Whipple disease is a chronic, rare, infectious disease that manifests with systemic symptoms. This disease is caused by the gram-positive bacterium Tropheryma whipplei (T. whipplei). Common manifestations include gastrointestinal symptoms indicative of malabsorption, such as chronic diarrhea, unintentional weight loss (despite normal nutrient intake), and greasy, voluminous, foul-smelling stool. Other, less common manifestations include cardiovascular, endocrine, musculoskeletal, neurologic, and renal signs and symptoms. The prevalence of the disease is rare, affecting 3 in 1 million patients.¹ This case highlights the importance of considering Whipple disease when treating patients with multiple symptoms and concurrent disease processes.

Case Presentation

A 53-year-old male with a medical history of hypertension, hyperlipidemia, hypothyroidism, and microcytic anemia presented with an 8-month history of persistent diarrhea associated with abdominal bloating, abdominal discomfort, and a 30-lb weight loss. He also reported fatigue, headaches, inability to concentrate, memory distortion, and visual disturbances involving flashes and floaters. The patient reported no fever, chills, nuchal rigidity, or prior neurologic symptoms. He reported intermittent bilateral hand and knee arthralgias. An autoimmune evaluation for arthralgia was negative, and a prior colonoscopy had been normal.

The patient’s hobbies included gardening, hiking, fishing, and deer hunting in Wyoming and Texas. He had spent time around cattle, dogs, and cats. He consumed alcohol twice weekly but reported no tobacco or illicit drug use or recent international travel. The patient’s family history was positive for rheumatoid arthritis, diabetes mellitus, and hypertension.

The patient’s vital signs were all within reference ranges, and lung auscultation revealed clear breathing sounds with no cardiac murmurs, gallops, or rubs. An abdominal examination revealed decreased bowel sounds, while the rest of the physical examination was otherwise normal.

Initial laboratory results showed that his sodium was 134 mEq/L (reference range, 136-145 mEq/L), hemoglobin was 9.3 g/dL (reference range for men, 14.0-18.0 g/dL), and hematocrit was 30.7% (reference range for men 42%-52%). His white blood cell (WBC) count and thyroid-stimulating hormone level were within normal limits. A cerebrospinal fluid (CSF) analysis revealed the following: WBCs 1.0/μL (0-5/μL), segmented neutrophils 10% (reference range, 7%), lymphocytes 80% (reference range, 40-80%), macrophages 10% (reference range, 2%), red blood cells 3 × 10⁶ /μL (reference range, 4.3- 5.9 × 10⁶ /µL), protein 23.5 mg/dL (reference range, 15-60 mg/dL), and glucose 44 mg/dL (reference range, 50-80 mg/dL).

Upper endoscopy with duodenal biopsy showed benign duodenal mucosa. Histopathologic evaluation revealed abundant foamy macrophages within lamina propria. Periodic acid–Schiff (PAS) stain was positive, diastase-resistant material was visualized within the macrophages (Figures 1 and 2). Polymerase chain reaction (PCR) testing of duodenal biopsy tissue was positive for T. whipplei. A lumbar puncture was performed, and PCR testing of CSF for T. whipplei was also positive. A stool PCR test was positive for Giardia. Transthoracic echocardiogram and brain magnetic resonance imaging were normal.

We treated the patient’s giardiasis with a single dose of oral tinidazole 2 g. To treat Whipple disease with central nervous system (CNS) involvement, we started the patient on ceftriaxone 2 g intravenous every 24 hours for 4 weeks, followed by oral trimethoprim and sulfamethoxazole (TMPSMX) 160/800 mg twice daily with an expected 1-year course.

Two months into TMP-SMX therapy, the patient developed an acute kidney injury with hyperkalemia (potassium, 5.5 mEq/L). We transitioned the therapy to doxycycline 100 mg twice daily and hydroxychloroquine 200 mg orally 3 times daily to complete 18 months of therapy. A lumbar puncture for CSF PCR and duodenal biopsy was planned for 6 months and 1 year after diagnosis.

Discussion

Whipple disease is often overlooked when making a diagnosis due to the nonspecific nature of its associated signs and symptoms. Classic Whipple disease has 2 stages: an initial prodromal stage marked by intermittent arthralgias, followed by a second gastrointestinal stage that involves chronic diarrhea, abdominal pain, and weight loss.^1-3 Infection can sometimes be misdiagnosed as seronegative rheumatoid arthritis and a definite diagnosis can be missed for extended periods, with 1 case taking up to 8 years to diagnose after the first joint manifestations.^2,4,5 Blood culture-negative endocarditis has also been well documented.^1-5

The most common CNS clinical manifestations of Whipple disease include cognitive changes (eg, dementia), ocular movement disturbances (eg, oculomasticatory myorhythmia, which is pathognomonic for Whipple disease), involuntary movements, and hypothalamic dysfunction.^1,6 Other neurologic symptoms include seizures, ataxia, meningitis, and myelopathy. Cerebrospinal fluid studies vary, with some results being normal and others revealing elevated protein counts.¹

Disease Course

A retrospective study by Compain and colleagues reports that Whipple disease follows 3 patterns of clinical CNS involvement: classic Whipple disease with neurologic involvement, Whipple disease with isolated neurologic involvement, and neurologic relapse of previously treated Whipple disease.⁶ Isolated neurologic involvement is roughly 4% to 8%.^6-8 Previous studies showed that the average delay from the presentation of neurologic symptoms to diagnosis is about 30 months.⁹

Diagnosis can be made with histologic evaluation of duodenal tissue using hematoxylin-eosin and PAS stains, which reveal foamy macrophages in expanded duodenal lamina propria, along with a positive tissue PCR.^1,5 The slow replication rate of T. whipplei limits the effectiveness of bacterial cultures. After adequate treatment, relapses are still possible and regularly involve the CNS.^1,4

Treatment typically involves blood-brain barrier-crossing agents, such as 2 weeks of meropenem 1 g every 24 hours or 2 to 4 weeks of ceftriaxone 2 g every 24 hours, followed by 1 year of TMP-SMX 160/800 mg twice daily. Doxycycline 100 mg twice daily and hydroxychloroquine 200 mg orally 3 times daily have also been shown to be effective, as seen in our patient.

