137 patients (17%) identified by the algorithm had an MASLD-associated diagnostic code. For these patients, the mean time from initial imaging with steatosis to diagnosis was 33 days, according to patient records.

An additional 26 patients received an MASLD diagnosis during the study period, with a mean time to diagnosis of 56.2 days.

In terms of patient management, 245 patients (26%) had contact with a gastroenterologist or hepatologist based on documentation of a letter, phone call, or office visit. In addition, 546 patients (57%) were screened for hepatitis C.

After adjusting for an over-inclusion error rate of 12.8% and an overdiagnosis rate of 0.02%, the research team found 697 patients (83%) lacked a relevant diagnosis. After multiple iterations, the algorithm achieved an accuracy of about 88%, Stuart said.

 

Considering Future AI Use

Stuart and colleagues are now testing the algorithm in larger groups and across longer periods.

After that, they intend to implement a quality improvement program to increase awareness for clinicians and primary care providers, as well as train users on how to interpret and move forward with findings of hepatic steatosis in patient records.

For instance, future AI models could flag patients for additional testing, improve chart review, and aid in research efforts around cardiometabolic comorbidities associated with MASLD, she said.

Looking ahead, AI tools such as these represent what’s possible for advancements in research, patient care, and clinical workflows, said Ashley Spann, MD, assistant professor and transplant hepatologist at Vanderbilt University, Nashville, Tennessee, and director of clinical research informatics for Vanderbilt’s Gastroenterology Division.

“AI, in my view, is actually augmented intelligence,” she added. “We need to think about the people and processes involved.”

Spann, who spoke about the use of AI tools in medicine in general, stressed the need for transparency in AI use, careful validation of input-output data, frameworks for machine learning models in medicine, and standardization across institutions.

“What we ultimately need is an infrastructure that supports the simultaneous deployment and evaluation of these models,” she said. “We all need to be on the same page and make sure our models work in multiple settings and make adjustments based on algorithmovigilance afterward.”

Stuart reported no relevant disclosures. Spann serves on Epic’s hepatology steering board, which has focused on how to use AI tools in electronic medical records.

A version of this article appeared on Medscape.com.

SAN DIEGO — An artificial intelligence (AI)–driven algorithm may be able to accurately detect early-stage metabolic dysfunction–associated steatotic liver disease (MASLD) based on imaging findings and other criteria in patient electronic medical records, according to new research.

Among the patients identified by the algorithm as meeting the criteria for MASLD, only a small percentage had an MASLD-associated diagnostic code.

“A significant portion of patients who meet criteria for MASLD go undiagnosed, which can lead to delays in care and progression to advanced liver disease,” said lead author Ariana Stuart, MD, an internal medicine resident at the University of Washington, Seattle, who presented the findings at The Liver Meeting 2024: American Association for the Study of Liver Diseases (AASLD).

“However, people shouldn’t interpret our findings as a lack of primary care training or management,” she said. “Instead, this study indicates that AI can complement physician workflow and address the limitations of traditional clinical practice.”

 

Developing an MASLD Algorithm

Typically, the identification of MASLD has relied on clinician recognition and descriptions in chart notes, Stuart said. Early-stage disease often goes unnoticed, particularly if patients remain asymptomatic, until cirrhosis develops.

To address this, Stuart and colleagues created a machine learning, natural language processing AI algorithm on the basis of MASLD criteria from AASLD: Hepatic steatosis on imaging and at least one metabolic factor (elevated body mass index, hypertension, prediabetes or diabetes, or dyslipidemia). The model was validated by two physicians, who manually reviewed monthly cohorts generated by the algorithm.

Between December 2023 and May 2024, the researchers used the algorithm to analyze an MASLD cohort from medical centers in the Seattle area. The mean age was 51 years, 44% were women, and 68% were White. Those with alcohol-associated liver disease, metastatic malignancy, and autoimmune, genetic, and infectious causes of liver disease were excluded.

The algorithm identified 957 patients with imaging that matched MASLD criteria.

Among those, 137 patients (17%) identified by the algorithm had an MASLD-associated diagnostic code. For these patients, the mean time from initial imaging with steatosis to diagnosis was 33 days, according to patient records.

An additional 26 patients received an MASLD diagnosis during the study period, with a mean time to diagnosis of 56.2 days.

In terms of patient management, 245 patients (26%) had contact with a gastroenterologist or hepatologist based on documentation of a letter, phone call, or office visit. In addition, 546 patients (57%) were screened for hepatitis C.

After adjusting for an over-inclusion error rate of 12.8% and an overdiagnosis rate of 0.02%, the research team found 697 patients (83%) lacked a relevant diagnosis. After multiple iterations, the algorithm achieved an accuracy of about 88%, Stuart said.

 

Considering Future AI Use

Stuart and colleagues are now testing the algorithm in larger groups and across longer periods.

After that, they intend to implement a quality improvement program to increase awareness for clinicians and primary care providers, as well as train users on how to interpret and move forward with findings of hepatic steatosis in patient records.

