Gastroenterology & Endoscopy News - Special Edition Annual Supplement 2025-2026

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@=206.9 216A6<; Annual Supplement to Gastroenterology & Endoscopy News • 2025-2026

A #MondayNightIBD Conversation: Approach to a Patient With IBD-Associated Peripheral Spondyloarthropathies Decoding IBD: 5 Practice-Changing Lessons Highlights From the 2025 Gut Microbiota For Health World Summit Diagnosis and Management of Barrett’s Esophagus: A Case-Based Approach Deciphering Dysphagia in Clinical Practice: A Case-Based Review The Frontiers of Therapeutic Endoscopic Ultrasound in 2025: Advances In EUS Scope Design A Gastroenterologist’s Guide To Bowel Preparation New Guidance Issued on HLD and Sterilization Highlights of Updated EGD Quality Indicators

FOR ADULTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS (UC) OR CROHN’S DISEASE (CD)

THEIR UC AND CD GOALS ARE IN REACH. AND SO ARE YOURS WITH OMVOH. Learn more about Omvoh by visiting omvoh.lilly.com/hcp

INDICATIONS AND IMPORTANT SAFETY INFORMATION Omvoh is an IL-23p19 antagonist indicated for adults with moderately to severely active ulcerative colitis (UC) or moderately to severely active Crohn’s disease (CD).

IMPORTANT SAFETY INFORMATION for Omvoh (mirikizumab-mrkz) CONTRAINDICATIONS Omvoh is contraindicated in patients with a history of serious hypersensitivity reaction to mirikizumab-mrkz or any of the excipients. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis during intravenous infusion, have been reported with Omvoh administration. Infusion-related hypersensitivity reactions, including mucocutaneous erythema and pruritus, were reported during induction. If a severe hypersensitivity reaction occurs, discontinue Omvoh immediately and initiate appropriate treatment. Infections Omvoh may increase the risk of infection. Do not initiate treatment with Omvoh in patients with a clinically important active infection until the infection resolves or is adequately treated. In patients with a chronic infection or a history of

recurrent infection, consider the risks and benefits prior to prescribing Omvoh. Instruct patients to seek medical advice if signs or symptoms of clinically important acute or chronic infection occur. If a serious infection develops or an infection is not responding to standard therapy, monitor the patient closely and do not administer Omvoh until the infection resolves. Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Omvoh. Do not administer Omvoh to patients with active TB infection. Initiate treatment of latent TB prior to administering Omvoh. Consider anti-TB therapy prior to initiation of Omvoh in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after Omvoh treatment. In clinical trials, subjects were excluded if they had evidence of active TB, a history of active TB, or were diagnosed with latent TB at screening. Hepatotoxicity Drug-induced liver injury in conjunction with pruritus was reported in a clinical trial subject following a longer than recommended induction regimen. Omvoh was discontinued. Liver test abnormalities eventually returned to baseline. Evaluate liver enzymes and bilirubin at baseline and for at least 24 weeks of treatment. Monitor thereafter according to routine patient

See additional Important Safety Information on next page.

management. Consider other treatment options in patients with evidence of liver cirrhosis. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of druginduced liver injury. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction. Immunizations Avoid use of live vaccines in patients treated with Omvoh. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Prior to initiating therapy, complete all age-appropriate vaccinations according to current immunization guidelines. No data are available on the response to live or non-live vaccines in patients treated with Omvoh. ADVERSE REACTIONS Most common adverse reactions associated with Omvoh (≥2% of subjects and at a higher frequency than placebo) in ulcerative colitis treatment are upper respiratory tract infections and arthralgia during the induction study (UC-1), and upper respiratory tract infections, injection site reactions, arthralgia, rash, headache, and herpes viral infection during the maintenance study (UC-2).

Most common adverse reactions associated with Omvoh in the Crohn’s disease study (CD-1) (≥5% of subjects and at a higher frequency than placebo) are upper respiratory tract infections, injection site reactions, headache, arthralgia, and elevated liver tests.

Omvoh injection is available as a 300 mg/15 mL solution in a single-dose vial for intravenous infusion, and as a 100 mg/mL solution or a 200 mg/2 mL solution in a single dose prefilled pen or prefilled syringe for subcutaneous injection. Refer to the Prescribing Information for dosing information.

MR HCP ISI CD APP See Brief Summary of Prescribing Information on subsequent pages. See Instructions for Use included with the device.

Omvoh® and its delivery device base are trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. PP-MR-US-0961 01/2025 © Lilly USA, LLC 2025. All rights reserved.

Omvoh® (mirikizumab-mrkz) injection, for intravenous or subcutaneous use Brief Summary: Consult the package insert for complete prescribing information. INDICATIONS AND USAGE Omvoh is an interleukin-23 antagonist indicated for the treatment of: • moderately to severely active ulcerative colitis in adults • moderately to severely active Crohn’s disease in adults.

ADVERSE REACTIONS The following topics are also discussed in detail in the Warnings and Precautions section: • Hypersensitivity Reactions • Infections • Tuberculosis • Hepatotoxicity

CONTRAINDICATIONS Omvoh is contraindicated in patients with a history of serious hypersensitivity reaction to mirikizumab-mrkz or any of the excipients [see Warnings and Precautions].

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis during intravenous infusion, have been reported with Omvoh administration. Infusion-related hypersensitivity reactions, including mucocutaneous erythema and pruritus, were reported during induction [see Adverse Reactions]. If a severe hypersensitivity reaction occurs, discontinue Omvoh immediately and initiate appropriate treatment.

Ulcerative Colitis Omvoh was studied up to 12 weeks in subjects with moderately to severely active ulcerative colitis in a randomized, double-blind, placebo-controlled induction study (UC-1). In subjects who responded to induction therapy in UC-1, long-term safety up to 52 weeks was evaluated in a randomized, double-blind, placebo-controlled maintenance study (UC-2) and a long-term extension study.

Infections Omvoh may increase the risk of infection [see Adverse Reactions].

In the induction study (UC-1), 1279 subjects were enrolled of whom 958 received Omvoh 300 mg administered as an intravenous infusion at Weeks 0, 4, and 8. In the maintenance study (UC-2), 581 subjects were enrolled of whom 389 received Omvoh 200 mg administered as a subcutaneous injection every 4 weeks.

Do not initiate treatment with Omvoh in patients with a clinically important active infection until the infection resolves or is adequately treated. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing Omvoh. Instruct patients to seek medical advice if signs or symptoms of clinically important acute or chronic infection occur. If a serious infection develops or an infection is not responding to standard therapy, monitor the patient closely and do not administer Omvoh until the infection resolves. Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Omvoh.

Table 1 summarizes the adverse reactions reported in at least 2% of subjects and at a higher frequency than placebo during UC-1. Table 1: Adverse Reactionsa in Subjects with Ulcerative Colitis through Week 12 in a Placebo-Controlled Induction Study (UC-1)

Adverse Reactions

Placebo

OMVOH 300 mg Intravenous Infusionb N=958 n (%)

N=321 n (%)

Do not administer Omvoh to patients with active TB infection. Initiate treatment of latent TB prior to administering Omvoh. Consider anti-TB therapy prior to initiation of Omvoh in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after Omvoh treatment.

Upper respiratory 72 (8%) 20 (6%) tract infectionsc Arthralgia 20 (2%) 4 (1%) a Reported in at least 2% of subjects and at a higher frequency than placebo. b Omvoh 300 mg as an intravenous infusion at Weeks 0, 4, and 8. c Upper respiratory tract infections includes related terms (e.g., COVID-19, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection).

In clinical trials, subjects were excluded if they had evidence of active TB, a past history of active TB, or were diagnosed with latent TB at screening.

In the induction study (UC-1), infusion-related hypersensitivity reactions were reported by 4 (0.4%) subjects treated with Omvoh and 1 (0.3%) subject treated with placebo.

Hepatotoxicity A case of drug-induced liver injury (alanine aminotransferase [ALT] 18x the upper limit of normal (ULN), aspartate aminotransferase [AST] 10x ULN, and total bilirubin 2.4x ULN) in conjunction with pruritus was reported in a clinical trial subject following a longer than recommended induction regimen. Omvoh was discontinued. Liver test abnormalities eventually returned to baseline.

Table 2 summarizes the adverse reactions reported in at least 2% of subjects and at a higher frequency than placebo during the 40-week controlled period of UC-2.

Evaluate liver enzymes and bilirubin at baseline and for at least 24 weeks of treatment. Monitor thereafter according to routine patient management.

Adverse Reactions

Consider other treatment options in patients with evidence of liver cirrhosis. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction.

Upper respiratory tract 53 (14%) 23 (12%) infectionsc d Injection site reactions 34 (9%) 8 (4%) Arthralgia 26 (7%) 8 (4%) 16 (4%) 2 (1%) Rashe Headache 16 (4%) 2 (1%) 9 (2%) 1 (1%) Herpes viral infectionf a Reported in at least 2% of subjects and at a higher frequency than placebo b Omvoh 200 mg as a subcutaneous injection at Week 12 and every 4 weeks thereafter for up to an additional 40 weeks.

Immunizations Avoid use of live vaccines in patients treated with Omvoh. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Prior to initiating therapy with Omvoh, complete all age-appropriate vaccinations according to current immunization guidelines. No data are available on the response to live or non-live vaccines in patients treated with Omvoh. ®

Omvoh (mirikizumab-mrkz) injection, for intravenous or subcutaneous use

MR HCP BS CD APP

Table 2: Adverse Reactionsa in Subjects with Ulcerative Colitis through Week 40 In a Placebo-Controlled Maintenance Study (UC-2) OMVOH 200 mg Subcutaneous Injectionb N=389 n (%)

Placebo N=192 n (%)

See Brief Summary of Prescribing Information on adjacent page. Omvoh® (mirikizumab-mrkz) injection, for intravenous or subcutaneous use

MR HCP BS CD APP

c

Upper respiratory tract infections includes related terms (e.g., COVID-19, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection). d Injection site reactions includes related terms (e.g., erythema, hypersensitivity, pain, reaction, and urticaria at the injection site). e Rash is composed of several similar terms. f Herpes viral infection includes related terms (e.g., herpes zoster, herpes simplex, and oral herpes.) Infections In UC-1 through Week 12, infections were reported by 145 (15%) subjects treated with Omvoh 300 mg and 45 (14%) subjects treated with placebo. Serious infections were reported by less than 1% in both groups. Serious infections in the Omvoh group included intestinal sepsis, listeria sepsis, and pneumonia. In the maintenance study (UC-2) through Week 40 (a total of 52 weeks of treatment), infections were reported by 93 (24%) subjects treated with Omvoh 200 mg and 44 (23%) subjects treated with placebo. A case of COVID-19 pneumonia was reported as a serious infection in the Omvoh group. Hepatic Enzyme Elevations In UC-1 through Week 12, alanine aminotransferase (ALT) ≥5X ULN was reported by 1 (0.1%) subject treated with Omvoh 300 mg and 1 (0.3%) subject treated with placebo. Aspartate aminotransferase (AST) ≥5X ULN was reported by 2 (0.2%) subjects treated with Omvoh 300 mg and no subject treated with placebo. These elevations have been noted with and without concomitant elevations in total bilirubin. In the maintenance study (UC-2) through Week 40 (a total of 52 weeks of treatment), 3 (0.8%) subjects treated with Omvoh 200 mg reported ALT ≥5X ULN and 3 (0.8%) subjects reported AST ≥5X ULN; with or without concomitant elevations in total bilirubin. No subjects treated with placebo experienced similar elevations [see Warnings and Precautions]. Crohn’s Disease Omvoh was studied up to 52 weeks in subjects with moderately to severely active Crohn’s disease in a randomized, double-blind, placebo-controlled study (CD-1). The safety population consisted of 630 subjects who received Omvoh 900 mg administered as an intravenous infusion during induction at Weeks 0, 4, and 8 followed by Omvoh 300 mg administered as a subcutaneous injection every 4 weeks and 211 subjects who received placebo. Eighty-five of the 211 placebo subjects in the safety population who did not achieve clinical response by patient- reported outcome at Week 12 were switched to blinded induction and maintenance treatment with Omvoh. Observed data from these 85 subjects are included in the placebo cohort up to Week 12 and in the Omvoh cohort after Week 12. In CD-1, Omvoh and placebo-treated subjects had different lengths of exposure, therefore, exposure adjusted incidence rates (EAIRs) are also displayed in Table 3 to compare adverse reactions. Common Adverse Reactions Table 3 summarizes the frequencies and EAIRs per 100 person-years (PY) for adverse reactions reported in at least 5% of subjects treated with OMVOH and at a higher frequency than placebo during CD-1. Table 3: Adverse Reactionsa in Subjects with Crohn’s Disease through Week 52 In a Placebo-Controlled Study (CD-1) Adverse Reactions

Upper respiratory tract infectionsd Injection site reactionse Headachef Arthalgia Elevated liver testsg

Omvohb N=715, PY=655 n (%) [EAIRC]

Placebo N=211, PY=120 n (%) [EAIRC]

199 (28) [37]

47 (22) [47]

69 (10) [11] 45 (6) [7] 44 (6) [7] 36 (5) [6]

8 (4) [7] 9 (4) [8] 11 (5) [10] 8 (4) [7]

Abbreviations: EAIR, exposure-adjusted incidence rate; PY, person-years a b

Reported in at least 5% of subjects and at a higher frequency than placebo. Following Omvoh 900 mg as an intravenous infusion at Week 0, Week 4, and Week 8, subjects received Omvoh 300 mg as a subcutaneous injection at Week 12 and every 4 weeks thereafter for up to an additional 40 weeks. In addition, eighty- five placebo subjects who did not achieve clinical response by ®