Mortality rates vary for patients with Whipple disease and CNS involvement. One study reported poor overall prognosis in patients with CNS involvement, with mortality rates as high as 27%.¹⁰ However, rates of early detection and appropriate treatment may be improving, with 1 case series reporting 11% mortality in 18 patients with Whipple disease.⁶

Diagnosis

Because Whipple disease mimics many other diseases, misdiagnosis as infectious and noninfectious etiologies is common. PAS stain and tissue PCR helped uncover Whipple disease in a patient erroneously diagnosed with refractory Crohn disease.¹¹

Weight loss, diarrhea, arthralgias, and cognitive impairment can also be seen in celiac disease. However, dermatologic manifestations, metabolic bone disease, and vitamin deficiencies are characteristics of celiac disease and can help distinguish it from T. whipplei infection.¹²

Whipple disease can also be mistaken for tropical sprue. Both can manifest with chronic diarrhea and duodenal villous atrophy; however, tropical sprue is more prevalent in specific geographic areas, and clinical manifestations are primarily gastrointestinal. Weight loss, diarrhea, steatorrhea, and folate deficiency are unique findings in tropical sprue that help differentiate it from Whipple disease.¹³ Likewise, other infectious diseases can be misdiagnosed as Whipple disease. Duodenal villi blunting and positive PAS staining have been reported in a Mycobacterium avium complex intestinal infection in a patient with AIDS, leading to a misdiagnosis of Whipple disease.¹⁴

Some parasitic infections have gastrointestinal symptoms similar to those of Whipple disease and others, such as giardiasis, are known to occur concurrently with Whipple disease.^15-17 Giardiasis can also account for weight loss, malabsorptive symptoms, and greasy diarrhea. One case report hypothesized that 1 disease may predispose individuals to the other, as they both affect villous architecture.¹⁷ Additional research is needed to determine where the case reports have left off and to explore the connection between the 2 conditions.

Conclusions

The diagnosis of Whipple disease is challenging and frequently missed due to the rare and protean nature of the disease. This case highlights the importance of clinical suspicion for Whipple disease, especially in patients presenting with chronic seronegative arthritis, gastrointestinal abnormalities, and cognitive changes. Furthermore, this case points to the importance of additional testing for Whipple disease, even when a concurrent infection, such as giardiasis, has been identified.

Whipple disease is a chronic, rare, infectious disease that manifests with systemic symptoms. This disease is caused by the gram-positive bacterium Tropheryma whipplei (T. whipplei). Common manifestations include gastrointestinal symptoms indicative of malabsorption, such as chronic diarrhea, unintentional weight loss (despite normal nutrient intake), and greasy, voluminous, foul-smelling stool. Other, less common manifestations include cardiovascular, endocrine, musculoskeletal, neurologic, and renal signs and symptoms. The prevalence of the disease is rare, affecting 3 in 1 million patients.¹ This case highlights the importance of considering Whipple disease when treating patients with multiple symptoms and concurrent disease processes.

Case Presentation

A 53-year-old male with a medical history of hypertension, hyperlipidemia, hypothyroidism, and microcytic anemia presented with an 8-month history of persistent diarrhea associated with abdominal bloating, abdominal discomfort, and a 30-lb weight loss. He also reported fatigue, headaches, inability to concentrate, memory distortion, and visual disturbances involving flashes and floaters. The patient reported no fever, chills, nuchal rigidity, or prior neurologic symptoms. He reported intermittent bilateral hand and knee arthralgias. An autoimmune evaluation for arthralgia was negative, and a prior colonoscopy had been normal.

The patient’s hobbies included gardening, hiking, fishing, and deer hunting in Wyoming and Texas. He had spent time around cattle, dogs, and cats. He consumed alcohol twice weekly but reported no tobacco or illicit drug use or recent international travel. The patient’s family history was positive for rheumatoid arthritis, diabetes mellitus, and hypertension.

The patient’s vital signs were all within reference ranges, and lung auscultation revealed clear breathing sounds with no cardiac murmurs, gallops, or rubs. An abdominal examination revealed decreased bowel sounds, while the rest of the physical examination was otherwise normal.

Initial laboratory results showed that his sodium was 134 mEq/L (reference range, 136-145 mEq/L), hemoglobin was 9.3 g/dL (reference range for men, 14.0-18.0 g/dL), and hematocrit was 30.7% (reference range for men 42%-52%). His white blood cell (WBC) count and thyroid-stimulating hormone level were within normal limits. A cerebrospinal fluid (CSF) analysis revealed the following: WBCs 1.0/μL (0-5/μL), segmented neutrophils 10% (reference range, 7%), lymphocytes 80% (reference range, 40-80%), macrophages 10% (reference range, 2%), red blood cells 3 × 10⁶ /μL (reference range, 4.3- 5.9 × 10⁶ /µL), protein 23.5 mg/dL (reference range, 15-60 mg/dL), and glucose 44 mg/dL (reference range, 50-80 mg/dL).

Upper endoscopy with duodenal biopsy showed benign duodenal mucosa. Histopathologic evaluation revealed abundant foamy macrophages within lamina propria. Periodic acid–Schiff (PAS) stain was positive, diastase-resistant material was visualized within the macrophages (Figures 1 and 2). Polymerase chain reaction (PCR) testing of duodenal biopsy tissue was positive for T. whipplei. A lumbar puncture was performed, and PCR testing of CSF for T. whipplei was also positive. A stool PCR test was positive for Giardia. Transthoracic echocardiogram and brain magnetic resonance imaging were normal.

We treated the patient’s giardiasis with a single dose of oral tinidazole 2 g. To treat Whipple disease with central nervous system (CNS) involvement, we started the patient on ceftriaxone 2 g intravenous every 24 hours for 4 weeks, followed by oral trimethoprim and sulfamethoxazole (TMPSMX) 160/800 mg twice daily with an expected 1-year course.

Two months into TMP-SMX therapy, the patient developed an acute kidney injury with hyperkalemia (potassium, 5.5 mEq/L). We transitioned the therapy to doxycycline 100 mg twice daily and hydroxychloroquine 200 mg orally 3 times daily to complete 18 months of therapy. A lumbar puncture for CSF PCR and duodenal biopsy was planned for 6 months and 1 year after diagnosis.

Discussion

Whipple disease is often overlooked when making a diagnosis due to the nonspecific nature of its associated signs and symptoms. Classic Whipple disease has 2 stages: an initial prodromal stage marked by intermittent arthralgias, followed by a second gastrointestinal stage that involves chronic diarrhea, abdominal pain, and weight loss.^1-3 Infection can sometimes be misdiagnosed as seronegative rheumatoid arthritis and a definite diagnosis can be missed for extended periods, with 1 case taking up to 8 years to diagnose after the first joint manifestations.^2,4,5 Blood culture-negative endocarditis has also been well documented.^1-5

The most common CNS clinical manifestations of Whipple disease include cognitive changes (eg, dementia), ocular movement disturbances (eg, oculomasticatory myorhythmia, which is pathognomonic for Whipple disease), involuntary movements, and hypothalamic dysfunction.^1,6 Other neurologic symptoms include seizures, ataxia, meningitis, and myelopathy. Cerebrospinal fluid studies vary, with some results being normal and others revealing elevated protein counts.¹

Disease Course

A retrospective study by Compain and colleagues reports that Whipple disease follows 3 patterns of clinical CNS involvement: classic Whipple disease with neurologic involvement, Whipple disease with isolated neurologic involvement, and neurologic relapse of previously treated Whipple disease.⁶ Isolated neurologic involvement is roughly 4% to 8%.^6-8 Previous studies showed that the average delay from the presentation of neurologic symptoms to diagnosis is about 30 months.⁹

Diagnosis can be made with histologic evaluation of duodenal tissue using hematoxylin-eosin and PAS stains, which reveal foamy macrophages in expanded duodenal lamina propria, along with a positive tissue PCR.^1,5 The slow replication rate of T. whipplei limits the effectiveness of bacterial cultures. After adequate treatment, relapses are still possible and regularly involve the CNS.^1,4

Treatment typically involves blood-brain barrier-crossing agents, such as 2 weeks of meropenem 1 g every 24 hours or 2 to 4 weeks of ceftriaxone 2 g every 24 hours, followed by 1 year of TMP-SMX 160/800 mg twice daily. Doxycycline 100 mg twice daily and hydroxychloroquine 200 mg orally 3 times daily have also been shown to be effective, as seen in our patient.