For instance, future AI models could flag patients for additional testing, improve chart review, and aid in research efforts around cardiometabolic comorbidities associated with MASLD, she said.

Looking ahead, AI tools such as these represent what’s possible for advancements in research, patient care, and clinical workflows, said Ashley Spann, MD, assistant professor and transplant hepatologist at Vanderbilt University, Nashville, Tennessee, and director of clinical research informatics for Vanderbilt’s Gastroenterology Division.

“AI, in my view, is actually augmented intelligence,” she added. “We need to think about the people and processes involved.”

Spann, who spoke about the use of AI tools in medicine in general, stressed the need for transparency in AI use, careful validation of input-output data, frameworks for machine learning models in medicine, and standardization across institutions.

“What we ultimately need is an infrastructure that supports the simultaneous deployment and evaluation of these models,” she said. “We all need to be on the same page and make sure our models work in multiple settings and make adjustments based on algorithmovigilance afterward.”

Stuart reported no relevant disclosures. Spann serves on Epic’s hepatology steering board, which has focused on how to use AI tools in electronic medical records.

A version of this article appeared on Medscape.com.

SAN DIEGO — An artificial intelligence (AI)–driven algorithm may be able to accurately detect early-stage metabolic dysfunction–associated steatotic liver disease (MASLD) based on imaging findings and other criteria in patient electronic medical records, according to new research.

Among the patients identified by the algorithm as meeting the criteria for MASLD, only a small percentage had an MASLD-associated diagnostic code.

“A significant portion of patients who meet criteria for MASLD go undiagnosed, which can lead to delays in care and progression to advanced liver disease,” said lead author Ariana Stuart, MD, an internal medicine resident at the University of Washington, Seattle, who presented the findings at The Liver Meeting 2024: American Association for the Study of Liver Diseases (AASLD).

“However, people shouldn’t interpret our findings as a lack of primary care training or management,” she said. “Instead, this study indicates that AI can complement physician workflow and address the limitations of traditional clinical practice.”

 

Developing an MASLD Algorithm

Typically, the identification of MASLD has relied on clinician recognition and descriptions in chart notes, Stuart said. Early-stage disease often goes unnoticed, particularly if patients remain asymptomatic, until cirrhosis develops.

To address this, Stuart and colleagues created a machine learning, natural language processing AI algorithm on the basis of MASLD criteria from AASLD: Hepatic steatosis on imaging and at least one metabolic factor (elevated body mass index, hypertension, prediabetes or diabetes, or dyslipidemia). The model was validated by two physicians, who manually reviewed monthly cohorts generated by the algorithm.

Between December 2023 and May 2024, the researchers used the algorithm to analyze an MASLD cohort from medical centers in the Seattle area. The mean age was 51 years, 44% were women, and 68% were White. Those with alcohol-associated liver disease, metastatic malignancy, and autoimmune, genetic, and infectious causes of liver disease were excluded.

The algorithm identified 957 patients with imaging that matched MASLD criteria.

Among those, 137 patients (17%) identified by the algorithm had an MASLD-associated diagnostic code. For these patients, the mean time from initial imaging with steatosis to diagnosis was 33 days, according to patient records.

An additional 26 patients received an MASLD diagnosis during the study period, with a mean time to diagnosis of 56.2 days.

In terms of patient management, 245 patients (26%) had contact with a gastroenterologist or hepatologist based on documentation of a letter, phone call, or office visit. In addition, 546 patients (57%) were screened for hepatitis C.

After adjusting for an over-inclusion error rate of 12.8% and an overdiagnosis rate of 0.02%, the research team found 697 patients (83%) lacked a relevant diagnosis. After multiple iterations, the algorithm achieved an accuracy of about 88%, Stuart said.

 

Considering Future AI Use

Stuart and colleagues are now testing the algorithm in larger groups and across longer periods.

After that, they intend to implement a quality improvement program to increase awareness for clinicians and primary care providers, as well as train users on how to interpret and move forward with findings of hepatic steatosis in patient records.

For instance, future AI models could flag patients for additional testing, improve chart review, and aid in research efforts around cardiometabolic comorbidities associated with MASLD, she said.

Looking ahead, AI tools such as these represent what’s possible for advancements in research, patient care, and clinical workflows, said Ashley Spann, MD, assistant professor and transplant hepatologist at Vanderbilt University, Nashville, Tennessee, and director of clinical research informatics for Vanderbilt’s Gastroenterology Division.

“AI, in my view, is actually augmented intelligence,” she added. “We need to think about the people and processes involved.”

Spann, who spoke about the use of AI tools in medicine in general, stressed the need for transparency in AI use, careful validation of input-output data, frameworks for machine learning models in medicine, and standardization across institutions.

“What we ultimately need is an infrastructure that supports the simultaneous deployment and evaluation of these models,” she said. “We all need to be on the same page and make sure our models work in multiple settings and make adjustments based on algorithmovigilance afterward.”

Stuart reported no relevant disclosures. Spann serves on Epic’s hepatology steering board, which has focused on how to use AI tools in electronic medical records.

A version of this article appeared on Medscape.com.