Omvoh (mirikizumab-mrkz) injection, for intravenous or subcutaneous use

MR HCP BS CD APP

patient-reported outcome at Week 12 were switched to blinded induction and maintenance treatment with Omvoh. The observed data after Week 12 from these eighty-five subjects were included in the Omvoh cohort. c EAIRs are per 100 PY. The EAIR per 100 PY can be interpreted as an estimated number of first occurrences of the adverse reaction of interest if 100 subjects were treated for one year. d Upper respiratory tract infections includes related terms (e.g., COVID-19, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection). e Injection site reactions includes related terms (e.g., erythema, hematoma, induration, pain, pruritus, and reaction at the injection site). f Headache includes related terms (i.e., headache and migraine). g Elevated liver tests include related terms (e.g., ALT increased, AST increased, alkaline phosphatase increased, bilirubin increased, and GGT increased). Hepatic Enzyme Elevations Of the subjects with reported adverse reactions of elevated liver tests (see Table 3), 3 subjects treated with Omvoh reported ALT ≥5X ULN and 2 subjects reported AST ≥5X ULN. Neither subject had a concomitant elevation in total bilirubin. No subjects treated with placebo experienced similar elevations. Less Common Adverse Reactions (<5%) In CD-1 through Week 52, urticaria was reported by 13 (2%, 2 per 100 PY) subjects treated with Omvoh and no subjects treated with placebo. Infections In CD-1 through Week 52, infections were reported by 282 (39%, 58 per 100 PY) subjects treated with Omvoh and 73 (35%, 81 per 100 PY) subjects treated with placebo. Serious infections in the Omvoh group included abscess (including abdominal abscess, anal abscess, gluteal abscess, and perineal abscess), cellulitis, pneumonia, and sepsis. DRUG INTERACTIONS CYP450 Substrates Increased concentrations of cytokines (e.g., IL-1, IL-6, IL-10, TNF9, IFN) during chronic inflammation associated with certain diseases including Crohn’s disease may suppress the formation of CYP450 enzymes. Therapeutic proteins, including mirikizumab-mrkz, that decrease the concentrations of these pro-inflammatory cytokines may increase the formation of CYP450 enzymes resulting in decreased CYP450 substrate exposure. Upon initiation or discontinuation of Omvoh in patients treated with concomitant CYP450 substrates, monitor drug concentrations or other therapeutic parameters, and adjust the dosage of the CYP450 substrate as needed. See the prescribing information of specific CY450 substrates. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Omvoh during pregnancy. Pregnant women exposed to Omvoh and healthcare providers are encouraged to call Eli Lilly and Company at 1-800-Lilly-Rx (1-800-545-5979). Risk Summary Available data from case reports of mirikizumab-mrkz use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Although there are no data on mirikizumab-mrkz, monoclonal antibodies can be actively transported across the placenta, and mirikizumab-mrkz may cause immunosuppression in the in utero-exposed infant. An enhanced pre- and post-natal development study conducted in pregnant monkeys at a dose 20 times the maximum recommended human dose (MRHD) revealed no adverse developmental effects to the developing fetus, or harm to infant monkeys from birth through 6 months of age. There are risks of adverse pregnancy outcomes associated with increased disease activity in women with inflammatory bowel disease (see Clinical Considerations). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. See Brief Summary of Prescribing Information on adjacent page. Omvoh® (mirikizumab-mrkz) injection, for intravenous or subcutaneous use

MR HCP BS CD APP

Clinical Considerations Disease-Associated Maternal and Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. It is unclear whether mirikizumab-mrkz may interfere with an infant's immune response to infections. Therefore, monitoring for the development of serious infection during the first 2 months of life in infants exposed in utero is recommended. Data Animal Data An enhanced pre- and postnatal development study was conducted in cynomolgus monkeys administered mirikizumab-mrkz by intravenous injection during organogenesis to parturition at a dose of 300 mg/kg twice weekly (20 times the MRHD based on exposure comparisons). Mirikizumab-mrkz crossed the placenta in monkeys. No maternal toxicity was noted in this study. No mirikizumab-mrkz-related effects on morphological, functional, or immunological development were observed in infant monkeys from birth through 6 months of age. However, incidences of embryo/ fetal loss were higher in the treated groups compared to control (6.7% [1 of 15] in controls vs 26.7% [4 of 15] at 300 mg/kg (20 times the MRHD, based on exposure comparisons) but were within the range of historical control data. Following delivery, most adult female cynomolgus monkeys and all infants from the mirikizumab-mrkztreated group had measurable serum concentrations up to 28 days postpartum. In the infant monkeys, mean serum concentrations were approximately 4.8 times the respective mean maternal concentrations. Lactation Risk Summary There are no data on the presence of mirikizumab-mrkz in human milk, the effects on the breastfed infant, or the effects on milk production. Endogenous maternal IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to mirikizumab-mrkz are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Omvoh and any potential adverse effects on the breastfed infant from Omvoh or from the underlying maternal condition. Pediatric Use The safety and effectiveness of Omvoh have not been established in pediatric patients. Geriatric Use Of the 795 Omvoh-treated subjects in the two ulcerative colitis clinical trials, 64 subjects (8%) were 65 years of age and older, while 10 subjects (1%) were 75 years of age and older. These clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger adult subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. No clinically meaningful differences in the pharmacokinetics of mirikizumab-mrkz were observed in subjects 65 years of age and older compared to younger adult subjects [see Clinical Pharmacology information in USPI]. Clinical studies of Omvoh for the treatment of Crohn’s disease did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger adult subjects. No clinically meaningful differences in the pharmacokinetics of mirikizumab-mrkz were observed in subjects 65 years of age and older compared to younger adult subjects [see Clinical Pharmacology information in USPI]. DOSING Recommended Dosage for Ulcerative Colitis Induction Dosage: Week 0, Week 4, and Week 8: Infuse 300 mg intravenously over at least 30 minutes. A full induction dose requires 1 Omvoh vial containing 300 mg/15 mL solution. Maintenance Dosage: Week 12 and every 4 weeks thereafter: Inject 200 mg subcutaneously (given as two consecutive injections of 100 mg each). ®

Omvoh (mirikizumab-mrkz) injection, for intravenous or subcutaneous use

MR HCP BS CD APP

Recommended Dosage for Crohn’s Disease Induction Dosage: Week 0, Week 4, and Week 8: Infuse 900 mg intravenously over at least 90 minutes. A full induction dose requires 3 Omvoh vials containing 300 mg/15 mL solution. Maintenance Dosage: Week 12 and every 4 weeks thereafter: Inject 300 mg subcutaneously (given as two consecutive injections of 100 mg and 200 mg in any order). PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Hypersensitivity Reactions Advise patients to discontinue Omvoh and seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions]. Infections Advise patients that Omvoh may lower the ability of their immune system to fight infections and to contact their healthcare provider immediately if they develop any symptoms of infection [see Warnings and Precautions]. Tuberculosis Advise patients to contact their healthcare provider if they experience symptoms suggestive of TB (e.g., unexplained fever, cough, or difficulty breathing) [see Warnings and Precautions]. Hepatotoxicity Inform patients that Omvoh may cause liver injury. Advise patients to seek immediate medical attention if they experience symptoms suggestive of liver dysfunction (e.g., unexplained rash, nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine) [see Warnings and Precautions]. Immunizations Advise patients that vaccination with live vaccines is not recommended during Omvoh treatment and immediately prior to or after Omvoh treatment. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Instruct patients to inform their healthcare provider that they are taking Omvoh prior to receiving a vaccination [see Warnings and Precautions]. Pregnancy Advise patients who are exposed to Omvoh during pregnancy to contact Eli Lilly and Company [see Use in Specific Populations]. Administration Instruct patients in preparation and administration of Omvoh, including choosing anatomical sites for subcutaneous administration, and proper subcutaneous injection technique. Instruct patients in the technique of pen or syringe disposal. Instruct ulcerative colitis patients or caregivers to administer two 100 mg prefilled pens or two 100 mg prefilled syringes to achieve the full 200 mg dose of Omvoh. Instruct Crohn’s disease patients or caregivers to administer a 100 mg prefilled pen or prefilled syringe and a 200 mg prefilled pen or prefilled syringe in any order to achieve the full 300 mg dose of Omvoh. Important Administration Instructions The 200 mg/2 mL prefilled pen and prefilled syringe are only for maintenance treatment of Crohn’s disease. MR HCP BS CD APP Additional information can be found at www.Omvoh.lilly.com. Call the Lilly Answers Center at 1-800-LillyRx (1-800-545-5979)

See Instructions for Use accompanying the product device. PP-MR-US-1074 Omvoh® (mirikizumab-mrkz) injection, for intravenous or subcutaneous use

MR HCP BS CD APP

EDITORIAL ADVISORY BOARD ANDREW ALBERT, MD, MPH Chicago, Illinois MANOOP S. BHUTANI, MD, FASGE Houston, Texas BROOKS D. CASH, MD, AGAF, FACG, FACP, FASGE Houston, Texas ALINE CHARABATY, MD, AGAF, FACG Washington, D.C. AUSTIN CHIANG, MD, MPH Philadelphia, Pennsylvania SARAH ENSLIN, PA-C Rochester, New York RONNIE FASS, MD, MACG Cleveland, Ohio HARISH K. GAGNEJA, MD, FACG, FASGE, AGAF Austin, Texas FRANK G. GRESS, MD, MACG, FASGE New York, New York SETH GROSS, MD, FASGE New York, New York VIVEK KAUL, MD, FACG, FASGE, AGAF Rochester, New York GARY R. LICHTENSTEIN, MD, FACG Philadelphia, Pennsylvania JENIFER R. LIGHTDALE, MD, MPH Worcester, Massachusetts DANA J. LUKIN, MD, PHD, FACG New York, New York PETER R. MCNALLY, DO Fort Carson, Colorado KLAUS MERGENER, MD, PHD, MBA, MASGE Tacoma, Washington

E D I T O R I A L S TA F F SARAH TILYOU Managing Editor smtilyou@mcmahonmed.com KATIE PRINCE Senior Editor kprince@mcmahonmed.com DAVID BRONSTEIN Vice President, Editorial DONALD M. PIZZI Editorial Director KRISTIN JANNACONE Copy Chief

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VAN VELLE President, Partner MATTHEW MCMAHON General Manager, Partner LAUREN SMITH MICHAEL P. MCMAHON MICHELE MCMAHON VELLE Partners RAY AND ROSANNE MCMAHON Co-founders

JOSEPH MALICHIO Vice President, Medical Education jmalichio@mcmahonmed.com

SATISH RAO, MD, PHD Augusta, Georgia JOEL E. RICHTER, MD, MACG Tampa, Florida DISCLAIMER—The reviews in this issue are designed to be a summary of information, and

DAVID ROBBINS, MD New York, New York

they represent the opinions of the authors. Although detailed, the reviews are not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete

ELLEN J. SCHERL, MD New York, New York

prescribing information available in the package insert of each drug, and the appropriate

PRATEEK SHARMA, MD, FACG, FACP, FASGE Kansas City, Kansas

of typographical errors is not guaranteed.

ASHWANI K. SINGAL, MD, MS, FACG, FAASLD, AGAF Louisville, Kentucky

clinical protocols. No liability will be assumed for the use of these reviews, and the absence

Copyright © 2025 McMahon Publishing Group, 545 West 45th Street, 8th Floor, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

GASTROENTEROLOGY & ENDOSCOPY NEWS SPECIAL EDITION • 2025-2026

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TABLE OF CONTENTS 10 A #MondayNightIBD Conversation: Approach to a Patient With IBD-Associated Peripheral Spondyloarthropathies Beatriz Carrillo Cubero, MD Aline Charabaty, MD, AGAF, FACG Beatriz Gros, MD

21 Decoding IBD: 5 Practice-Changing Lessons Caroline Helwick

24 Highlights From the 2025 Gut Microbiota for Health World Summit Elena Ivanina, DO, MPH

29 Diagnosis and Management of Barrett’s Esophagus: A Case-Based Approach Swathi Eluri, MD, MSCR

36 Deciphering Dysphagia in Clinical Practice: A CaseBased Review Alexander T. Reddy, MD Amit Patel, MD, AGAF, FACG

43 The Frontiers of Therapeutic Endoscopic Ultrasound in 2025: Advances in EUS Scope Design Andrew C. Storm, MD

53 A Gastroenterologist’s Guide to Bowel Preparation Jonathan Beard, MD Audrey H. Calderwood, MD, MS

61 New Guidance Issued on HLD And Sterilization Jenny Blair

64 Highlights of Updated EGD Quality Indicators Ajai Srinivas

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A #MondayNightIBD Conversation

Approach to a Patient With IBD-Associated Peripheral Spondyloarthropathies BEATRIZ CARRILLO CUBERO, MD Department of Gastroenterology Reina Sofía University Hospital Cordoba, Spain

ALINE CHARABATY, MD, AGAF, FACG Associate Professor of Medicine The Johns Hopkins University School of Medicine Medical Director Division of Gastroenterology and Hepatology Clinical Director, IBD Center Johns Hopkins Sibley Memorial Hospital Washington, DC @DCharabaty

BEATRIZ GROS, MD Department of Gastroenterology Reina Sofía University Hospital IMIBIC, University of Cordoba Cordoba, Spain

xtraintestinal manifestations (EIMs) are common in patients with inflammatory bowel disease (IBD). They usually appear during the course of IBD, but in 25% of cases, they precede or are concurrent with IBD diagnosis.1,2 The most common EIMs are IBD-associated spondyloarthropathies (SpAs), which occur in almost one-third of patients during their IBD course, and are classified as axial SpA or peripheral SpA, which includes arthritis, dactylitis or “sausage fingers,” and enthesitis or inflammation at the bony insertion sites of ligaments, tendons, and fascia.3,4

E

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Take-Home Points • Ask your patients with IBD about joint pain at diagnosis and periodically during the disease course. SpAs and arthralgias are the most common EIMs in IBD, and they negatively affect daily activities, as well as patients’ quality of life. • Involve a rheumatologist early in the diagnostic and therapeutic process. • The differential diagnosis of peripheral arthritis in IBD includes drug reactions, infectious or post-infection reactions, and concomitant rheumatologic disease. • When IBD and SpA coexist at diagnosis, choose a therapy that co-treats the luminal and joint disease. Although type 1 peripheral SpA usually responds to any MOA that controls the luminal inflammation, type 2 (and some type 1) peripheral and axial SpAs are best treated with a therapy that co-treats IBD and SpA, such as an anti−TNF agent or a JAK inhibitor. • When SpA manifests later in the course of IBD, tailor treatment strategies according to IBD activity, severity of SpA symptoms, and current use/efficacy of an advanced therapy. • Initial management of SpA includes anti-inflammatory agents, such as a COX-2 inhibitor or prednisone; physical therapy; and lifestyle changes. Sulfasalazine and methotrexate can be effective for peripheral SpA. Anti-TNF therapies and JAK inhibitors are effective for peripheral and axial SpA. • Decision-making should be personalized and shared. Consider disease course and patient factors such as occupation, pregnancy planning, other EIMs, and preferences in management strategy.

IBD-associated SpAs can parallel disease activity or be independent of luminal inflammation (Table 1) and often worsen the patient’s quality of life. SpAs require a multidisciplinary management approach that includes a rheumatologist, radiologist, physiotherapist, and, in many cases, a psychologist.3,4 Peripheral arthritis, the most frequent type of IBDrelated SpA, can be subclassified into type 1, which involves fewer than 5 joints (pauciarticular), typically the large joints of the lower extremities, and closely follows the course of IBD activity (SpA flares coincide with IBD flares and resolve when luminal disease is in remission). Type 2 involves more than 5 joints (polyarticular), often the smaller joints of the hands symmetrically, and follows a chronic course independent of IBD activity.5 Axial SpA is less common, with a prevalence of 10% to 20% in patients with IBD.3 It involves inflammation of the sacroiliac joints, or sacroiliitis, which often is asymptomatic

but can manifest as buttock pain, inflammatory back pain, and ankylosing spondylitis (AS). Inflammatory back pain is defined as back pain for longer than 3 months that is exacerbated by rest—often waking up the patient at night or present in the early morning—and is improved with physical activity. AS, which manifests as inflammatory back pain with radiographic evidence of sacroiliitis and spinal inflammation, can progress to spinal fusion (bamboo spine), leading to limitation of lumbar motion in both frontal and sagittal planes and limitation of chest expansion.6 In the United States, the genetic marker HLA-B27 is found in most White but only 50% of Black patients with AS.7 In this article, we summarize an @MondayNightIBD case conversation that focused on the management of a patient with IBD and peripheral SpA and explore factors to consider in treatment decisions based on the available data and expert opinions. We review the efficacy and safety data of therapies with varying mechanisms of action (MOAs) that can treat both luminal and joint disease.