Mortality rates vary for patients with Whipple disease and CNS involvement. One study reported poor overall prognosis in patients with CNS involvement, with mortality rates as high as 27%.¹⁰ However, rates of early detection and appropriate treatment may be improving, with 1 case series reporting 11% mortality in 18 patients with Whipple disease.⁶

Diagnosis

Because Whipple disease mimics many other diseases, misdiagnosis as infectious and noninfectious etiologies is common. PAS stain and tissue PCR helped uncover Whipple disease in a patient erroneously diagnosed with refractory Crohn disease.¹¹

Weight loss, diarrhea, arthralgias, and cognitive impairment can also be seen in celiac disease. However, dermatologic manifestations, metabolic bone disease, and vitamin deficiencies are characteristics of celiac disease and can help distinguish it from T. whipplei infection.¹²

Whipple disease can also be mistaken for tropical sprue. Both can manifest with chronic diarrhea and duodenal villous atrophy; however, tropical sprue is more prevalent in specific geographic areas, and clinical manifestations are primarily gastrointestinal. Weight loss, diarrhea, steatorrhea, and folate deficiency are unique findings in tropical sprue that help differentiate it from Whipple disease.¹³ Likewise, other infectious diseases can be misdiagnosed as Whipple disease. Duodenal villi blunting and positive PAS staining have been reported in a Mycobacterium avium complex intestinal infection in a patient with AIDS, leading to a misdiagnosis of Whipple disease.¹⁴

Some parasitic infections have gastrointestinal symptoms similar to those of Whipple disease and others, such as giardiasis, are known to occur concurrently with Whipple disease.^15-17 Giardiasis can also account for weight loss, malabsorptive symptoms, and greasy diarrhea. One case report hypothesized that 1 disease may predispose individuals to the other, as they both affect villous architecture.¹⁷ Additional research is needed to determine where the case reports have left off and to explore the connection between the 2 conditions.

Conclusions

The diagnosis of Whipple disease is challenging and frequently missed due to the rare and protean nature of the disease. This case highlights the importance of clinical suspicion for Whipple disease, especially in patients presenting with chronic seronegative arthritis, gastrointestinal abnormalities, and cognitive changes. Furthermore, this case points to the importance of additional testing for Whipple disease, even when a concurrent infection, such as giardiasis, has been identified.

Whipple disease is a chronic, rare, infectious disease that manifests with systemic symptoms. This disease is caused by the gram-positive bacterium Tropheryma whipplei (T. whipplei). Common manifestations include gastrointestinal symptoms indicative of malabsorption, such as chronic diarrhea, unintentional weight loss (despite normal nutrient intake), and greasy, voluminous, foul-smelling stool. Other, less common manifestations include cardiovascular, endocrine, musculoskeletal, neurologic, and renal signs and symptoms. The prevalence of the disease is rare, affecting 3 in 1 million patients.¹ This case highlights the importance of considering Whipple disease when treating patients with multiple symptoms and concurrent disease processes.

Case Presentation

A 53-year-old male with a medical history of hypertension, hyperlipidemia, hypothyroidism, and microcytic anemia presented with an 8-month history of persistent diarrhea associated with abdominal bloating, abdominal discomfort, and a 30-lb weight loss. He also reported fatigue, headaches, inability to concentrate, memory distortion, and visual disturbances involving flashes and floaters. The patient reported no fever, chills, nuchal rigidity, or prior neurologic symptoms. He reported intermittent bilateral hand and knee arthralgias. An autoimmune evaluation for arthralgia was negative, and a prior colonoscopy had been normal.

The patient’s hobbies included gardening, hiking, fishing, and deer hunting in Wyoming and Texas. He had spent time around cattle, dogs, and cats. He consumed alcohol twice weekly but reported no tobacco or illicit drug use or recent international travel. The patient’s family history was positive for rheumatoid arthritis, diabetes mellitus, and hypertension.

The patient’s vital signs were all within reference ranges, and lung auscultation revealed clear breathing sounds with no cardiac murmurs, gallops, or rubs. An abdominal examination revealed decreased bowel sounds, while the rest of the physical examination was otherwise normal.

Initial laboratory results showed that his sodium was 134 mEq/L (reference range, 136-145 mEq/L), hemoglobin was 9.3 g/dL (reference range for men, 14.0-18.0 g/dL), and hematocrit was 30.7% (reference range for men 42%-52%). His white blood cell (WBC) count and thyroid-stimulating hormone level were within normal limits. A cerebrospinal fluid (CSF) analysis revealed the following: WBCs 1.0/μL (0-5/μL), segmented neutrophils 10% (reference range, 7%), lymphocytes 80% (reference range, 40-80%), macrophages 10% (reference range, 2%), red blood cells 3 × 10⁶ /μL (reference range, 4.3- 5.9 × 10⁶ /µL), protein 23.5 mg/dL (reference range, 15-60 mg/dL), and glucose 44 mg/dL (reference range, 50-80 mg/dL).

Upper endoscopy with duodenal biopsy showed benign duodenal mucosa. Histopathologic evaluation revealed abundant foamy macrophages within lamina propria. Periodic acid–Schiff (PAS) stain was positive, diastase-resistant material was visualized within the macrophages (Figures 1 and 2). Polymerase chain reaction (PCR) testing of duodenal biopsy tissue was positive for T. whipplei. A lumbar puncture was performed, and PCR testing of CSF for T. whipplei was also positive. A stool PCR test was positive for Giardia. Transthoracic echocardiogram and brain magnetic resonance imaging were normal.

We treated the patient’s giardiasis with a single dose of oral tinidazole 2 g. To treat Whipple disease with central nervous system (CNS) involvement, we started the patient on ceftriaxone 2 g intravenous every 24 hours for 4 weeks, followed by oral trimethoprim and sulfamethoxazole (TMPSMX) 160/800 mg twice daily with an expected 1-year course.