Table 1. IBD-Associated SpA Manifestations And Management Type of SpA

Manifestation

Management

Type 1 peripheral arthritis

• Pauciarticular (<5 joints) • Asymmetric, often involving large lower joints • Nonerosive, no deformity, acute • Less severe course, self-limiting • Associated with IBD activity

• Management of IBD • Acetaminophen • NSAIDsa

Type 2 peripheral arthritis

• Polyarticular (>5 joints) • Symmetric, often involving small upper-extremity joints • Erosive, more aggressive, chronic • Not associated with IBD activity; HLA-B27–negative

• Acetaminophen • NSAIDsa • COX-2 inhibitor • Sulfasalazine • Methotrexate • Anti-TNF • JAK inhibitor

Enthesitis

• Pain and swelling at the tendon insertion site • Most commonly, Achilles tendinitis, plantar fasciitis

• NSAIDsa • Sulfasalazine • Intraarticular steroid

Dactylitis

• Pain and swelling of the entire digit (“sausage digit”)

• NSAIDsa • COX-2 inhibitor

Axial SpA

• Generally not associated with IBD activity

• NSAIDsa • COX-2 inhibitor • Anti-TNF • JAK inhibitor

Clinical Scenario A 35-year-old woman with ulcerative colitis (UC) who has been in remission on infliximab (IFX) for the last 3 years developed a moderate/severe flare and was found to have high levels of anti-IFX antibodies. Her therapy was changed to ustekinumab (Stelara, Johnson & Johnson), which led to UC remission. However, the patient now complains of pain in both hands and knees, mainly in the morning, that partially improves with activity. The pain is limiting her ability to grasp objects, hindering her work as a hairdresser. There is a 4-month wait until she can be seen by a rheumatologist. The @MondayNightIBD gastroenterologists and health professionals were polled on what they would do next.

COX-2, cyclooxygenase-2; HLA, human leukocyte antigen; IBD, inflammatory bowel disease; JAK, Janus kinase; NSAIDs, nonsteroidal anti-inflammatory drugs; SpA, spondyloarthropathy; TNF, tumor necrosis factor. a

NSAIDs are not the preferred first-line therapies in patients with IBD.

Case Discussion The discussion focused on the differential diagnosis of peripheral arthritis in a patient with IBD; treatment options for IBD-associated peripheral SpA; and personalizing treatment choice based on disease and patient details, including the burden of her joint pain on her daily activities and work; short-term pain relief and long-term treatment plan; and the safety of different MOAs in pregnancy in a woman of childbearing age.

Differential Diagnosis of Peripheral Arthritis With IBD There is no specific test to diagnose IBD-associated peripheral SpA, but a thorough history, physical exam that reveals joint swelling, tenderness to palpation, dysaesthesia, and redness, as well as judicious use of tests to rule out other causes of arthritis (inflammatory, infectious, or systemic conditions) can lead to the diagnosis. Common inflammatory conditions can be associated

with IBD and cause arthritis, such as rheumatoid arthritis (RA) and psoriatic arthritis.8,9 Crystal arthropathies, such as gout, also may arise due to metabolic changes associated with IBD. Systemic autoimmune diseases, including systemic lupus erythematosus and Sjogren’s syndrome, often affect the joints but have distinct clinical and serologic markers. Infectious causes, such as septic arthritis or reactive arthritis following an infectious enterocolitis, also should be considered. Delayed serum sickness−like reactions have been reported in patients who receive IFX and have developed anti-IFX antibodies; the activation of complement by antigen (IFX)-antibody immune complexes deposited in blood vessels, skin, and joint tissue leads to arthritis and pain in large joints and typically the jaw, and can cause urticaria, fever, lymphadenopathy, and rarely, glomerulonephritis. These types of reactions have not been reported with newer MOAs that have a low incidence of anti-drug antibodies.10 Drug-induced lupus has been reported primarily with anti−tumor necrosis factor (TNF) agents and can

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present with arthritis with a malar rash, and occasionally can lead to serious lupus complications.11 Finally, several clinicians reported that in their clinical practice they have occasionally observed new-onset arthralgias or arthritis in IBD patients after stopping anti-TNF therapy, suggesting that anti-TNFs mask IBD-associated SpA that can become symptomatic when IBD treatment is changed to a different MOA that doesn’t target joint disease.12

Treatment of IBD-Associated Peripheral SpA In the case presented, in which ustekinumab is controlling the luminal UC activity but not the peripheral arthritis, clinicians evaluated the options of adding a short course of an anti-inflammatory agent (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], selective cyclooxygenase-2 [COX2] inhibitor, prednisone); adding a conventional antirheumatic drug such as sulfasalazine or methotrexate; adding another advanced therapy; or switching the IBD therapy altogether from an anti-interleukin (IL) 12/23p40 to a drug with an MOA that can co-treat the luminal and the joint disease, such as an anti-TNF agent or a Janus kinase (JAK) inhibitor. Acute management. COX-2 inhibitors, such as celecoxib (Celebrex, Pfizer) at a dose of 100 mg twice daily, are effective for arthritis and have a lower risk for GI toxicities than nonselective NSAIDs.13,14 However, their safety in IBD patients is not well established, and long-term use

may still pose risks. NSAIDs are first-line therapies for different types of arthritis due to their low cost and high efficacy. Rheumatologists often use naproxen at doses of 375 to 500 mg twice daily. However, NSAID use in the IBD population is limited because of their potential risk of triggering an IBD flare by increasing mucosal permeability and exposure to luminal antigens and toxins. Although several retrospective studies suggested an association between NSAID use and IBD flares, a recent meta-analysis did not find a consistent association.15 In addition, the largest study on NSAIDs and IBD exacerbation could not confirm an association between IBD flare and NSAID exposure within 2 weeks to 6 months after exposure after adjusting for confounders.16 Alternatively, a short course of prednisone, starting at a low dose of 20 mg per day tapered over 2 weeks, can provide fast relief from arthritis and pain. Conventional antirheumatic drugs. Although mesalamine products are used more commonly because they are better tolerated, sulfasalazine (unlike mesalamine) is effective for treating peripheral SpAs as well as mild/ moderate UC. 12,14 Clinical studies have shown that sulfasalazine at a dose of 2 to 3 g daily can improve peripheral SpA symptoms in IBD patients, leading to a significant decrease in morning stiffness, erythrocyte sedimentation rate, and the daily NSAID dose.17 It is best to start sulfasalazine at a low dose (500 mg twice per day) to prevent GI side effects, increasing the dose progressively every

Table 2. Approved IBD Therapies and Their Indications and Efficacy in Rheumatologic Disorders Target

Current agents

Approved for IBD

Approved for musculoskeletal rheumatic disease

TNF

Adalimumab Certolizumab (Cimzia, UCB)

CD and UC RA, PsA, juvenile idiopathic arthritis CD

Golimumab (Simponi, Janssen)

UC

Approved for axial SpA/AS

Effective for IBD-associated peripheral SpAa

Yes

Yes

Infliximab

CD and UC

Integrin

Vedolizumab (Entyvio, Takeda)

CD and UC No

No

Type 1 associated with IBD activity

P40 subunit (IL-12/IL-23)

Ustekinumab (Stelara, Johnson & Johnson)

CD and UC PsA

No

Type 1 associated with IBD activity

P19 subunit (IL-23)

Guselkumab (Tremfya, Johnson & Johnson)

CD and UC PsA

No No No

Type 1 associated with IBD activity

UC

Yes

Yes

Mirikizumab (Omvoh, Lilly) Risankizumab (Skyrizi, AbbVie) Pan-JAK

Tofacitinib (Xeljanz, Pfizer)

RA, PsA, juvenile idiopathic arthritis

Preferential JAK1 Upadacitinib (Rinvoq, AbbVie)

CD and UC RA, PsA

Yes

Yes

S1P

UC

No

Type 1 associated with IBD activity

Etrasimod (Velsipity, Pfizer)

No

a

Most peripheral SpAs (type 1) resolve with effective therapy of the luminal disease, regardless of the MOA. However, some peripheral SpAs (type 2, and some type 1) and axial SpAs respond only to specific MOAs. CD, Crohn’s disease; IBD, inflammatory bowel disease; IL, interleukin; JAK, Janus kinase; MOA, mechanism of action; NSAIDs, nonsteroidal anti-inflammatory drugs; PsA, psoriatic arthritis; RA, rheumatoid arthritis; S1P, sphingosine 1-phosphate; TNF, tumor necrosis factor; UC, ulcerative colitis.

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2 weeks; supplementation also is recommended with 1 mg daily of folic acid, and checking blood cell counts after the first 4 to 8 weeks of initiation also is recommended to monitor for the rare side effect of agranulocytosis. Sulfasalazine is safe during pregnancy, but because it inhibits folic acid absorption, high-dose supplementation with 2 to 5 mg daily of folic acid is recommended from 3 months before conception through pregnancy in women taking sulfasalazine. Although methotrexate is not effective as monotherapy in treating UC,15,16 it often is used by rheumatologists in the management of peripheral SpAs. The typical dose is 15 mg weekly, which can be escalated by 5 mg per month to 25 to 30 mg weekly or the highest tolerable and lowest effective dose. In the case of nonresponse, a switch to subcutaneous methotrexate can lead to increased efficacy, Again, it is important to monitor blood cell counts and liver enzymes and supplement folic acid at a dose of 1 mg per day or 5 mg per week. However, it is important to discuss with women of childbearing age that methotrexate is an abortifacient that can lead to congenital malformations if used during conception and pregnancy. Women of childbearing age should use an effective contraceptive method while taking methotrexate, and the drug should be stopped at least 3 months prior to conception. Advanced therapies to target luminal and joint disease. Adding another advanced therapy to ustekinumab to treat the joint disease (dual advanced therapy) or switching to an MOA that treats both IBD and arthritis are each reasonable options (Table 2). The 2 drug classes with MOAs that have been shown to be effective for IBD as well as peripheral and axial SpAs are the antiTNF agents and JAK inhibitors. Adalimumab and infliximab are the most used anti-TNF agents in this setting; they are approved for axial SpAs, AS, RA, and psoriatic arthritis and have been shown to be effective for IBD-associated peripheral SpAs. Although ustekinumab (IL-12/23p40 inhibitor) is approved for psoriatic arthritis, its efficacy in the treatment of peripheral and axial SpAs is limited. Similarly, IL-23p19 inhibitors such as risankizumab (Skyrizi, AbbVie) and guselkumab (Tremfya, Johnson & Johnson) also are approved for psoriatic arthritis, but there are limited data on their efficacy for IBD-associated SpAs.18,19 In the JAK inhibitor family, tofacitinib (Xeljanz, Pfizer) and upadacitinib (Rinvoq, AbbVie) are approved for axial SpAs, RA, and psoriatic arthritis, and are clinically effective for IBD-associated peripheral SpAs.20-23 Lifestyle changes. Finally, regardless of the medical therapy plan, it is important to include lifestyle changes. Lowimpact exercises and/or physical therapy can improve joint function and reduce pain and stiffness. Smoking cessation can improve the outcome and response to therapy for EIM, and an IBD anti-inflammatory diet that limits ultra-processed foods and prioritizes fruit, vegetables, legumes, nuts, healthy fats, and lean protein can improve overall patient well-being.

Personalized Management Based On Disease and Patient Factors The rationale for a short course of an anti-inflammatory

Add sulfasalazine 41%

Add or switch to adalimumab or a JAK inhibitor 23%

Figure.

Add methotrexate 22%

Short course of COX-2/prednisone 14%

A 35-year-old woman with ulcerative colitis experienced a secondary loss of response to infliximab after 3 years of therapy due to high levels of anti-infliximab antibodies. She was started on ustekinumab and her UC is in remission. She now reports new hand and knee joint pain, mainly in the morning, which partially improves with activity but limits her ability to grasp objects, impacting her work as a hairdresser. She is on a 4-month waiting list to see a rheumatologist. What’s next?

agent is to provide fast and effective relief for joint pain in a patient whose ability to work is impeded by peripheral arthritis. Most @MondayNightIBD participants reported being comfortable using a short course of NSAIDs or a COX-2 inhibitor in a patient in endoscopic remission. This short-term management is a good option to consider while waiting for the patient to be seen by rheumatology, for the effective dose of sulfasalazine or methotrexate to be achieved, or for another advanced therapy to be approved. Several participants in our #MondayNightIBD discussion reported experiencing limited efficacy of sulfasalazine or methotrexate in controlling SpAs, so it is important to discuss adding or switching to an effective advanced therapy, either as an initial strategy or if a conservative approach is not tolerated or effective. An initial strategy of switching from ustekinumab to a different MOA that co-treats both the luminal and joint disease is more likely to be considered if the current advanced therapy is not controlling the luminal disease. In this patient, whose UC is in remission on ustekinumab, the rationale for maintaining ustekinumab and adding a second agent—whether sulfasalazine, methotrexate, or a second advanced therapy, such as an antiTNF drug or a JAK inhibitor—to treat the SpA stems from the legitimate concern that switching to a new advanced therapy altogether poses a risk of non-response to the new MOA and an IBD flare. Indeed, because most therapies have a therapeutic ceiling of 30% to 50% for disease remission, there is no guarantee that the luminal disease currently in remission on ustekinumab would respond to a different MOA. We also know from trials leading to approval of IBD drugs that patients who have been exposed to more than one advanced

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therapy, in particular to an anti-TNF therapy, often have lower response to a new agent than bio-naive patients would have. Therefore, it is reasonable to consider dual advanced therapy if conservative management is unsuccessful. The main concern with this strategy is the potential increased risk for serious events, mainly infectious complications. A systematic review and meta-analysis of studies reporting on dual advanced therapies (2 biologics or 1 biologic and 1 small-molecule therapy) for either refractory IBD or IBD with concurrent EIM showed that this strategy is effective and generally safe, with a pooled rate of 6% for serious adverse events.24 One strategy is to add a second advanced therapy to ustekinumab and once the peripheral SpA is in remission, stop ustekinumab and keep the patient on the monotherapy that co-treats the IBD and SpA, while closely monitoring for IBD relapse according to inflammatory markers such as fecal calprotectin and C-reactive protein, endoscopic assessment, and clinical symptoms. Finally, when selecting a therapy for women of childbearing age, it is important to consider whether the patient has plans for pregnancy or if she is able and willing to use an

effective contraceptive method, recognizing that methotrexate and JAK inhibitors are contraindicated during conception, pregnancy, and breastfeeding. Finally, the patient’s preferences for the agent’s method of delivery and safety and efficacy profile need to be discussed for effective shared decision-making.

Conclusion IBD-associated SpAs add a significant comorbidity to IBD and often have a negative impact on patients’ daily activities and overall quality of life. SpA deserves careful assessment and multidisciplinary management. Before choosing an IBD therapy, gastroenterologists should inquire about the presence of EIMs—particularly SpA—and choose an MOA that preferentially co-treats the luminal and joint disease when possible. If SpA becomes symptomatic, management and treatment choices should take into account whether the luminal disease is in remission on current therapy, whether the patient is already taking an advanced therapy, and whether short-term use of antiinflammatory agents is effective or a long-term drug therapy strategy is needed.

References 1.