Two months into TMP-SMX therapy, the patient developed an acute kidney injury with hyperkalemia (potassium, 5.5 mEq/L). We transitioned the therapy to doxycycline 100 mg twice daily and hydroxychloroquine 200 mg orally 3 times daily to complete 18 months of therapy. A lumbar puncture for CSF PCR and duodenal biopsy was planned for 6 months and 1 year after diagnosis.

Discussion

Whipple disease is often overlooked when making a diagnosis due to the nonspecific nature of its associated signs and symptoms. Classic Whipple disease has 2 stages: an initial prodromal stage marked by intermittent arthralgias, followed by a second gastrointestinal stage that involves chronic diarrhea, abdominal pain, and weight loss.^1-3 Infection can sometimes be misdiagnosed as seronegative rheumatoid arthritis and a definite diagnosis can be missed for extended periods, with 1 case taking up to 8 years to diagnose after the first joint manifestations.^2,4,5 Blood culture-negative endocarditis has also been well documented.^1-5

The most common CNS clinical manifestations of Whipple disease include cognitive changes (eg, dementia), ocular movement disturbances (eg, oculomasticatory myorhythmia, which is pathognomonic for Whipple disease), involuntary movements, and hypothalamic dysfunction.^1,6 Other neurologic symptoms include seizures, ataxia, meningitis, and myelopathy. Cerebrospinal fluid studies vary, with some results being normal and others revealing elevated protein counts.¹

Disease Course

A retrospective study by Compain and colleagues reports that Whipple disease follows 3 patterns of clinical CNS involvement: classic Whipple disease with neurologic involvement, Whipple disease with isolated neurologic involvement, and neurologic relapse of previously treated Whipple disease.⁶ Isolated neurologic involvement is roughly 4% to 8%.^6-8 Previous studies showed that the average delay from the presentation of neurologic symptoms to diagnosis is about 30 months.⁹

Diagnosis can be made with histologic evaluation of duodenal tissue using hematoxylin-eosin and PAS stains, which reveal foamy macrophages in expanded duodenal lamina propria, along with a positive tissue PCR.^1,5 The slow replication rate of T. whipplei limits the effectiveness of bacterial cultures. After adequate treatment, relapses are still possible and regularly involve the CNS.^1,4

Treatment typically involves blood-brain barrier-crossing agents, such as 2 weeks of meropenem 1 g every 24 hours or 2 to 4 weeks of ceftriaxone 2 g every 24 hours, followed by 1 year of TMP-SMX 160/800 mg twice daily. Doxycycline 100 mg twice daily and hydroxychloroquine 200 mg orally 3 times daily have also been shown to be effective, as seen in our patient.

Mortality rates vary for patients with Whipple disease and CNS involvement. One study reported poor overall prognosis in patients with CNS involvement, with mortality rates as high as 27%.¹⁰ However, rates of early detection and appropriate treatment may be improving, with 1 case series reporting 11% mortality in 18 patients with Whipple disease.⁶

Diagnosis

Because Whipple disease mimics many other diseases, misdiagnosis as infectious and noninfectious etiologies is common. PAS stain and tissue PCR helped uncover Whipple disease in a patient erroneously diagnosed with refractory Crohn disease.¹¹

Weight loss, diarrhea, arthralgias, and cognitive impairment can also be seen in celiac disease. However, dermatologic manifestations, metabolic bone disease, and vitamin deficiencies are characteristics of celiac disease and can help distinguish it from T. whipplei infection.¹²

Whipple disease can also be mistaken for tropical sprue. Both can manifest with chronic diarrhea and duodenal villous atrophy; however, tropical sprue is more prevalent in specific geographic areas, and clinical manifestations are primarily gastrointestinal. Weight loss, diarrhea, steatorrhea, and folate deficiency are unique findings in tropical sprue that help differentiate it from Whipple disease.¹³ Likewise, other infectious diseases can be misdiagnosed as Whipple disease. Duodenal villi blunting and positive PAS staining have been reported in a Mycobacterium avium complex intestinal infection in a patient with AIDS, leading to a misdiagnosis of Whipple disease.¹⁴

Some parasitic infections have gastrointestinal symptoms similar to those of Whipple disease and others, such as giardiasis, are known to occur concurrently with Whipple disease.^15-17 Giardiasis can also account for weight loss, malabsorptive symptoms, and greasy diarrhea. One case report hypothesized that 1 disease may predispose individuals to the other, as they both affect villous architecture.¹⁷ Additional research is needed to determine where the case reports have left off and to explore the connection between the 2 conditions.

Conclusions

The diagnosis of Whipple disease is challenging and frequently missed due to the rare and protean nature of the disease. This case highlights the importance of clinical suspicion for Whipple disease, especially in patients presenting with chronic seronegative arthritis, gastrointestinal abnormalities, and cognitive changes. Furthermore, this case points to the importance of additional testing for Whipple disease, even when a concurrent infection, such as giardiasis, has been identified.

Anticholinergic medications block the activity of the neurotransmitter acetylcholine by binding to either muscarinic or nicotinic receptors in both the peripheral and central nervous system. Anticholinergic medications typically refer to antimuscarinic medications and have been prescribed to treat a variety of conditions common in older adults, including overactive bladder, allergies, muscle spasms, and sleep disorders.^1,2 Since muscarinic receptors are present throughout the body, anticholinergic medications are associated with many adverse effects (AEs), including constipation, urinary retention, xerostomia, and delirium. Older adults are more sensitive to these AEs due to physiological changes associated with aging.¹

The American Geriatric Society Beers Criteria for Potentially Inappropriate Medications Use in Older Adults identifies drugs with strong anticholinergic properties. The Beers Criteria strongly recommends avoiding these medications in patients with dementia or cognitive impairment due to the risk of central nervous system AEs. In the updated 2023 Beers Criteria, the rationale was expanded to recognize the risks of the cumulative anticholinergic burden associated with concurrent anticholinergic use.^3,4

Given the prevalent use of anticholinergic medications in older adults, there has been significant research demonstrating their AEs, specifically delirium and cognitive impairment in geriatric patients. A systematic review of 14 articles conducted in 7 different countries of patients with median age of 76.4 to 86.1 years reviewed clinical outcomes of anticholinergic use in patients with dementia. Five studies found anticholinergics were associated with increased all-cause mortality in patients with dementia, and 3 studies found anticholinergics were associated with longer hospital stays. Other studies found that anticholinergics were associated with delirium and reduced health-related quality of life.⁵

About 35% of veterans with dementia have been prescribed a medication regimen with a high anticholinergic burden.⁶ In 2018, the US Department of Veterans Affairs (VA) Pharmacy Benfits Management Center for Medical Safety completed a centrally aggregated medication use evaluation (CAMUE) to assess the appropriateness of anticholinergic medication use in patients with dementia. The retrospective chart review included 1094 veterans from 19 sites. Overall, about 15% of the veterans experienced new falls, delirium, or worsening dementia within 30 days of starting an anticholinergic medication. Furthermore, < 40% had documentation of a nonanticholinergic alternative medication trial, and < 20% had documented nonpharmacologic therapy. The documentation of risk-benefit assessment acknowledging the risks of anticholinergic medication use in veterans with dementia occurred only about 13% of the time. The CAMUE concluded that the risks of initiating an anticholinergic medication in veterans with dementia are likely underdocumented and possibly under considered by prescribers.⁷

Developed within the Veterans Health Administration (VHA), VIONE (Vital, Important, Optional, Not Indicated, Every medication has an indication) is a medication management methodology that aims to reduce polypharmacy and improve patient safety consistent with high-reliability organizations. Since it launched in 2016, VIONE has gradually been implemented at many VHA facilities. The VIONE deprescribing dashboard had not been used at the VA Louisville Healthcare System prior to this quality improvement project.

This dashboard uses the Beers Criteria to identify potentially inappropriate anticholinergic medications. It uses the Anticholinergic Cognitive Burden (ACB) scale to calculate the cumulative anticholinergic risk for each patient. Medications with an ACB score of 2 or 3 have clinically relevant cognitive effects such as delirium and dementia (Table 1). For each point increase in total ACB score, a decline in mini-mental state examination score of 0.33 points over 2 years has been shown. Each point increase has also been correlated with a 26% increase in risk of death.^8-10

Methods

The purpose of this quality improvement project was to determine the impact of pharmacist-driven deprescribing on the anticholinergic burden in veterans with dementia at VA Louisville Healthcare System. Data were obtained through the Computerized Patient Record System (CPRS) and VIONE deprescribing dashboard and entered in a secure Microsoft Excel spreadsheet. Pharmacist deprescribing steps were entered as CPRS progress notes. A deprescribing note template was created, and 11 templates with indication-specific recommendations were created for each anticholinergic indication identified (contact authors for deprescribing note template examples). Usage of anticholinergic medications was reexamined 3 months after the deprescribing note was entered.

Eligible patients identified in the VIONE deprescribing dashboard had an outpatient order for a medication with strong anticholinergic properties as identified using the Beers Criteria and were aged ≥ 65 years. Patients also had to be diagnosed with dementia or cognitive impairment. Patients were excluded if they were receiving hospice care or if the anticholinergic medication was from a non-VA prescriber or filled at a non-VA pharmacy. The VIONE deprescribing dashboard also excluded skeletal muscle relaxants if the patient had a spinal cord-related visit in the previous 2 years, first-generation antihistamines if the patient had a vertigo diagnosis, hydroxyzine if the indication was for anxiety, trospium if the indication was for overactive bladder, and antipsychotics if the patient had been diagnosed with schizophrenia or bipolar disorder. The following were included in the deprescribing recommendations if the dashboard identified the patient due to receiving a second strongly anticholinergic medication: first generation antihistamines if the patient was diagnosed with vertigo and hydroxyzine if the indication is for anxiety.

Each eligible patient received a focused medication review by a pharmacist via electronic chart review and a templated CPRS progress note with patient-specific recommendations. The prescriber and the patient’s primary care practitioner were recommended to perform a patient-specific risk-benefit assessment, deprescribe potentially inappropriate anticholinergic medications, and consider nonanticholinergic alternatives (both pharmacologic and nonpharmacologic). Data collected included baseline age, sex, prespecified comorbidities (type of dementia, cognitive impairment, delirium, benign prostatic hyperplasia/lower urinary tract symptoms), duration of prescribed anticholinergic medication, indication and deprescribing rate for each anticholinergic agent, and concurrent dementia medications (acetylcholinesterase inhibitors, memantine, or both).

The primary outcome was the number of patients that had = 1 medication with strong anticholinergic properties deprescribed. Deprescribing was defined as medication discontinuation or reduction of total daily dose. Secondary outcomes were the mean change in ACB scale, the number of patients with dose tapering, documented patient-specific risk-benefit assessment, and initiated nonanticholinergic alternative per pharmacist recommendation.

Results

The VIONE deprescribing dashboard identified 121 patients; 45 were excluded for non-VA prescriber or pharmacy, and 8 patients were excluded for other reasons. Sixty-eight patients were included in the deprescribing initiative. The mean age was 73.4 years (range, 67-93), 65 (96%) were male, and 34 (50%) had unspecified dementia (Table 2). Thirty-one patients (46%) had concurrent cholinesterase inhibitor prescriptions for dementia. The median duration of use of a strong anticholinergic medication was 11 months.

Twenty-nine patients (43%) had ≥ 1 medication with strong anticholinergic properties deprescribed. Anticholinergic medication was discontinued for 26 patients, and the dose was decreased for 3 patients. ACB score fell by a mean of 1.1 per patient. There was an increase in the documented risk-benefit assessment for anticholinergic medications from a baseline of 4 (6%) to 19 (28%) 3 months after the deprescribing note. Cyclobenzaprine, paroxetine, and oxybutynin were deprescribed the most, and amitriptyline had the lowest rate of deprescribing (Table 3). Thirty patients (44%) had a pharmacologic, nonanticholinergic alternative initiated per pharmacist recommendation, and 6 patients (9%) had a nonpharmacologic alternative initiated per pharmacist recommendation.

Discussion

This quality improvement project suggests that with the use of population health management tools such as the VIONE deprescribing dashboard, pharmacists can help identify and deprescribe strong anticholinergic medications in patients with cognitive impairment or dementia. Pharmacists can also aid in deprescribing through evidence-based recommendations to guide risk-benefit discussion and consider safer, nonanticholinergic alternatives. The authors were able to help reduce anticholinergic cognitive burden in 43% of patients in this sample. The mean 1.1 ACB score reduction was considered clinically significant based on prior studies that found that each 1-point increase in ACB score correlated with declined cognition and increased mortality.^8,10 The VIONE deprescribing dashboard provided real-time patient data and helped target patients at the highest risk of anticholinergic AEs. The creation of the note templates based on the indication helped streamline recommendations. Typically, the prescriber addressed the recommendations at a routine follow-up appointment. The deprescribing method used in this project was time-efficient and could be easily replicated once the CPRS note templates were created. Future deprescribing projects could consider more direct pharmacist intervention and medication management.

Limitations

There was no direct assessment of clinical outcomes such as change in cognition using cognitive function tests. However, multiple studies have demonstrated AEs associated with strong anticholinergic medication use and additive anticholinergic burden in patients with dementia or cognitive impairment.1,5 Also, the 3-month follow-up period was relatively short. The pharmacist’s deprescribing recommendations may have been accepted after 3 months, or patients could have restarted their anticholinergic medications. Longer follow-up time could provide more robust results and conclusions. Thirdly, there was no formal definition of what constituted a risk-benefit assessment of anticholinergic medications. The risk-benefit assessment was determined at the discretion of the authors, which was subjective and allowed for bias. Finally, 6 patients died during the 3-month follow-up. The data for these patients were included in the baseline characteristics but not in the study outcomes. If these patients had been excluded from the results, a higher percentage of patients (47%) would have had ≥ 1 anticholinergic medication deprescribed.