Algaba A, Guerra I, Ricart E, et al. Extraintestinal manifestations in patients with inflammatory bowel disease: study based on the ENEIDA Registry. Dig Dis Sci. 2021;66(6):2014-2023. 2. Kilic Y, Kamal S, Jaffar F, et al. Prevalence of extraintestinal manifestations in inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2024;30(2):230-239. 3. Gordon H, Burisch J, Ellul P, et al. ECCO guidelines on extraintestinal manifestations in inflammatory bowel disease. J Crohns Colitis. 2024;18(1):1-37. 4. Vavricka SR, Schoepfer A, Scharl M, et al. Extraintestinal manifestations of inflammatory bowel disease. Inflamm Bowel Dis. 2015;21(8):1982-1992. 5. Rogler G, Singh A, Kavanaugh A, et al. Extraintestinal manifestations of inflammatory bowel disease: current concepts, treatment, and implications for disease management. Gastroenterology. 2021;161(4):1118-1132. 6. Salvarani C, Fries W. Clinical features and epidemiology of spondyloarthritides associated with inflammatory bowel disease. World J Gastroenterol. 2009;15(20):2449. 7. Khan MA, Braun WE, Kushner I, et al. HLA B27 in ankylosing spondylitis: differences in frequency and relative risk in American Blacks and Caucasians. J Rheumatol. 2023;50(1):39-43. 8. Freuer D, Linseisen J, Meisinger C. Association between inflammatory bowel disease and both psoriasis and psoriatic arthritis. JAMA Dermatol. 2022;158(11):1262. 9. Ono K, Kishimoto M, Deshpande GA, et al. Clinical characteristics of patients with spondyloarthritis and -inflammatory bowel disease versus -inflammatory bowel disease-related arthritis. Rheumatol Int. 2022;42(10):1751-1766. 10. Ghosh S, Feagan BG, Ott E, et al. Safety of ustekinumab in inflammatory bowel disease: pooled safety analysis through 5 years in Crohn’s disease and 4 years in ulcerative colitis. J Crohns Colitis. 2024;18(7):1091-1101. 11. Almoallim H. Anti-tumor necrosis factor-α induced systemic lupus erythematosus. Open Rheumatol J. 2012;6(1):315-319. 12. Diaz LI, Keihanian T, Schwartz I, et al. Vedolizumab-induced de novo extraintestinal manifestations. Gastroenterol Hepatol (NY). 2020;16(2):75-81. 13. Kvasnovsky CL, Aujla U, Bjarnason I. Nonsteroidal anti-inflammatory drugs and exacerbations of inflammatory bowel disease. Scand J Gastroenterol. 2015;50(3):255-263.

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14. Kefalakes H, Stylianides TJ, Amanakis G, et al. Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality? Eur J Clin Pharmacol. 2009;65(10):963-970. 15. Moninuola OO, Milligan W, Lochhead P, et al. Systematic review with meta- analysis: association between acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) and risk of Crohn’s disease and ulcerative colitis exacerbation. Aliment Pharmacol Ther. 2018;47(11):1428-1439. 16. Cohen-Mekelburg S, Van T, Wallace B, et al. The association between nonsteroidal anti-inflammatory drug use and inflammatory bowel disease exacerbations: a true association or residual bias? Am J Gastroenterol. 2022;117(11):1851-1857. 17.

Dougados M, Maetzel A, Mijiyawa M, et al. Evaluation of sulphasalazine in the treatment of spondyloarthropathies. Ann Rheum Dis. 1992;51(8):955-958.

18. Louis E, Schreiber S, Panaccione R, et al. Risankizumab for ulcerative colitis: two randomized clinical trials. JAMA. 2024;332(11):881-897. 19. Peyrin-Biroulet L, Chapman JC, Colombel JF, et al. Risankizumab versus ustekinumab for moderate-to-severe Crohn’s disease. N Engl J Med. 2024;391(3):213-223. 20. Cozzi G, Scagnellato L, Lorenzin M, et al. Spondyloarthritis with inflammatory bowel disease: the latest on -biologic and targeted therapies. Nat Rev Rheumatol. 2023;19(8):503-518. 21. Suzuki K, Akiyama M, Inokuchi H, et al. Successful -treatment of Crohn’s disease-related peripheral spondyloarthritis with upadacitinib: two case reports and case-based review. Rheumatol Int. 2024;44(12):3127-3133. 22. Vavricka SR, Gubler M, Gantenbein C, et al. Anti-TNF treatment for extraintestinal manifestations of inflammatory bowel disease in the Swiss IBD cohort study. Inflamm Bowel Dis. 2017;23(7):1174-1181. 23. Greuter T, Bertoldo F, Rechner R, et al. Extraintestinal manifestations of pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2017;65(2):200-206. 24. Ahmed W, Galati J, Kumar A, et al. Dual biologic or small molecule therapy for treatment of inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022;20(3):e361-e379.

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SAFETY CONSIDERATIONS1 SKYRIZI is contraindicated in patients with a history of serious hypersensitivity reaction to risankizumab-rzaa or any of its excipients. Serious hypersensitivity reactions, including anaphylaxis, have been reported with use of SKYRIZI. If a serious hypersensitivity reaction occurs, discontinue SKYRIZI and initiate appropriate therapy immediately. SKYRIZI may increase the risk of infection. Instruct patients to report signs or symptoms of clinically important infection during treatment. Should such an infection occur, discontinue SKYRIZI until infection resolves. Evaluate patients for tuberculosis infection prior to initiating treatment with SKYRIZI. Drug-induced liver injury was reported in a patient with Crohn’s disease during induction dosing of SKYRIZI. For the treatment of Crohn’s disease and ulcerative colitis, evaluate liver enzymes and bilirubin at baseline and during induction (12 weeks). Interrupt treatment with SKYRIZI if drug-induced liver injury is suspected, until this diagnosis is excluded. Avoid use of live vaccines in SKYRIZI patients. Please see additional Important Safety Information on the last page of this advertisement. Please see Brief Summary of full Prescribing Information on adjacent pages of this advertisement.

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SAFETY CONSIDERATIONS1 SKYRIZI is contraindicated in patients with a history of serious hypersensitivity reaction to risankizumab-rzaa or any of its excipients. Serious hypersensitivity reactions, including anaphylaxis, have been reported with use of SKYRIZI. If a serious hypersensitivity reaction occurs, discontinue SKYRIZI and initiate appropriate therapy immediately. SKYRIZI may increase the risk of infection. Instruct patients to report signs or symptoms of clinically important infection during treatment. Should such an infection occur, discontinue SKYRIZI until infection resolves. Evaluate patients for tuberculosis infection prior to initiating treatment with SKYRIZI. Drug-induced liver injury was reported in a patient with Crohn’s disease during induction dosing of SKYRIZI. For the treatment of Crohn’s disease and ulcerative colitis, evaluate liver enzymes and bilirubin at baseline and during induction (12 weeks). Interrupt treatment with SKYRIZI if drug-induced liver injury is suspected, until this diagnosis is excluded. Avoid use of live vaccines in SKYRIZI patients. Please see additional Important Safety Information on the last page of this advertisement. Please see Brief Summary of full Prescribing Information on adjacent pages of this advertisement.

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*Clinical remission in Crohn’s is defined as a CDAI score <150 points. † Endoscopic response in Crohn’s is defined as a decrease in SES-CD >50% from baseline, or a decrease of at least 2 points for subjects with a baseline score of 4 and isolated ileal disease, based on central reading. The sections evaluated on endoscopy are the rectum, sigmoid and left colon, transverse colon, right colon, and ileum (per SES-CD assessment). ‡ Clinical remission in UC is defined as stool frequency subscore ≤1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore of ≤1 without friability.1 § Endoscopic improvement in UC is defined as Mayo endoscopic subscore of 0 or 1 without friability.1 Endoscopic results are based on a full colonoscopy or flexible sigmoidoscopy, at the discretion of the investigator. ¶ Clinical response at Week 4 in UC per partial modified Mayo Score is a composite of Mayo stool frequency and rectal bleeding subscores and was defined as a decrease in total score ≥30% and ≥1 point from baseline and a decrease in rectal bleeding subscore ≥1 or rectal bleeding subscore of 0 or 1.1

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IMPORTANT SAFETY INFORMATION1 Hypersensitivity Reactions SKYRIZI® (risankizumab-rzaa) is contraindicated in patients with a history of serious hypersensitivity reaction to risankizumab-rzaa or any of the excipients. Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of SKYRIZI. If a serious hypersensitivity reaction occurs, discontinue SKYRIZI and initiate appropriate therapy immediately. Infection SKYRIZI may increase the risk of infection. Do not initiate treatment with SKYRIZI in patients with a clinically important active infection until it resolves or is adequately treated. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefi ts prior to prescribing SKYRIZI. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy, closely monitor and discontinue SKYRIZI until the infection resolves. Tuberculosis (TB) Prior to initiating treatment with SKYRIZI, evaluate for TB infection and consider treatment in patients with latent or active TB for whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after SKYRIZI treatment. Do not administer SKYRIZI to patients with active TB. Hepatotoxicity in Treatment of Inflammatory Bowel Disease Drug-induced liver injury was reported in a patient with Crohn’s disease who was hospitalized for a rash during induction dosing of SKYRIZI. For the treatment of Crohn’s disease and ulcerative colitis, evaluate liver enzymes and bilirubin at baseline and during induction (12 weeks); monitor thereafter according to routine patient management. Consider an alternate treatment for patients with evidence of liver cirrhosis. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct your patient to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction. Administration of Vaccines Avoid use of live vaccines in patients treated with SKYRIZI. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Prior to initiating SKYRIZI, complete all age-appropriate vaccinations according to current immunization guidelines. Adverse Reactions Most common (>3%) adverse reactions associated with SKYRIZI in Crohn’s disease are upper respiratory infections, headache, and arthralgia in induction, and arthralgia, abdominal pain, injection site reactions, anemia, pyrexia, back pain, arthropathy, and urinary tract infection in maintenance. Most common (≥3%) adverse reactions associated with SKYRIZI in ulcerative colitis are arthralgia in induction, and arthralgia, pyrexia, injection site reactions, and rash in maintenance. Lipid Elevations: Increases from baseline and increases relative to placebo were observed at Week 4 and remained stable to Week 12 in patients treated with SKYRIZI in Crohn’s disease. Lipid elevations observed in patients with ulcerative colitis were similar to those in Crohn’s disease. Dosage Forms and Strengths: SKYRIZI (risankizumab-rzaa) is available in a 600 mg/10 mL single-dose vial for intravenous infusion and a 180 mg/1.2 mL or 360 mg/2.4 mL single-dose prefilled cartridge with on-body injector. Please see Brief Summary of full Prescribing Information on adjacent pages of this advertisement. Coverage requirements and benefits designs vary by payer and may change over time. Please consult with payers directly for the most current reimbursement policies. Eligibility: Available to patients with commercial insurance coverage for SKYRIZI® (risankizumab-rzaa) who meet eligibility criteria. This co-pay assistance program is not available to patients receiving prescription reimbursement under any federal, state, or government-funded insurance programs (for example, Medicare [including Part D], Medicare Advantage, Medigap, Medicaid, TRICARE, Department of Defense, or Veterans Affairs programs) or where prohibited by law. Offer subject to change or termination without notice. Restrictions, including monthly maximums, may apply. This is not health insurance. For full Terms and Conditions, visit SKYRIZISavingsCard.com or call 1.866.SKYRIZI for additional information. To learn about AbbVie’s privacy practices and your privacy choices, visit https://abbv.ie/corpprivacy.

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CDAI=Crohn’s disease activity index; IBD=irritable bowel disease; IV=intravenous; SES-CD=simplified endoscopic activity score for Crohn’s disease. References: 1. SKYRIZI [package insert]. North Chicago, IL: AbbVie Inc. 2. Data on file, AbbVie Inc. ABVRRTI80032. 3. Data on file, AbbVie Inc. AbbVie Internal Analytics and Managed Markets Insight and Technology, LLC, a trademark of MMIT as of January 2025. © 2025 AbbVie. All rights reserved. SKYRIZI ® and its design are registered trademarks of AbbVie Biotechnology Ltd. US-SKZG-250113

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SKYRIZI (sky-RIZZ-ee) (risankizumab-rzaa) injection, for subcutaneous or intravenous use 90 mg/mL single-dose prefilled syringe 150 mg/mL single-dose pen and prefilled syringe 600 mg/10 mL single-dose vial for intravenous infusion 180 mg/1.2 mL single-dose prefilled cartridge with on-body injector 360 mg/2.4 mL single-dose prefilled cartridge with on-body injector INDICATIONS AND USAGE Plaque Psoriasis SKYRIZI® is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Psoriatic Arthritis SKYRIZI is indicated for the treatment of active psoriatic arthritis in adults. Crohn’s Disease SKYRIZI is indicated for the treatment of moderately to severely active Crohn’s disease in adults. Ulcerative Colitis SKYRIZI is indicated for the treatment of moderately to severely active ulcerative colitis in adults. CONTRAINDICATIONS SKYRIZI is contraindicated in patients with a history of serious hypersensitivity reaction to risankizumab-rzaa or any of the excipients [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported with use of SKYRIZI. If a serious hypersensitivity reaction occurs, discontinue SKYRIZI and initiate appropriate therapy immediately [see Adverse Reactions]. Infections SKYRIZI may increase the risk of infections [see Adverse Reactions]. Treatment with SKYRIZI should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing SKYRIZI. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy, monitor the patient closely and do not administer SKYRIZI until the infection resolves. Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SKYRIZI. Across the Phase 3 psoriasis clinical studies, of the 72 subjects with latent TB who were concurrently treated with SKYRIZI and appropriate TB prophylaxis during the studies, none developed active TB during the mean follow-up of 61 weeks on SKYRIZI. Two subjects taking isoniazid for treatment of latent TB discontinued treatment due to liver injury. Of the 31 subjects from the PsO-3 study with latent TB who did not receive prophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks on SKYRIZI. Consider anti-TB therapy prior to initiating SKYRIZI in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after SKYRIZI treatment. Do not administer SKYRIZI to patients with active TB. Hepatotoxicity in Treatment of Inflammatory Bowel Disease A serious adverse reaction of drug-induced liver injury in conjunction with a rash that required hospitalization was reported in a patient with Crohn’s disease (ALT 54x ULN, AST 30x ULN, and total bilirubin 2.2x ULN) following two 600 mg intravenous doses of SKYRIZI. The liver test abnormalities resolved following administration of steroids. SKYRIZI was subsequently discontinued. For the treatment of Crohn’s disease and ulcerative colitis, evaluate liver enzymes and bilirubin at baseline, and during induction at least up to 12 weeks of treatment. Monitor thereafter according to routine patient management. Consider other treatment options in patients with evidence of liver cirrhosis. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction. Administration of Vaccines Avoid use of live vaccines in patients treated with SKYRIZI. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Prior to initiating therapy with SKYRIZI, complete all age-appropriate vaccinations according to current immunization guidelines. No data are available on the response to live or inactive vaccines. ADVERSE REACTIONS The following adverse reactions are discussed in other sections of labeling: • Hypersensitivity Reactions [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Tuberculosis [see Warnings and Precautions] • Hepatotoxicity in Treatment of Inflammatory Bowel Disease [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse drug reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Plaque Psoriasis A total of 2234 subjects were treated with SKYRIZI in clinical development trials in plaque psoriasis. Of these, 1208 subjects with psoriasis were exposed to SKYRIZI for at least one year. Data from placebo- and active-controlled trials were pooled to evaluate the safety of SKYRIZI for up to 16 weeks. In total, 1306 subjects were evaluated in the SKYRIZI 150 mg group.

Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% and at a higher rate in the SKYRIZI group than the placebo group during the 16-week controlled period of pooled clinical trials. Table 1. Adverse Drug Reactions Occurring in ≥ 1% of Subjects with Plaque Psoriasis on SKYRIZI through Week 16 SKYRIZI Placebo Adverse Drug Reactions N = 1306 N = 300 n (%) n (%) Upper respiratory infectionsa 170 (13.0) 29 (9.7) 46 (3.5) 6 (2.0) Headacheb 33 (2.5) 3 (1.0) Fatiguec d 19 (1.5) 3 (1.0) Injection site reactions 15 (1.1) 1 (0.3) Tinea infectionse a Includes: respiratory tract infection (viral, bacterial or unspecified), sinusitis (including acute), rhinitis, nasopharyngitis, pharyngitis (including viral), tonsillitis b Includes: headache, tension headache, sinus headache, cervicogenic headache c Includes: fatigue, asthenia d Includes: injection site bruising, erythema, extravasation, hematoma, hemorrhage, infection, inflammation, irritation, pain, pruritus, reaction, swelling, warmth e Includes: tinea pedis, tinea cruris, body tinea, tinea versicolor, tinea manuum, tinea infection, onychomycosis Adverse drug reactions that occurred in < 1% but > 0.1% of subjects in the SKYRIZI group and at a higher rate than in the placebo group through Week 16 were folliculitis and urticaria. Specific Adverse Drug Reactions Infections In the first 16 weeks, infections occurred in 22.1% of the SKYRIZI group (90.8 events per 100 subject-years) compared with 14.7% of the placebo group (56.5 events per 100 subject-years) and did not lead to discontinuation of SKYRIZI. The rates of serious infections for the SKYRIZI group and the placebo group were ≤0.4%. Serious infections in the SKYRIZI group included cellulitis, osteomyelitis, sepsis, and herpes zoster. In Studies PsO-1 and PsO-2, through Week 52, the rate of infections (73.9 events per 100 subject-years) was similar to the rate observed during the first 16 weeks of treatment. Safety Through Week 52 Through Week 52, no new adverse reactions were identified, and the rates of the adverse reactions were similar to those observed during the first 16 weeks of treatment. During this period, serious infections that led to study discontinuation included pneumonia. Psoriatic Arthritis The overall safety profile observed in subjects with psoriatic arthritis treated with SKYRIZI is generally consistent with the safety profile in subjects with plaque psoriasis. Additionally, in the Phase 3 placebo-controlled trials the incidence of hepatic events was higher in the SKYRIZI group (5.4%, 16.7 events per 100 patient years) compared to the placebo group (3.9%, 12.6 events per 100 patient years). Of these, the most common events that were reported more frequently in both the placebo group and the SKYRIZI group were ALT increased (placebo: n=12 (1.7%); SKYRIZI: n=16 (2.3%)), AST increased (placebo: n=9 (1.3%); SKYRIZI: n=13 (1.8%)), and GGT increased (placebo: n=5 (0.7%); SKYRIZI: n=8 (1.1%)). There were no serious hepatic events reported. The incidence of hypersensitivity reactions was higher in the SKYRIZI group (n=16, 2.3%) compared to the placebo group (n=9, 1.3%). In the Phase 3 placebo-controlled trials, hypersensitivity reactions reported at a higher rate in the SKYRIZI group included rash (placebo: n=4 (0.6%); SKYRIZI: n=5 (0.7%), allergic rhinitis (placebo: n=1 (0.1%); SKYRIZI: n=2 (0.3%), and facial swelling (placebo: n=0 (0.0%); SKYRIZI n=1 (0.1%). One case of anaphylaxis was reported in a subject who received SKYRIZI in the Phase 2 clinical trial. Crohn’s Disease SKYRIZI was studied up to 12 weeks in subjects with moderately to severely active Crohn’s disease in two randomized, double-blind, placebo-controlled induction studies (CD-1, CD-2) and a randomized, double-blind, placebocontrolled, dose-finding study (CD-4; NCT02031276). Long-term safety up to 52 weeks was evaluated in subjects who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (CD-3). In the two induction studies (CD-1, CD-2) and the dose finding study (CD-4), 620 subjects received the SKYRIZI intravenous induction regimen at Weeks 0, 4 and 8. In the maintenance study (CD-3), 297 subjects who achieved clinical response, defined as a reduction in CDAI of at least 100 points from baseline after 12 weeks of induction treatment with intravenous SKYRIZI in studies CD-1 and CD-2, received a maintenance regimen of SKYRIZI either 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks. Adverse reactions reported in > 3% of subjects in induction studies and at a higher rate than placebo are shown in Table 2.

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

Table 2. Adverse Drug Reactions Reported in > 3% of Subjects with Crohn’s Disease Treated with SKYRIZI in Placebo-Controlled 12-Week Induction Studies (CD-1, CD-2, and CD-4) SKYRIZI Placebo 600 mg Intravenous N = 432 Infusiona n (%) N = 620 n (%) Upper respiratory infectionsb 66 (10.6) 40 (9.3) 41 (6.6) 24 (5.6) Headachec Arthralgia 31 (5.0) 19 (4.4) a SKYRIZI 600 mg as an intravenous infusion at Week 0, Week 4, and Week 8. b Includes: influenza like illness, nasopharyngitis, influenza, pharyngitis, upper respiratory tract infection, viral upper respiratory tract infection, COVID-19, nasal congestion, respiratory tract infection viral, viral pharyngitis, tonsillitis, upper respiratory tract inflammation c Includes: headache, tension headache Adverse Drug Reactions

Adverse reactions reported in >3% of subjects in the maintenance study and at a higher rate than placebo are shown in Table 3. Table 3. Adverse Reactions Reported in >3% of Subjects with Crohn’s Disease Treated with SKYRIZIa in Placebo-Controlled 52-Week Maintenance Study (CD-3) SKYRIZI SKYRIZI Placebo 180 mg 360 mg N = 143 Subcutaneous Subcutaneous n (%) Adverse Drug Reactions Injection Injection N = 155 N = 142 n (%) n (%) Arthralgia 13 (8.4) 13 (9.2) 12 (8.4) Abdominal painb 9 (5.8) 12 (8.5) 6 (4.2) 7 (4.5) 8 (5.6) 4 (2.8) Injection site reactionsc,d Anemia 7 (4.5) 7 (4.9) 6 (4.2) Pyrexia 4 (2.6) 7 (4.9) 4 (2.8) Back pain 3 (1.9) 6 (4.2) 3 (2.1) Arthropathy 1 (0.6) 5 (3.5) 2 (1.4) Urinary tract infection 1 (0.6) 5 (3.5) 4 (2.8) a SKYRIZI 180 mg or 360 mg at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks b Includes: abdominal pain, abdominal pain upper, abdominal pain lower c Includes: injection site rash, injection site erythema, injection site swelling, injection site urticaria, injection site warmth, injection site pain, injection site hypersensitivity, injection site reaction d Some subjects had multiple occurrences of injection site reactions. In this table, injection site reactions are counted only once per subject for the rate calculations. Specific Adverse Drug Reactions Infections In the maintenance study (CD-3) through Week 52, the rate of infections was 32.3% (50.2 events per 100 subject-years) in subjects who received SKYRIZI 180 mg and 36.6% (60.8 events per 100 subject-years) in subjects who received SKYRIZI 360 mg compared to 36.4% (60.3 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction. The rate of serious infections was 2.6% (2.7 events per 100 subject-years) in subjects who received SKYRIZI 180 mg and 5.6% (7.4 events per 100 subject-years) in subjects who received SKYRIZI 360 mg compared to 2.1% (2.4 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction. Lipid Elevations Elevations in lipid parameters (total cholesterol and low-density lipoprotein cholesterol [LDL-C]) were first assessed at 4 weeks following initiation of SKYRIZI in the induction trials (CD-1, CD-2). Increases from baseline and increases relative to placebo were observed at Week 4 and remained stable to Week 12. Following SKYRIZI induction, mean total cholesterol increased by 9.4 mg/dL from baseline to a mean absolute value of 175.1 mg/dL at Week 12. Similarly, mean LDL-C increased by 6.6 mg/dL from baseline to a mean absolute value of 92.6 mg/dL at Week 12. Mean LDL-C increased by 3.1 mg/dL from baseline to a mean absolute value of 99.0 mg/dL at Week 52 with SKYRIZI 180 mg maintenance treatment and by 2.3 mg/dL from baseline to a mean absolute value of 102.2 mg/dL at Week 52 with SKYRIZI 360 mg maintenance treatment (CD-3). Ulcerative Colitis SKYRIZI was studied up to 12 weeks in subjects with moderately to severely active ulcerative colitis in a randomized, double-blind, placebo-controlled induction study (UC-1) and a randomized, double-blind, placebo-controlled, dose-finding study (UC-3). Long-term safety up to 52 weeks was evaluated in subjects who responded to induction therapy in a randomized, doubleblind, placebo-controlled maintenance study (UC-2). In the induction studies (UC-1 and UC-3), 712 subjects received the SKYRIZI 1,200 mg intravenous induction regimen at Weeks 0, 4 and 8. In the maintenance study (UC-2), 347 subjects who achieved clinical response, defined as a decrease in mMS of ≥2 points and ≥30% from baseline and a decrease in RBS ≥1 from baseline or an absolute RBS ≤1, received a maintenance regimen of SKYRIZI either 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks. The adverse reaction reported in ≥3% subjects treated with SKYRIZI in the ulcerative colitis induction studies (UC-1 and UC-3) and at a higher rate than placebo was arthralgia (3% SKYRIZI vs 1% placebo).

Adverse reactions reported in ≥3% of subjects treated with SKYRIZI in the maintenance study (UC-2) and at a higher rate than placebo are shown in Table 4. Table 4. Adverse Reactions Reported in ≥3% of Subjects with Ulcerative Colitis Treated with SKYRIZIa in Placebo-Controlled 52-Week Maintenance Study (UC-2)

Adverse Drug Reactions

SKYRIZI SKYRIZI 180 mg 360 mg Subcutaneous Subcutaneous Injection Injection N = 170 N = 177 n (%) n (%)

Placebo N = 173 n (%)

Arthralgia

9 (5.3)

17 (9.6)

8 (4.6)

Pyrexia

8 (4.7)

7 (4.0)

6 (3.5)

Injection site reactionsb,c

5 (2.9)

5 (2.8)

2 (1.2)

Rashd

7 (4.1)

1 (0.6)

3 (1.7)

a SKYRIZI 180 mg or 360 mg at Week 12 and every 8 weeks thereafter for

up to an additional 52 weeks b Includes: application site pain, injection site erythema, injection site pain, injection site pruritus, injection site reaction c Some subjects had multiple occurrences of injection site reactions. In this table, injection site reactions are counted only once per subject for the rate calculations. d Includes: rash and rash macular Specific Adverse Drug Reactions The rates of infections, serious infections, and lipid elevations in subjects with UC who received SKYRIZI compared to subjects who received placebo in the induction studies (UC-1 and UC-3) and maintenance study (UC-2) were similar to the rates in subjects with CD who received SKYRIZI compared to subjects who received placebo in the induction studies (CD-1, CD-2, and CD-4) and maintenance study (CD-3). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products, including other risankizumab products, may be misleading. Plaque Psoriasis By Week 52, approximately 24% (263/1079) of subjects treated with SKYRIZI at the recommended dose developed antibodies to risankizumab-rzaa. Of the subjects who developed antibodies to risankizumab-rzaa, approximately 57% (14% of all subjects treated with SKYRIZI) had antibodies that were classified as neutralizing. Higher antibody titers in approximately 1% of subjects treated with SKYRIZI were associated with lower risankizumab-rzaa concentrations and reduced clinical response. Psoriatic Arthritis By Week 28, approximately 12.1% (79/652) of subjects treated with SKYRIZI at the recommended dose developed antibodies to risankizumab-rzaa. None of the subjects who developed antibodies to risankizumab-rzaa had antibodies that were classified as neutralizing. Antibodies to risankizumabrzaa were not associated with changes in clinical response for psoriatic arthritis. A higher proportion of subjects with anti-drug antibodies experienced hypersensitivity reactions (6.3% (5/79)) and injection site reactions (2.5% (2/79)) compared to subjects without anti-drug antibodies (3.8% (22/574) with hypersensitivity reactions and 0.7% (4/574) with injection site reactions). None of these hypersensitivity and injection site reactions led to discontinuation of risankizumab-rzaa. Crohn’s Disease By Week 64, antibodies to risankizumab-rzaa developed in approximately 3.4% (2/58) of subjects treated with SKYRIZI induction followed by 360 mg maintenance regimen. No subjects (0/57) treated with SKYRIZI induction followed by 180 mg maintenance regimen developed antibodies to risankizumab-rzaa. None of the subjects who developed antibodies to risankizumab-rzaa had antibodies that were classified as neutralizing. Ulcerative Colitis By Week 64, antibodies to risankizumab-rzaa developed in approximately 8.9% (8/90) or 4.4% (4/91) of subjects treated with SKYRIZI induction followed by the 180 mg or 360 mg maintenance regimen, respectively. Of the subjects who developed antibodies to risankizumab-rzaa, 75% (6.7% of all subjects treated with SKYRIZI induction followed by the 180 mg maintenance regimen) or 50% (2.2% of all subjects treated with SKYRIZI induction followed by the 360 mg maintenance regimen), respectively, had antibodies that were classified as neutralizing. Postmarketing Experience The following adverse reactions have been reported during post-approval of SKYRIZI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to SKYRIZI exposure: • Skin and subcutaneous tissue disorders: eczema and rash USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors outcomes in women who become pregnant while treated with SKYRIZI. Patients should be encouraged to enroll by calling 1-877-302-2161 or visiting http://glowpregnancyregistry.com. Risk Summary Available pharmacovigilance and clinical trial data with risankizumab use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Although there are no data on risankizumab-rzaa, monoclonal antibodies can be actively transported across the placenta, and SKYRIZI may cause immunosuppression in the in utero-exposed infant. There are adverse pregnancy outcomes in women with inflammatory bowel disease (see Clinical Considerations). In an enhanced pre- and post-natal developmental toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of 5 or 50 mg/kg risankizumab-rzaa once weekly during the period of

organogenesis up to parturition. Increased fetal/infant loss was noted in pregnant monkeys at the 50 mg/kg dose (see Data). The 50 mg/kg dose in pregnant monkeys resulted in approximately 5 times the exposure (AUC) in humans administered the maximum recommended induction dose (1,200 mg) and 32 times the exposure (AUC) to the maximum recommended maintenance dose (360 mg). No risankizumab-rzaa-related effects on functional or immunological development were observed in infant monkeys from birth through 6 months of age. The clinical significance of these findings for humans is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and embryo/fetal risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth. Fetal/Neonatal adverse reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Because risankizumab may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants exposed to SKYRIZI in utero. There are insufficient data regarding infant serum levels of risankizumab at birth and the duration of persistence of risankizumab in infant serum after birth. Although a specific timeframe to delay live virus immunizations in infants exposed in utero is unknown, a minimum of 5 months after birth should be considered because of the half-life of the product. Data Animal Data An enhanced pre- and post-natal developmental toxicity study was conducted in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered weekly subcutaneous doses of risankizumab-rzaa of 5 or 50 mg/kg from gestation day 20 to parturition, and the cynomolgus monkeys (mother and infants) were monitored for 6 months after delivery. No maternal toxicity was noted in this study. There were no treatment-related effects on growth and development, malformations, developmental immunotoxicology, or neurobehavioral development. However, a dose-dependent increase in fetal/infant loss was noted in the risankizumab-rzaa-treated groups (32% and 43% in the 5 mg/kg and 50 mg/kg groups, respectively) compared with the vehicle control group (19%). The increased fetal/infant loss in the 50 mg/kg group was considered to be related to risankizumab-rzaa treatment. The no-observed adverse effect level (NOAEL) for maternal toxicity was identified as 50 mg/kg, and the NOAEL for developmental toxicity was identified as 5 mg/kg. The 5 mg/kg dose in pregnant monkeys resulted in approximately 0.6 times the exposure (AUC) in humans administered the maximum recommended induction dose (1,200 mg) and 5 times the exposure (AUC) in humans administered the maximum recommended maintenance dose (360 mg). In the infants, mean serum concentrations increased in a dose-dependent manner and were approximately 17%-86% of the respective maternal concentrations. Following delivery, most adult female cynomolgus monkeys and all infants from the risankizumab-rzaa-treated groups had measurable serum concentrations of risankizumab-rzaa up to 91 days postpartum. Serum concentrations were below detectable levels at 180 days postpartum. Lactation Risk Summary There are no data on the presence of risankizumab-rzaa in human milk, the effects on the breastfed infant, or the effects on milk production. Endogenous maternal IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to risankizumab-rzaa are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SKYRIZI and any potential adverse effects on the breastfed infant from SKYRIZI or from the underlying maternal condition. Pediatric Use The safety and effectiveness of SKYRIZI have not been established in pediatric patients. Geriatric Use Of the 6,862 subjects exposed to SKYRIZI, a total of 664 were 65 years or older (243 subjects with plaque psoriasis, 246 subjects with psoriatic arthritis, 72 subjects with Crohn’s disease and 103 subjects with ulcerative colitis), and 71 subjects were 75 years or older. Clinical studies of SKYRIZI, within each indication, did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects. No clinically meaningful differences in the pharmacokinetics of risankizumab-rzaa were observed based on age. PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Hypersensitivity Reactions Advise patients to discontinue SKYRIZI and seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions]. Infections Inform patients that SKYRIZI may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any symptoms of an infection [see Warnings and Precautions]. Hepatotoxicity in Treatment of Inflammatory Bowel Disease Inform patients that SKYRIZI may cause liver injury, especially during the initial 12 weeks of treatment. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of liver dysfunction. (e.g., unexplained rash, nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine) [see Warnings and Precautions].

Administration of Vaccines Advise patients that vaccination with live vaccines is not recommended during SKYRIZI treatment and immediately prior to or after SKYRIZI treatment. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Instruct patients to inform the healthcare practitioner that they are taking SKYRIZI prior to a potential vaccination [see Warnings and Precautions]. Administration Instruction Instruct patients or caregivers to perform the first self-injected dose under the supervision and guidance of a qualified healthcare professional for training in preparation and administration of SKYRIZI, including choosing anatomical sites for administration, and proper subcutaneous injection technique. If using SKYRIZI 90 mg/mL, instruct patients or caregivers to administer two 90 mg single-dose syringes to achieve the full 180 mg maintenance dose or four 90 mg single-dose syringes to achieve the full 360 mg maintenance dose of SKYRIZI for Crohn’s disease. Instruct patients or caregivers in the technique of pen or syringe disposal. Pregnancy Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to SKYRIZI during pregnancy [see Use in Specific Populations]. Manufactured by: AbbVie Inc. North Chicago, IL 60064, USA US License Number 1889 SKYRIZI® is a registered trademark of AbbVie Biotechnology Ltd. © 2019-2025 AbbVie Inc. Ref: 20092907

Revised: May, 2025

LAB-12882 MASTER

Decoding IBD: 5 Practice-Changing Lessons SAN DIEGO—Managing inflammatory bowel disease involves precise diagnosis, vigilant monitoring and strategic treatment selection. Uma Mahadevan, MD, the Lynne and Marc Benioff Professor of Gastroenterology at the University of California, San Francisco, and director of UCSF’s Center for Colitis and Crohn’s Disease, offered five key lessons for enhancing patient care in a presentation at DDW 2025.

1

Optimize Disease Staging at Index Colonoscopy

“This initial assessment is highly predictive of future disease course, making thorough and accurate reporting paramount, especially as many initial scopes are performed in community settings,” Dr. Mahadevan said. She emphasized that every report should include explicit details on the extent of disease, severity (using validated scoring systems such as the Mayo endoscopic score for ulcerative colitis or the Simple Endoscopic Score

for Crohn’s Disease), presence of masses or strictures, and precise locations of all findings (Am J Gastroenterol 2019;114[3]:384-413). According to Dr. Mahadevan, vague reports simply stating “colitis” are inadequate. Structured reporting tools facilitate the establishment of an accurate baseline—critical for longterm management decisions, including choice of therapy and frequency of monitoring. Clear, comprehensive reports also enhance the continuity of care between community settings and specialized IBD centers, said Dr. Mahadevan, noting that this improves overall patient outcomes.

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Table. Endoscopy Intervals for Therapeutic Monitoring and Surveillance To monitor for response to therapy and for endoscopic and histologic remission: UC: flexible sigmoidoscopy at 14-16 weeks CD: colonoscopy at 6 months and postoperative assessment at 6-12 months For dysplasia surveillance: Primary sclerosing cholangitis or history of dysplasia: annual cancer surveillance All other colitis: surveillance every 1-3 years after 8 years of colonic involvement Ileal pouch: every 3-5 years, or annually post-dysplasia colectomy (crucial, frequently overlooked)

2

Implement Rigorous Disease Monitoring

Effective monitoring is essential to ensure therapies are working and detect complications early. Referencing the STRIDE-II (Selecting Therapeutic Targets in Inflammatory Bowel Disease) guidelines, Dr. Mahadevan outlined a phased approach to evaluating treatment response. Within one to three months after initiating treatment, clinicians should assess symptomatic response and normalized C-reactive protein. At three to six months, goals include reduced fecal calprotectin levels and normal growth in pediatric patients. By six months, targets encompass endoscopic healing, normalized quality of life, absence of disability and, for CD, transmural healing via imaging. Although histologic healing in UC is desirable, the guidelines do not cite this goal because there is insufficient evidence supporting it (Gastroenterology 2021;160[5]:1570-1583). Dr. Mahadevan also cautioned against allowing patients to suffer with progressive disease, noting that once CD progresses to stricturing, it often is irreversible. “We’ll see a patient will be started on therapy, and whether it works or not, they don’t come back for many months and the disease will progress,” she said. If treatment adjustments are needed, clinicians should use objective markers to avoid confusion with noninflammatory conditions such as irritable bowel syndrome and small intestinal bacteria overgrowth. The optimal timing of endoscopy extends to diagnosis, treatment monitoring and surveillance for cancer. According to Dr. Mahadevan, endoscopy is recommended at various intervals for monitoring of therapeutic response and remission and for dysplasia surveillance (Table).

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3

Be Strategic When Selecting Therapies

Dr. Mahadevan said she selects therapy based on patient history and disease features. For UC patients naive to biologics who have no extraintestinal manifestations (EIMs), she said she prefers vedolizumab (Entyvio, Takeda), interleukin (IL)-23 inhibitors or sphingosine-1-phosphate (S1P) modulators. If EIMs are present, she noted that IL-23 inhibitors or anti–tumor necrosis factor medications effectively target the skin, eyes and joints and can be good choices; S1P modulators are suitable for concurrent multiple sclerosis. Biologics-exposed UC patients may have reduced response to vedolizumab or S1P modulators after infliximab failure, she said, so IL-23 inhibitors or Janus kinase (JAK) inhibitors such as upadacitinib, especially in patients with low albumin, are better choices. Crohn’s disease allows therapeutic flexibility, with antiTNFs and JAK inhibitors suitable for EIMs and fistulizing disease. Switching therapeutic classes after initial treatment failure often proves beneficial. Mesalamine is ineffective and not FDA approved for ileal CD, providing minimal benefit even in mild colonic disease. Adalimumab shows low efficacy in UC and is not recommended, Dr. Mahadevan said, given that there are superior alternatives (Gastroenterology 2024;167[7]:1307-1343).

4

Master Postsurgical Endoscopic Anatomy

Postsurgical anatomy comprehension is vital for accurate endoscopic evaluation. In CD patients with side-to-side ileocolic anastomosis, accurately locating and inspecting the

neoterminal ileum is challenging but necessary. For ileoanal J-pouch patients, standardized documentation involves four key views: “owl eyes” (cross-sectional pouch), retroflex (pouch base), neoterminal ileum/afferent limb and ileoanal anastomosis. Routine biopsies (two distal, two proximal pouch) should follow best practices. “Vigilant assessment of the ileoanal anastomosis, a common cancer site, is crucial,” Dr. Mahadevan said, emphasizing the importance of “meticulous endoscopic technique and thorough documentation.”

5

Know When to Engage the Surgeon

Finally, Dr. Mahadevan underscored the value of surgery as a therapeutic option rather than a sign of medical failure. Early surgical consultation is mandatory in two primary scenarios:

• Fibrotic strictures with pre-stenotic dilation. These strictures rarely respond to medical therapy alone, and delaying surgery by cycling through multiple biologics worsens outcomes. Early surgical consultation can significantly improve quality of life and prevent serious complications such as obstruction and perforation. Furthermore, she said, surgery initially may be superior for isolated ileal CD, which is notoriously challenging to manage medically. The LIR!C randomized controlled trial and a large Danish retrospective study demonstrated better outcomes and reduced long-term medication dependence with early surgical resection compared with infliximab therapy (Lancet Gastroenterol Hepatol 2020;5[10]:900-907; Gastroenterology 2023;165[4]:976-985.e3). According to Dr. Mahadevan, these studies underscore the importance of discussing surgical options early and clearly with patients facing difficult-to-treat disease. “Clear communication between gastroenterologists and surgeons optimizes patient preparedness and decision-making.”

• Acute severe UC hospitalizations. Approximately 50% of these cases require colectomy during or shortly after admission. Immediate surgical involvement ensures patient readiness and informed decisions. Despite medical advances, approximately 10% of UC patients still require colectomy within a year of diagnosis.

—Caroline Helwick Dr. Mahadevan reported financial relationships with AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly. Enveda, Gilead, Janssen, The Leona M. and Harry B. Helmsley Trust, Merck/Prometheus, Pfizer, Protagonist, Rani, Roivant, Takeda and Trex.

WOULD YOU LIKE TO CONTRIBUTE AN ARTICLE OR COMMENTARY TO THE PUBLICATION?

All topics considered. Please email the editor at SMTilyou@mcmahonmed.com

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Highlights From the 2025 Gut Microbiota for Health World Summit ELENA IVANINA, DO, MPH E C Center for Integrative Gut Health New York, New York N

WASHINGTON—The 2025 Gut Microbiota for Health World Summit featured cutting-edge research on microbiome science and medicine, underscoring the importance of the microbiome in gastrointestinal health and beyond. Conference speakers from prestigious research centers all over the world came to share their advances in microbiome science, addressing topics such as food, neurodegenerative disease, and cancer.

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Food and the Microbiome The conference began with lectures by nutritionists focusing on food and the microbiome. Janelle Smith, MS, RDN, CEDS, the senior dietitian with the UCLA Health Digestive Diseases Nutrition Program, in Los Angeles, discussed the role of the microbiome in eating disorders. Specifically, she explained the role polyunsaturated fatty acids may play in anorexia nervosa, as well as microbiome manipulation in the treatment of eating disorders. Other topics addressed included research tools to assess diet and its effects on the microbiome, how to improve communication with patients during dietary counseling, such as being careful when labeling diets for “weight loss,” and microbiome-directed food for children with malnutrition. Benoit Chassaing, PhD, a microbiologist at Institut Pasteur, in Paris, discussed the topic of dietary emulsifiers and inflammatory bowel disease, highlighting that although most emulsifiers have deleterious effects, some are more harmful than others. For example, carboxymethyl cellulose (CMC) and carrageenan are potentially harmful for health, but soy lecithin is less worrisome. He described the host– microbiome interactions at the mucosal surface, explaining that under normal circumstances, the inner mucous layer is sterile. However, in the presence of dietary emulsifiers, microbial encroachment can lead to intestinal inflammation. In murine studies, even 12 weeks of emulsifiers such as CMC or polysorbate 80 (P80) caused altered microbial composition and microbial encroachment with increased flagellin, which facilitated colonization of the mucous layer and increased the pro-inflammatory composition of the microbiome. When Dr. Chassaing transplanted fecal microbiota from the CMC or P80 mouse to a germ-free mouse, gut inflammation developed in the germ-free mouse. The microbial encroachment from emulsifier exposure may be associated with increased intestinal permeability and increased antibodies against bacterial antigens, leading to increased stimulation and exposure of the mucosal lining to the immune system.

The Microbiome and Neurodegenerative Diseases Andrea Merchak, PhD, of the University of Florida, in Gainesville, discussed the connection between the microbiome and neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Exposures throughout life affect brain health, she said, from direct effects such as gut permeability and inflammation to indirect consequences including microbial products and bacterial diversity. She reviewed how aspects of diet affect the central nervous system: Prebiotic dietary fiber, polyphenols, and fermented food can lead to commensal growth, and short-chain fatty acid production and dietary tryptophan influence the vagus nerve and neuroactive molecules. In addition, multiple sclerosis has been linked to decreased serum levels of bile acids, and studies show bile acid supplementation may lead to benefits such as a decrease in circulating immune cells. Gut inflammation also has been linked to increased

brain inflammation and neurodegeneration. Lipopolysaccharides, produced by gram-negative bacteria, have been found to induce systemic inflammation. One fascinating study showed how colonocytes in patients with IBD and Parkinson’s disease communicate with antibody-producing peripheral immune cells in a similarly disordered fashion, unlike that in healthy patients. The summit made it clear there are a lot of promising studies exploring microbiome manipulation in neurodegenerative diseases, including fecal microbiota transplant leading to full functional recovery in multiple sclerosis and maintenance of cognitive function in Alzheimer’s disease (Neurol Neuroimmunol Neuroinflamm 2018;5[4]:e459; J Int Med Res 2020;48[6]:300060520925930).