Conclusions

In collaboration with the interdisciplinary team, pharmacist recommendations resulted in deprescribing of anticholinergic medications in veterans with dementia or cognitive impairment. The VIONE deprescribing dashboard, an easily accessible population health management tool, can identify patients prescribed potentially inappropriate medications and help target patients at the highest risk of anticholinergic AEs. To prevent worsening cognitive impairment, delirium, falls, and other AEs, this deprescribing initiative can be replicated at other VHA facilities. Future projects could have a longer follow-up period, incorporate more direct pharmacist intervention, and assess clinical outcomes of deprescribing.

Anticholinergic medications block the activity of the neurotransmitter acetylcholine by binding to either muscarinic or nicotinic receptors in both the peripheral and central nervous system. Anticholinergic medications typically refer to antimuscarinic medications and have been prescribed to treat a variety of conditions common in older adults, including overactive bladder, allergies, muscle spasms, and sleep disorders.^1,2 Since muscarinic receptors are present throughout the body, anticholinergic medications are associated with many adverse effects (AEs), including constipation, urinary retention, xerostomia, and delirium. Older adults are more sensitive to these AEs due to physiological changes associated with aging.¹

The American Geriatric Society Beers Criteria for Potentially Inappropriate Medications Use in Older Adults identifies drugs with strong anticholinergic properties. The Beers Criteria strongly recommends avoiding these medications in patients with dementia or cognitive impairment due to the risk of central nervous system AEs. In the updated 2023 Beers Criteria, the rationale was expanded to recognize the risks of the cumulative anticholinergic burden associated with concurrent anticholinergic use.^3,4

Given the prevalent use of anticholinergic medications in older adults, there has been significant research demonstrating their AEs, specifically delirium and cognitive impairment in geriatric patients. A systematic review of 14 articles conducted in 7 different countries of patients with median age of 76.4 to 86.1 years reviewed clinical outcomes of anticholinergic use in patients with dementia. Five studies found anticholinergics were associated with increased all-cause mortality in patients with dementia, and 3 studies found anticholinergics were associated with longer hospital stays. Other studies found that anticholinergics were associated with delirium and reduced health-related quality of life.⁵

About 35% of veterans with dementia have been prescribed a medication regimen with a high anticholinergic burden.⁶ In 2018, the US Department of Veterans Affairs (VA) Pharmacy Benfits Management Center for Medical Safety completed a centrally aggregated medication use evaluation (CAMUE) to assess the appropriateness of anticholinergic medication use in patients with dementia. The retrospective chart review included 1094 veterans from 19 sites. Overall, about 15% of the veterans experienced new falls, delirium, or worsening dementia within 30 days of starting an anticholinergic medication. Furthermore, < 40% had documentation of a nonanticholinergic alternative medication trial, and < 20% had documented nonpharmacologic therapy. The documentation of risk-benefit assessment acknowledging the risks of anticholinergic medication use in veterans with dementia occurred only about 13% of the time. The CAMUE concluded that the risks of initiating an anticholinergic medication in veterans with dementia are likely underdocumented and possibly under considered by prescribers.⁷

Developed within the Veterans Health Administration (VHA), VIONE (Vital, Important, Optional, Not Indicated, Every medication has an indication) is a medication management methodology that aims to reduce polypharmacy and improve patient safety consistent with high-reliability organizations. Since it launched in 2016, VIONE has gradually been implemented at many VHA facilities. The VIONE deprescribing dashboard had not been used at the VA Louisville Healthcare System prior to this quality improvement project.

This dashboard uses the Beers Criteria to identify potentially inappropriate anticholinergic medications. It uses the Anticholinergic Cognitive Burden (ACB) scale to calculate the cumulative anticholinergic risk for each patient. Medications with an ACB score of 2 or 3 have clinically relevant cognitive effects such as delirium and dementia (Table 1). For each point increase in total ACB score, a decline in mini-mental state examination score of 0.33 points over 2 years has been shown. Each point increase has also been correlated with a 26% increase in risk of death.^8-10

Methods

The purpose of this quality improvement project was to determine the impact of pharmacist-driven deprescribing on the anticholinergic burden in veterans with dementia at VA Louisville Healthcare System. Data were obtained through the Computerized Patient Record System (CPRS) and VIONE deprescribing dashboard and entered in a secure Microsoft Excel spreadsheet. Pharmacist deprescribing steps were entered as CPRS progress notes. A deprescribing note template was created, and 11 templates with indication-specific recommendations were created for each anticholinergic indication identified (contact authors for deprescribing note template examples). Usage of anticholinergic medications was reexamined 3 months after the deprescribing note was entered.

Eligible patients identified in the VIONE deprescribing dashboard had an outpatient order for a medication with strong anticholinergic properties as identified using the Beers Criteria and were aged ≥ 65 years. Patients also had to be diagnosed with dementia or cognitive impairment. Patients were excluded if they were receiving hospice care or if the anticholinergic medication was from a non-VA prescriber or filled at a non-VA pharmacy. The VIONE deprescribing dashboard also excluded skeletal muscle relaxants if the patient had a spinal cord-related visit in the previous 2 years, first-generation antihistamines if the patient had a vertigo diagnosis, hydroxyzine if the indication was for anxiety, trospium if the indication was for overactive bladder, and antipsychotics if the patient had been diagnosed with schizophrenia or bipolar disorder. The following were included in the deprescribing recommendations if the dashboard identified the patient due to receiving a second strongly anticholinergic medication: first generation antihistamines if the patient was diagnosed with vertigo and hydroxyzine if the indication is for anxiety.

Each eligible patient received a focused medication review by a pharmacist via electronic chart review and a templated CPRS progress note with patient-specific recommendations. The prescriber and the patient’s primary care practitioner were recommended to perform a patient-specific risk-benefit assessment, deprescribe potentially inappropriate anticholinergic medications, and consider nonanticholinergic alternatives (both pharmacologic and nonpharmacologic). Data collected included baseline age, sex, prespecified comorbidities (type of dementia, cognitive impairment, delirium, benign prostatic hyperplasia/lower urinary tract symptoms), duration of prescribed anticholinergic medication, indication and deprescribing rate for each anticholinergic agent, and concurrent dementia medications (acetylcholinesterase inhibitors, memantine, or both).

The primary outcome was the number of patients that had = 1 medication with strong anticholinergic properties deprescribed. Deprescribing was defined as medication discontinuation or reduction of total daily dose. Secondary outcomes were the mean change in ACB scale, the number of patients with dose tapering, documented patient-specific risk-benefit assessment, and initiated nonanticholinergic alternative per pharmacist recommendation.

Results

The VIONE deprescribing dashboard identified 121 patients; 45 were excluded for non-VA prescriber or pharmacy, and 8 patients were excluded for other reasons. Sixty-eight patients were included in the deprescribing initiative. The mean age was 73.4 years (range, 67-93), 65 (96%) were male, and 34 (50%) had unspecified dementia (Table 2). Thirty-one patients (46%) had concurrent cholinesterase inhibitor prescriptions for dementia. The median duration of use of a strong anticholinergic medication was 11 months.

Twenty-nine patients (43%) had ≥ 1 medication with strong anticholinergic properties deprescribed. Anticholinergic medication was discontinued for 26 patients, and the dose was decreased for 3 patients. ACB score fell by a mean of 1.1 per patient. There was an increase in the documented risk-benefit assessment for anticholinergic medications from a baseline of 4 (6%) to 19 (28%) 3 months after the deprescribing note. Cyclobenzaprine, paroxetine, and oxybutynin were deprescribed the most, and amitriptyline had the lowest rate of deprescribing (Table 3). Thirty patients (44%) had a pharmacologic, nonanticholinergic alternative initiated per pharmacist recommendation, and 6 patients (9%) had a nonpharmacologic alternative initiated per pharmacist recommendation.

Discussion

This quality improvement project suggests that with the use of population health management tools such as the VIONE deprescribing dashboard, pharmacists can help identify and deprescribe strong anticholinergic medications in patients with cognitive impairment or dementia. Pharmacists can also aid in deprescribing through evidence-based recommendations to guide risk-benefit discussion and consider safer, nonanticholinergic alternatives. The authors were able to help reduce anticholinergic cognitive burden in 43% of patients in this sample. The mean 1.1 ACB score reduction was considered clinically significant based on prior studies that found that each 1-point increase in ACB score correlated with declined cognition and increased mortality.^8,10 The VIONE deprescribing dashboard provided real-time patient data and helped target patients at the highest risk of anticholinergic AEs. The creation of the note templates based on the indication helped streamline recommendations. Typically, the prescriber addressed the recommendations at a routine follow-up appointment. The deprescribing method used in this project was time-efficient and could be easily replicated once the CPRS note templates were created. Future deprescribing projects could consider more direct pharmacist intervention and medication management.

Limitations

There was no direct assessment of clinical outcomes such as change in cognition using cognitive function tests. However, multiple studies have demonstrated AEs associated with strong anticholinergic medication use and additive anticholinergic burden in patients with dementia or cognitive impairment.1,5 Also, the 3-month follow-up period was relatively short. The pharmacist’s deprescribing recommendations may have been accepted after 3 months, or patients could have restarted their anticholinergic medications. Longer follow-up time could provide more robust results and conclusions. Thirdly, there was no formal definition of what constituted a risk-benefit assessment of anticholinergic medications. The risk-benefit assessment was determined at the discretion of the authors, which was subjective and allowed for bias. Finally, 6 patients died during the 3-month follow-up. The data for these patients were included in the baseline characteristics but not in the study outcomes. If these patients had been excluded from the results, a higher percentage of patients (47%) would have had ≥ 1 anticholinergic medication deprescribed.

Conclusions

In collaboration with the interdisciplinary team, pharmacist recommendations resulted in deprescribing of anticholinergic medications in veterans with dementia or cognitive impairment. The VIONE deprescribing dashboard, an easily accessible population health management tool, can identify patients prescribed potentially inappropriate medications and help target patients at the highest risk of anticholinergic AEs. To prevent worsening cognitive impairment, delirium, falls, and other AEs, this deprescribing initiative can be replicated at other VHA facilities. Future projects could have a longer follow-up period, incorporate more direct pharmacist intervention, and assess clinical outcomes of deprescribing.

Anticholinergic medications block the activity of the neurotransmitter acetylcholine by binding to either muscarinic or nicotinic receptors in both the peripheral and central nervous system. Anticholinergic medications typically refer to antimuscarinic medications and have been prescribed to treat a variety of conditions common in older adults, including overactive bladder, allergies, muscle spasms, and sleep disorders.^1,2 Since muscarinic receptors are present throughout the body, anticholinergic medications are associated with many adverse effects (AEs), including constipation, urinary retention, xerostomia, and delirium. Older adults are more sensitive to these AEs due to physiological changes associated with aging.¹

The American Geriatric Society Beers Criteria for Potentially Inappropriate Medications Use in Older Adults identifies drugs with strong anticholinergic properties. The Beers Criteria strongly recommends avoiding these medications in patients with dementia or cognitive impairment due to the risk of central nervous system AEs. In the updated 2023 Beers Criteria, the rationale was expanded to recognize the risks of the cumulative anticholinergic burden associated with concurrent anticholinergic use.^3,4

Given the prevalent use of anticholinergic medications in older adults, there has been significant research demonstrating their AEs, specifically delirium and cognitive impairment in geriatric patients. A systematic review of 14 articles conducted in 7 different countries of patients with median age of 76.4 to 86.1 years reviewed clinical outcomes of anticholinergic use in patients with dementia. Five studies found anticholinergics were associated with increased all-cause mortality in patients with dementia, and 3 studies found anticholinergics were associated with longer hospital stays. Other studies found that anticholinergics were associated with delirium and reduced health-related quality of life.⁵

About 35% of veterans with dementia have been prescribed a medication regimen with a high anticholinergic burden.⁶ In 2018, the US Department of Veterans Affairs (VA) Pharmacy Benfits Management Center for Medical Safety completed a centrally aggregated medication use evaluation (CAMUE) to assess the appropriateness of anticholinergic medication use in patients with dementia. The retrospective chart review included 1094 veterans from 19 sites. Overall, about 15% of the veterans experienced new falls, delirium, or worsening dementia within 30 days of starting an anticholinergic medication. Furthermore, < 40% had documentation of a nonanticholinergic alternative medication trial, and < 20% had documented nonpharmacologic therapy. The documentation of risk-benefit assessment acknowledging the risks of anticholinergic medication use in veterans with dementia occurred only about 13% of the time. The CAMUE concluded that the risks of initiating an anticholinergic medication in veterans with dementia are likely underdocumented and possibly under considered by prescribers.⁷

Developed within the Veterans Health Administration (VHA), VIONE (Vital, Important, Optional, Not Indicated, Every medication has an indication) is a medication management methodology that aims to reduce polypharmacy and improve patient safety consistent with high-reliability organizations. Since it launched in 2016, VIONE has gradually been implemented at many VHA facilities. The VIONE deprescribing dashboard had not been used at the VA Louisville Healthcare System prior to this quality improvement project.