The Microbiome and Cancer A fascinating area of medicine where microbiome manipulation is establishing a beneficial role in modulating treatment is in oncology. Jonathan Peled, MD, PhD, an oncologist at Memorial Sloan Kettering Cancer Center, in New York City, presented research that highlighted the benefit of microbiome manipulation in bone marrow transplant patients. Dr. Peled found that Enterococcus domination of the gut flora increased the risk for acute graftversus-host disease and reduced survival. He and his coinvestigators also found that sugar (sucrose) interacting with antibiotics is associated with Enterococcus expansion. Dr. Peled said they are investigating a probiotic (SER155) to preserve microbiome integrity in patients undergoing hematopoietic cell transplantation because gut dysbiosis in the setting of an impaired gut barrier has been found to be

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the source of bloodstream infections. When given a specifically formulated probiotic, patients had a significantly lower incidence of bloodstream infections than those given placebo (Transplant Cell Ther 2025;31[2]:s86). In fact, the probiotic conferred colonization resistance against Enterococcus, and the participants in the probiotic arm took less antibiotics and had a shorter hospital length of stay. Of note, there were no bloodstream infections from SER-155, despite increased gut permeability. The probiotic also is being researched in the setting of immunotherapy-related enterocolitis. Other cancers in which the microbiome plays a pivotal role include melanoma and colorectal cancer. The gut microbiome modulates the response to anti–programmed death ligand-1 immunotherapy in melanoma patients. Insufficient fiber intake at the initiation of treatment was associated with worse outcomes compared with sufficient fiber intake. Of interest, no probiotics were found to be helpful. In addition, oral antibiotic use has been linked to CRC, specifically in the proximal colon. Specific bacteria associated with CRC include polyketide synthases (pks+) Escherichia coli, enterotoxigenic Bacteroides fragilis, some strains of Clostridioides difficile and many others. Biofilms also can be disruptive and carcinogenic in the colon and have been associated with sporadic CRC, specifically on the right side of the colon.

Bacteria-Eating Viruses and Fungi Some presentations at the conference addressed bacteriophages and their potential therapeutic use, highlighting mechanisms that suppress or prevent bacterial pathogens such as C. difficile colitis, assist with antimicrobial resistance or even suppress bacteria that

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play a role in conditions such as adherent invasive E. coli in Crohn’s disease, high alcohol-producing Klebsiella pneumoniae in metabolic dysfunction–associated steatotic liver disease and auto-brewery syndrome. For example, in murine studies, Robert Schooley, MD, and co-researchers at the University of California San Diego found that phages of cytolytic Enterococcus faecalis reverse ethanol-induced liver disease (Microbiol Spectr 2025 Apr 15. doi:10.1128/spectrum.03303-24). In a presentation of the mycobiome and fungal dysbiosis, Kyla Ost, PhD, an assistant professor at the University of Colorado Anschutz School of Medicine, in Aurora, emphasized how commensal fungi influence host immunity. Yeast species such as Candida, Malassezia and Saccharomyces dominate the mycobiome. In healthy patients, fungi have been shown to stimulate T- and B-cell responses to protect from fungal and bacterial infection. A single species such as Candida albicans can be both beneficial—inducing Th17 cell responses, production of antibodies and increasing circulating granulocytes—and pathogenic (exacerbating cancer). Studies showed that early-life colonization with C. dubliniensis promoted metabolic health. In addition, immunoglobulin A has been shown to regulate the microbiome and mycobiome, and IgA deficiency has been associated with intestinal C. albicans overgrowth. The summit did not disappoint, with fascinating new studies on how the microbiome plays a pivotal role in the pathogenesis and treatment of many medical conditions. Using food as medicine and incorporating prebiotics, probiotics, synbiotics, and postbiotics into treatment plans is clearly the way medicine is moving! ■

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It’s time to think BEyond dysplasia Meet the first precision risk stratification test enabling better management of Barrett’s esophagus.

TissueCypher goes beyond the watch-and-wait approach to non-dysplastic BE. This extensively validated, precision medicine test analyzes 9 protein biomarkers in the context of 7 tissue structures to objectively predict a patient’s 5-year risk of progression to esophageal cancer. Non-dysplastic patients scoring high-risk on TissueCypher progress at a rate similar to expert-confirmed low-grade dysplasia.

TissueCypher predicts progression of Barrett’s esophagus to high-grade dysplasia or esophageal adenocarcinoma Provides individualized risk stratification independent of histological classification (or morphology) and other clinical risk factors Transforms patient management by enabling upstaging or downstaging based on individual patient risk

Explore TissueCypher castlebiosciences.com/beyond © 2025 Castle Biosciences Inc. TC-015v2-092025

Diagnosis and Management Of Barrett’s Esophagus: A Case-Based Approach SWATHI ELURI, MD, MSCR Senior Associate Consultant Director of Esophageal Subspecialty Group Division of Gastroenterology and Hepatology Mayo Clinic Jacksonville, Florida

B

arrett’s esophagus is a premalignant condition characterized

by replacement of normal stratified squamous epithelium of the esophagus with specialized columnar-lined epithelium with goblet cells.1,2 BE is the only known precursor to esophageal adenocarcinoma and is thought to progress through a sequence of intestinal metaplasia to dysplasia to carcinoma. The prevalence of BE is estimated to be around 1% to 2% of the Western population.3

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Current guidelines recommend upper endoscopy to screen for BE and EAC. Although there is some variability in BE screening guidelines, a common recommendation is to screen patients with chronic gastroesophageal reflux disease (GERD) and additional risk factors for BE, such as male sex, age older than 50 years, White race, central obesity, history of tobacco smoking, and a family history of BE or EAC in a first-degree relative. 4,5 However, more recent guidelines recommend treating GERD as one of the risk factors and not a requirement for screening.6,7 Because the risk for progression to EAC varies significantly across histologic grades, patients with BE should undergo periodic surveillance every 3 to 5 years with a high-quality endoscopic exam and Seattle protocol biopsies using both high-definition white light endoscopy (HD-WLE) and chromoendoscopy. This approach has some limitations, such as low adherence to Seattle protocol

biopsies and interobserver variability between pathologists in grading dysplasia. As a result, there is an emerging role for risk stratification tools to identify patients with BE who have a high risk for progression. Ongoing management of BE primarily consists of endoscopic surveillance, with biopsies for patients who have a low risk of progressing to EAC and endoscopic eradication therapy (EET) for those at high risk for progression. EET consists of resection of any visible lesions, followed by ablation (radiofrequency ablation [RFA] or cryoablation) every 2 to 3 months until complete eradication of dysplasia and intestinal metaplasia. This article presents a series of representative cases that illustrate the spectrum of management strategies for BE, highlighting best practices in diagnosis and management.

Case 1 A 59-year-old White man with a 20-year history of GERD presented to the clinic for evaluation. He described a 15-year history of heartburn and reflux symptoms that typically are worse after meals and when he is lying down. He takes over-the-counter antacids as needed to manage his symptoms. His body mass index (BMI) is 31 kg/m2; he has a 15 pack-year smoking history; and his family history includes a maternal uncle with esophageal cancer. The patient denied dysphagia, melena, and iron deficiency anemia.

A

Upper endoscopy showed a 5-cm circumferential segment of salmon-colored mucosa above the gastroesophageal junction (GEJ), with tongues of salmon-colored mucosa extending proximally to 8 cm (Prague classification: C5M8) (Figure 1). No visible lesions were noted within the BE segment. Biopsies obtained using the Seattle protocol demonstrated specialized intestinal metaplasia without evidence of dysplasia, and a follow-up endoscopy in 3 years was recommended.

B

Figure 1. Upper endoscopy showing a 5-cm circumferential segment of salmon-colored mucosa above the gastroesophageal junction, with tongues of salmon-colored mucosa extending proximally to 8 cm. (A) High-definition white light endoscopy. (B) Narrow band imaging.

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Case 1 Discussion This case illustrates a patient with long-segment nondysplastic Barrett’s esophagus (NDBE) who underwent an upper endoscopy for screening due to multiple risk factors. His risk of progressing from NDBE to EAC is low, with an annual progression rate of 0.33% per year.8 However, because the risk is non-negligible in patients with long-segment (≥3 cm) NDBE, endoscopic surveillance is recommended every 3 years4; a 5-year surveillance interval can be considered in patients with short-segment (<3 cm) NDBE.4 In addition, guidelines recommend that patients with BE receive maintenance therapy with a proton pump inhibitor at least once a day, regardless of GERD symptoms, for acid suppression and chemoprevention. 4 Pooled observational data have shown that PPI therapy was associated with a 71% reduction in the risk for high-grade

dysplasia (HGD) or EAC (adjusted odds ratio [OR], 0.29; 95% CI, 0.12-0.79).9 Use of histamine receptor antagonists do not confer the same benefit as PPI therapy in patients with BE. While the role for potassium-competitive acid blockers in the BE population needs further evaluation, these agents can be considered as an alternative for patients who are refractory to or intolerant of PPI therapy.10 As in this case, patients must be informed about the nature of BE, the risks associated with progression to dysplasia or EAC based on the histologic grade of disease, and the available treatment options—including risks, benefits, and indication for PPI therapy—at the initial diagnosis. In addition, patients who are overweight should be counseled on weight loss, and smokers should be counseled on the importance of smoking cessation.

Case 2 A 65-year-old woman with previously diagnosed shortsegment BE (Prague classification: C0M2) presented for surveillance endoscopy. She reported a 10-year history of reflux symptoms and said she currently takes 40 mg of esomeprazole daily. She said her GERD symptoms are well controlled and that she very rarely has heartburn or reflux. Upper endoscopy showed a 2-cm segment of salmon-colored mucosa, with no evidence of esophagitis or visible lesions (Figure 2). Biopsies obtained per protocol were consistent with BE indefinite for dysplasia (IND), and a second GI pathologist agreed with the interpretation.

Case 2 Discussion BE IND is found in about 8.4% of BE patients.11 Studies have shown variable progression rates to HGD/EAC in patients with IND.11 Some risk factors for progression are longer-segment BE, multifocal areas of IND, and persistent IND on multiple exams. However, many patients show no dysplasia on follow-up exams, especially after being treated with high-dose PPI therapy. Sometimes this lack of finding is due to regression of dysplasia. Alternatively, the lack of an IND finding on a subsequent exam could be a result of interobserver variation among pathologists in distinguishing dysplasia from reactive changes. On the initial diagnosis of IND, it is important to confirm the diagnosis by expert pathology review. Patients should be placed on high-dose, twice-a-day PPI therapy, with repeat high-quality exam by an expert endoscopist within 6 months to rule out any prevalent HGD/ EAC.4 Those with IND should undergo a surveillance exam every year until there is a change in dysplasia grade.10 If histology regresses to NDBE on a surveillance exam, then follow-up surveillance for NDBE every 3 to 5 years, depending on BE segment length, is appropriate. A meticulous and standardized approach to endoscopic evaluation of BE is essential for accurate diagnosis and surveillance.12 Identification of key esophageal landmarks,

such as the diaphragmatic hiatus, GEJ, and squamocolumnar junction, is critical for orientation and future exams. The use of a distal attachment cap, especially in patients with known dysplasia, improves visualization, while thorough mucosal cleaning with a water jet and careful suctioning removes debris and reduces trauma. Controlled insufflation and desufflation can help reveal subtle mucosal abnormalities. Adequate inspection time of the BE segment (1 minute per centimeter of BE) and visualization of the gastric cardia in retroflexion are crucial for detecting dysplasia. HD-WLE and chromoendoscopy enhance visualization of mucosal and vascular patterns. The Prague classification should be

Figure 2. Upper endoscopy showing a 2-cm segment of salmon-colored mucosa, with no evidence of esophagitis or visible lesions.

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used to describe the BE segment and the Paris classification to describe any visible lesions. In addition, biopsies should be obtained per Seattle protocol from any targeted

areas, as well as every 2 cm in patients without dysplasia and every 1 cm in those with a history of dysplasia, with a partially deflated esophagus.12

Case 3 A 73-year-old man with a 6-year history of BE presented for routine surveillance. He reported a history of chronic GERD, for which he has been taking 40 mg of pantoprazole twice a day, with good symptom control. His comorbidities include cirrhosis complicated by ascites, coronary artery disease with prior stent placement, stage III chronic kidney disease, and peripheral vascular disease. The patient has a BMI of 41 and lives independently with some mobility limitations. He denied dysphagia, weight loss, hematemesis, and melena. An EGD showed a 6-cm segment of BE (Prague classification: C4M6). Biopsies taken per Seattle protocol demonstrated low-grade dysplasia (LGD), with diagnosis confirmed by an expert GI pathologist. The diagnosis of LGD was discussed with the patient, including next steps in treatment of LGD with EET, as well as the risks and benefits of this approach. The patient expressed concern about undergoing therapeutic endoscopies for EET, the potential for adverse events given his comorbidities, and logistical challenges with travel and post-procedure care. Due to these concerns, he chose to undergo surveillance, with the understanding that he would reconsider treatment options if his condition progressed.

Case 3 Discussion Guidelines from the American Gastroenterological Association suggest that EET should be used rather than surveillance in patients with confirmed BE with LGD.10

However, surveillance is a reasonable management strategy in patients for whom concern about risks associated with the procedure outweigh the potential benefits. When discussing management with EET versus surveillance for LGD, shared decision-making is critical. Annual rates of progression in patients with LGD have been reported to be 5.7%.13 Although pooled data from 3 randomized controlled trials did not show a statistically significant decrease in progression to EAC in LGD patients who underwent EET versus surveillance,14-16 observational studies have suggested a statistically significant decrease in EAC with EET.17,18 Cost-effectiveness analyses also support EET for confirmed LGD.19 However, 28% to 66% of LGD will regress to NDBE on subsequent exams with optimal acid suppression.20,21 This could be due to sampling error or interobserver variability in the histologic interpretation of LGD, but either is an argument for surveillance over EET. Patients with LGD who choose surveillance should maintain high-dose acid-suppressive therapy and undergo highquality exams by an expert endoscopist at 6-month intervals for 1 year and annually thereafter. For LGD patients who choose EET, the primary goal is complete eradication of intestinal metaplasia (CEIM), as for HGD. If complete eradication of dysplasia is achieved after a few EET sessions or there is recurrence of NDBE after CEIM, the residual nondysplastic disease can be reasonably managed with surveillance rather than ongoing EET.

Case 4 A 56-year-old man with a known long-segment BE, previously under surveillance at a different center, presented with a 3-month history of intermittent solid-food dysphagia. He reported a long-standing history of GERD and said he was on daily omeprazole but admitted to poor medication adherence. The patient had not undergone endoscopic surveillance for 5 years due to relocation. Because the patient’s symptoms were poorly controlled, PPI dosing was increased to twice daily. Surveillance EGD revealed a 5-cm BE segment (Prague classification: C3M5) with a 15-mm area of nodularity at 39 cm from the incisors (Figure 3A). Endoscopic mucosal resection (EMR) was performed (Figure 3B). Histopathology showed a focus of stage T1a EAC in a background of HGD. The deep margin of the resection specimen was free of dysplasia and carcinoma. A CT scan of the chest/abdomen/pelvis showed

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no evidence of distant disease or lymphadenopathy. The patient underwent sequential sessions of ablative therapy with RFA until CEIM (Figure 3C).