This dashboard uses the Beers Criteria to identify potentially inappropriate anticholinergic medications. It uses the Anticholinergic Cognitive Burden (ACB) scale to calculate the cumulative anticholinergic risk for each patient. Medications with an ACB score of 2 or 3 have clinically relevant cognitive effects such as delirium and dementia (Table 1). For each point increase in total ACB score, a decline in mini-mental state examination score of 0.33 points over 2 years has been shown. Each point increase has also been correlated with a 26% increase in risk of death.^8-10

Methods

The purpose of this quality improvement project was to determine the impact of pharmacist-driven deprescribing on the anticholinergic burden in veterans with dementia at VA Louisville Healthcare System. Data were obtained through the Computerized Patient Record System (CPRS) and VIONE deprescribing dashboard and entered in a secure Microsoft Excel spreadsheet. Pharmacist deprescribing steps were entered as CPRS progress notes. A deprescribing note template was created, and 11 templates with indication-specific recommendations were created for each anticholinergic indication identified (contact authors for deprescribing note template examples). Usage of anticholinergic medications was reexamined 3 months after the deprescribing note was entered.

Eligible patients identified in the VIONE deprescribing dashboard had an outpatient order for a medication with strong anticholinergic properties as identified using the Beers Criteria and were aged ≥ 65 years. Patients also had to be diagnosed with dementia or cognitive impairment. Patients were excluded if they were receiving hospice care or if the anticholinergic medication was from a non-VA prescriber or filled at a non-VA pharmacy. The VIONE deprescribing dashboard also excluded skeletal muscle relaxants if the patient had a spinal cord-related visit in the previous 2 years, first-generation antihistamines if the patient had a vertigo diagnosis, hydroxyzine if the indication was for anxiety, trospium if the indication was for overactive bladder, and antipsychotics if the patient had been diagnosed with schizophrenia or bipolar disorder. The following were included in the deprescribing recommendations if the dashboard identified the patient due to receiving a second strongly anticholinergic medication: first generation antihistamines if the patient was diagnosed with vertigo and hydroxyzine if the indication is for anxiety.

Each eligible patient received a focused medication review by a pharmacist via electronic chart review and a templated CPRS progress note with patient-specific recommendations. The prescriber and the patient’s primary care practitioner were recommended to perform a patient-specific risk-benefit assessment, deprescribe potentially inappropriate anticholinergic medications, and consider nonanticholinergic alternatives (both pharmacologic and nonpharmacologic). Data collected included baseline age, sex, prespecified comorbidities (type of dementia, cognitive impairment, delirium, benign prostatic hyperplasia/lower urinary tract symptoms), duration of prescribed anticholinergic medication, indication and deprescribing rate for each anticholinergic agent, and concurrent dementia medications (acetylcholinesterase inhibitors, memantine, or both).

The primary outcome was the number of patients that had = 1 medication with strong anticholinergic properties deprescribed. Deprescribing was defined as medication discontinuation or reduction of total daily dose. Secondary outcomes were the mean change in ACB scale, the number of patients with dose tapering, documented patient-specific risk-benefit assessment, and initiated nonanticholinergic alternative per pharmacist recommendation.

Results

The VIONE deprescribing dashboard identified 121 patients; 45 were excluded for non-VA prescriber or pharmacy, and 8 patients were excluded for other reasons. Sixty-eight patients were included in the deprescribing initiative. The mean age was 73.4 years (range, 67-93), 65 (96%) were male, and 34 (50%) had unspecified dementia (Table 2). Thirty-one patients (46%) had concurrent cholinesterase inhibitor prescriptions for dementia. The median duration of use of a strong anticholinergic medication was 11 months.

Twenty-nine patients (43%) had ≥ 1 medication with strong anticholinergic properties deprescribed. Anticholinergic medication was discontinued for 26 patients, and the dose was decreased for 3 patients. ACB score fell by a mean of 1.1 per patient. There was an increase in the documented risk-benefit assessment for anticholinergic medications from a baseline of 4 (6%) to 19 (28%) 3 months after the deprescribing note. Cyclobenzaprine, paroxetine, and oxybutynin were deprescribed the most, and amitriptyline had the lowest rate of deprescribing (Table 3). Thirty patients (44%) had a pharmacologic, nonanticholinergic alternative initiated per pharmacist recommendation, and 6 patients (9%) had a nonpharmacologic alternative initiated per pharmacist recommendation.

Discussion

This quality improvement project suggests that with the use of population health management tools such as the VIONE deprescribing dashboard, pharmacists can help identify and deprescribe strong anticholinergic medications in patients with cognitive impairment or dementia. Pharmacists can also aid in deprescribing through evidence-based recommendations to guide risk-benefit discussion and consider safer, nonanticholinergic alternatives. The authors were able to help reduce anticholinergic cognitive burden in 43% of patients in this sample. The mean 1.1 ACB score reduction was considered clinically significant based on prior studies that found that each 1-point increase in ACB score correlated with declined cognition and increased mortality.^8,10 The VIONE deprescribing dashboard provided real-time patient data and helped target patients at the highest risk of anticholinergic AEs. The creation of the note templates based on the indication helped streamline recommendations. Typically, the prescriber addressed the recommendations at a routine follow-up appointment. The deprescribing method used in this project was time-efficient and could be easily replicated once the CPRS note templates were created. Future deprescribing projects could consider more direct pharmacist intervention and medication management.

Limitations

There was no direct assessment of clinical outcomes such as change in cognition using cognitive function tests. However, multiple studies have demonstrated AEs associated with strong anticholinergic medication use and additive anticholinergic burden in patients with dementia or cognitive impairment.1,5 Also, the 3-month follow-up period was relatively short. The pharmacist’s deprescribing recommendations may have been accepted after 3 months, or patients could have restarted their anticholinergic medications. Longer follow-up time could provide more robust results and conclusions. Thirdly, there was no formal definition of what constituted a risk-benefit assessment of anticholinergic medications. The risk-benefit assessment was determined at the discretion of the authors, which was subjective and allowed for bias. Finally, 6 patients died during the 3-month follow-up. The data for these patients were included in the baseline characteristics but not in the study outcomes. If these patients had been excluded from the results, a higher percentage of patients (47%) would have had ≥ 1 anticholinergic medication deprescribed.

Conclusions

In collaboration with the interdisciplinary team, pharmacist recommendations resulted in deprescribing of anticholinergic medications in veterans with dementia or cognitive impairment. The VIONE deprescribing dashboard, an easily accessible population health management tool, can identify patients prescribed potentially inappropriate medications and help target patients at the highest risk of anticholinergic AEs. To prevent worsening cognitive impairment, delirium, falls, and other AEs, this deprescribing initiative can be replicated at other VHA facilities. Future projects could have a longer follow-up period, incorporate more direct pharmacist intervention, and assess clinical outcomes of deprescribing.

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.