Case 4 Discussion For patients with HGD, EET is recommended because rates of progression to HGD/EAC have been reported to be as high as 19%.16 EET with RFA or cryoablation also is recommended in patients with stage T1a EAC.4,10 RFA has a larger body of efficacy and safety data and remains the first-line ablative modality for EET.15,16 Cryoablation is considered for salvage therapy for patients who are refractory to RFA or those with EAC due to the greater depth of treatment penetration achieved with this ablative technique.22 The 2 available cryoablation devices are liquid nitrogen spray cryotherapy using the truFreeze system

A

B

C

D

Figure 3. (A) Surveillance EGD revealed a 5-cm BE segment with a 15-mm area of nodularity 39 cm from the incisors. (B) EMR was performed. (C) Imaging following sequential sessions of ablative therapy with RFA. (D) Liquid nitrogen spray cryotherapy (truFreeze system) to treat the BE. BE, Barrett’s esophagus; EGD, esophagogastroduodenoscopy; EMR, endoscopic mucosal resection; RFA, radiofrequency ablation.

(Steris) and the C2 CryoBalloon (Pentax) (Figure 3D). EMR or endoscopic submucosal dissection (ESD) can be used for endoscopic resection of visible lesions in EET. Although the majority of visible lesions in BE can be managed with EMR, ESD has utility in treating large, bulky neoplastic lesions or those with features suspicious for deeper invasion. EET typically is performed in sessions that occur every 2 to 3 months until CEIM. It is important that patients are placed on high-dose acidsuppressive therapy before initiation of EET because most cases refractory to EET are due to inadequate acid suppression.10 After CEIM, patients should enter a post-CEIM

surveillance pathway, with periodic endoscopies with biopsies to monitor for disease recurrence at intervals dictated by the baseline severity of dysplasia. In patients with baseline HGD or intramucosal carcinoma, surveillance is recommended at 3, 6, and 12 months after CEIM and annually thereafter.4 For patients with LGD, endoscopic surveillance is recommended at 1 year after CEIM and every 2 years thereafter. In post-CEIM surveillance exams, biopsies should be obtained from the GEJ and distal esophagus (2-5 cm proximal to the GEJ) and placed in separate jars. Intestinal metaplasia of the cardia is not considered to be clinically significant and does not require treatment.

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Rubenstein JH, Sawas T, Wani S, et al. AGA clinical pratice guideline on endoscopic eradication therapy of Barrett’s esophagus and related neoplasia. Gastroenterology. 2024;166(6):1020-1055.

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Krishnamoorthi R, Mohan BP, Jayaraj M, et al. Risk of progression in Barrett’s esophagus indefinite for dysplasia: a systematic review and meta-analysis. Gastrointest Endosc. 2020;91(1):3-10.e3.

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Kolb JM, Wani S. Endoscopic eradication therapy for Barrett’s oesophagus: state of the art. Curr Opin Gastroenterol. 2020;36(4):351-358.

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20. Sharma P, Falk GW, Weston AP, et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett’s esophagus. Clin Gastroenterol Hepatol. 2006;4(5):566-572. 21.

Thota PN, Lee HJ, Goldblum JR, et al. Risk stratification of patients with Barrett’s esophagus and low-grade dysplasia or indefinite for dysplasia. Clin Gastroenterol Hepatol. 2015;13(3):459-465.e1.

22. Sengupta N, Ketwaroo GA, Bak DM, et al. Salvage cryotherapy after failed radiofrequency ablation for Barrett’s esophagusrelated dysplasia is safe and effective. Gastrointest Endosc. 2015;82(3):443-448.

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Deciphering Dysphagia In Clinical Practice: A Case-Based Review ALEXANDER T. REDDY, MD

AMIT PATEL, MD, AGAF, FACG

Assistant Professor of Medicine Division of Gastroenterology Duke University School of Medicine Durham, North Carolina

Professor of Medicine Division of Gastroenterology Duke University School of Medicine & Durham Veterans Affairs Medical Center Durham, North Carolina

D

ysphagia, the sensation of difficulty swallowing, may be experienced by up to 1 in 6 adults in the United States, according to population-based survey data,1,2 and is frequently encountered in gastroenterology clinical practice. Esophageal dysphagia may stem from various disease states, so discerning among potential etiologies is critical to facilitate effective, patient-tailored management. The initial evaluation of dysphagia should include a careful clinical history and physical exam, followed by consideration of diagnostic investigations, as appropriate.

Clinicians typically should pursue upper endoscopy with consideration of esophageal biopsies as a first step for esophageal-phase dysphagia.3 Additional physiologic testing such as high-resolution manometry (HRM) with provocative maneuvers,4,5 functional lumen imaging probe (FLIP) panometry,6,7 and/or a barium esophagram (typically as a timed upright barium esophagram)8 may be used for further assessment based on the clinical context and endoscopic findings. Here, we present 3 hypothetical cases that illustrate practical approaches to clinical presentations of esophageal dysphagia, highlighting the use of modern diagnostic and therapeutic options.

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Case 1 A 30-year-old man with a history of asthma was referred for 2 years of intermittent dysphagia to solids. His symptoms occurred several times weekly, particularly with meats, and were localized retrosternally. He had not used any pharmacotherapy to manage his symptoms. His physical exam was unremarkable, and upper endoscopy revealed esophageal edema (decreased vascularity), mild rings, exudates, and longitudinal furrows (Figure 1A; Eosinophilic Esophagitis [EoE] Endoscopic Reference Score [EREFS]: E1R1Ex1F2S0 [edema = 1, rings = 1, exudates = 1, furrows = 2, and strictures = 0]).9,10 Biopsies from the upper and lower esophagus revealed peak eosinophil counts of 50 and 40 eosinophils per high-power field, respectively.

Figure 1A. Upper endoscopy image of esophagus

Figure 1B. Upper endoscopy image of esophagus

with esophageal edema, mild rings, exudates, and longitudinal furrows (EREFS: E1R1Ex1F2S0).

after treatment with dupilumab with normalization of esophageal mucosa.

E1R1Ex1F2S0, edema = 1, rings = 1, exudates = 1, furrows = 2, and strictures = 0; EREFS, Eosinophilic Esophagitis Endoscopic Reference Score.

Diagnosis: EoE EoE is a chronic allergen-induced, immune-mediated disease of the esophagus resulting in symptoms of esophageal dysfunction, particularly dysphagia in adults.11 The clinicopathologic diagnosis requires compatible esophageal symptoms along with an eosinophil-predominant infiltrate on histologic assessment of endoscopic biopsies, with peak eosinophil counts of at least 15 eosinophils per highpower field.11 Clinicians should exclude alternate etiologies for esophageal eosinophilia (eg, gastroesophageal reflux disease [GERD], medication adverse effects, infection, achalasia, and hypereosinophilic syndrome) before making a diagnosis of EoE. Scoring tools such as the EREFS at endoscopic evaluation, as above,9,10 and the Index of Severity for EoE12 facilitate the standardization and systematic reporting of disease severity. Although the recognition and diagnosis of EoE have increased rapidly in recent decades,13 endoscopic findings of EoE may be subtle and/or overlooked, potentially contributing to diagnostic delay.14 Therefore, at least 2 to 4 esophageal biopsies from at least 2 levels of the esophagus should be pursued in all patients with symptoms suspicious for EoE, including at the time of food impaction.10,11,15

Management After a discussion of potential dietary and pharmacologic management options for EoE, the patient opted for 40 mg of omeprazole twice daily. Repeat endoscopy 2 months later demonstrated no improvement either endoscopically (based on EREFS) or histologically (based on peak eosinophil counts on esophageal biopsies). The patient then opted to switch to swallowed fluticasone (220 mcg at 4 puffs twice daily; total daily dose,

1,760 mcg). Evaluation after 2 months of adherence with fluticasone again demonstrated no significant improvement in his symptoms, EREFS, or peak eosinophil counts on esophageal biopsies. Based on his lack of response to proton pump inhibitor (PPI) and topical corticosteroid therapy, along with shared decision-making regarding his strong preference to avoid dietary elimination approaches, the patient started 300 mg of dupilumab (Dupixent, Regeneron/Sanofi) weekly. When evaluated 3 months after starting dupilumab, the patient reported resolution of dysphagia. His previous endoscopic findings of EoE had normalized, and no eosinophils were present on upper and lower esophageal biopsies (Figure 1B). Given dupilumab’s effectiveness, the patient opted to continue on it as maintenance therapy. For the management of EoE, clinicians should focus on both inflammatory and potential fibrostenotic aspects to improve patient symptoms and minimize complications such as food impaction, stricture formation, and esophageal perforation.11 Anti-inflammatory treatment options include strategic dietary elimination,16 PPIs, topical steroids (ie, budesonide or fluticasone formulations), and dupilumab.17 Dupilumab, approved for EoE by the FDA in May 2022, is a monoclonal antibody that blocks the effects of interleukin (IL)-4 and IL-13 involved in the type 2 inflammatory cascade.11 Given limited head-to-head clinical trial data among the anti-inflammatory options, individual disease characteristics and patient preferences via shared decision-making should guide treatment selection.18 Strategies for optimizing management include counseling on the risks and benefits of treatment options, consultation with gastroenterology-trained nutritionists when pursuing food elimination diets, and structured, timely assessment of response after initiating therapy. A willingness to pursue alternative therapies if indicated, as

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demonstrated in this case, is crucial. Beyond its use in patients with EoE who are nonresponsive to or intolerant of other therapies, dupilumab can be considered earlier in the management algorithm when a patient has concomitant atopic conditions that also could be treated with dupilumab.19 Endoscopic dilation as an adjunct to antiinflammatory approaches can be safely used to treat fibrostenotic features of EoE, including strictures and luminal narrowing. Finally, maintaining effective dietary or pharmacologic therapy can help prevent histologic inflammation and symptom recurrence.11

Case 2 A 55-year-old woman with a history of hypertension was referred for 2 years of progressively worsening dysphagia to solids and liquids, with regurgitation, which now is happening on a daily basis. One year prior, she was evaluated by an outside provider with an unrevealing upper endoscopy and esophageal biopsies. The patient had been taking omeprazole for several months without symptom benefit. Esophageal HRM was discussed and pursued, which revealed 100% failed peristalsis with panesophageal pressurization on single wet swallows and an elevated median integrated relaxation pressure (IRP) of 30 mm Hg in the primary supine position (Figure 2A).

Diagnosis: Type II Achalasia Achalasia is an esophageal motility disorder characterized by abnormal esophageal peristalsis and incomplete relaxation of the lower esophageal sphincter, classically defined by an abnormally elevated median IRP on esophageal HRM. 4,20 Thresholds for abnormal IRP vary based on patient position and HRM equipment manufacturer. Threshold values are 15 mm Hg in the supine position and 12 mm Hg in the upright position for Medtronic HRM systems, and 22 mm Hg in the supine position and 15 mm Hg in the upright position for the Diversatek and Laborie HRM systems.4,21 Achalasia is classified into 3 types based on peristaltic patterns at HRM, which can help guide prognosis and therapeutic interventions: Type I achalasia consists of 100% failed peristalsis without evidence of panesophageal pressurization, type II achalasia demonstrates 100% failed peristalsis with panesophageal pressurization in 20% or more of swallows, and type III achalasia is characterized by premature contraction in 20% or more of swallows without evidence of peristalsis. 4,20 Patients who are initially suspected of having GERD but who do not respond to acidsuppressive therapy should be evaluated for achalasia.20,22

Management Due to worsening symptoms, the patient underwent upper endoscopy with FLIP, which revealed an American Foregut Society hiatus grade 1 with no mechanical obstruction. FLIP assessment revealed an esophagogastric junction-distensibility index (EGJ-DI) of 0.6 mm 2/mm Hg at a

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Figure 2A. Esophageal HRM tracing image of failed supine wet swallow with panesophageal pressurization and inadequate LES relaxation. HRM, high-resolution manometry; LES, lower esophageal sphincter.

Figure 2B. Endoscopic FLIP panometry image with reduced EGJ opening (EGJ-DI <2.0 mm²/mm Hg and maximum EGJ diameter of <12 mm) and absent contractile response. EGJ, esophagogastric junction; EGJ-DI, esophagogastric junction-distensibility index; FLIP, functional lumen imaging probe.

60-mL fill volume and a maximum EGJ diameter of 8 mm at a 70-mL fill volume, consistent with a reduced EGJ opening (REO), and no esophageal body contractile response (Figure 2B). After discussion of treatment options based on her symptoms and diagnostic findings, the patient opted for per-oral endoscopic myotomy (POEM). At follow-up, she reported resolution of dysphagia and regurgitation symptoms off omeprazole. Surveillance endoscopy with FLIP and wireless pH monitoring 6 months after POEM revealed no reflux esophagitis, an EGJ-DI of 3 mm2/mm Hg with an EGJ diameter of 18 mm, and physiologic esophageal acid exposure times (AETs) less than 4% on all 4 days of the pH study. In a workup of suspected achalasia, a high-quality endoscopic exam should exclude the presence of pseudoachalasia or other causes of mechanical obstruction. Particularly in the setting of diagnostic uncertainty (eg, manometric EGJ outflow obstruction, borderline IRP, abnormal provocative maneuvers at HRM), evaluation with FLIP and/or a timed upright barium esophagram can be helpful in evaluation, as well as to increase confidence in an actionable diagnosis.8,20 FLIP is increasingly recognized as a useful tool for esophageal motility evaluation and should be considered if alternate investigations for dysphagia are inconclusive; it may even be considered as part of index endoscopy when the procedure and expertise are readily available.7,23 As per new consensus and American

Gastroenterological Association Clinical Practice Update guidance, an EGJ-DI less than 2.0 mm2/mm Hg and maximum EGJ diameter less than 12 mm on FLIP are classified as REO (as in this case), while a normal EGJ opening (EGJ-DI ≥2.0 mm 2/mm Hg and maximum EGJ diameter ≥16 mm) has a high negative predictive value for achalasia spectrum disorders on HRM.6,7 For the management of achalasia, definitive therapies with well-established clinical benefit include pneumatic dilation, surgical laparoscopic Heller myotomy (LHM) accompanied by partial fundoplication to help prevent GERD, and POEM. All 3 approaches are comparable and may be considered reasonable options for types I and II achalasia, with selection guided by individual patient characteristics, local expertise, discussions of potential risks and outcomes (eg, POEM may be associated with GERD), and shared decision-making.20,24 POEM is the preferred treatment for type III achalasia, given the potential to tailor the myotomy to the spastic segment of the esophageal body. 20,25,26 A botulinum toxin injection typically should be reserved for patients who are not candidates for the more definitive therapies described above. 20 When available, intraprocedural FLIP during myotomy, whether POEM or LHM, may be helpful in tailoring or guiding the adequacy of disruption to the lower esophageal sphincter. 26 Finally, patients who undergo POEM should be monitored for GERD, with treatment offered as appropriate.26

Case 3 A 50-year-old man with a history of obesity and diabetes mellitus was referred for endoscopy after experiencing 3 months of dysphagia to solids. He reported long-standing heartburn and regurgitation, for which he took over-the-counter antacids on an as-needed basis. Upper endoscopy revealed Los Angeles Grade D esophagitis with luminal narrowing at the EGJ (Figure 3A). He was started on 40 mg of omeprazole twice daily with plans for repeat upper endoscopy.

Diagnosis: Erosive Esophagitis (EE) And Peptic Stenosis GERD is a common condition in which refluxate of acidic contents from the stomach into the esophagus results in bothersome symptoms (commonly heartburn, regurgitation, and noncardiac chest pain). While these typical symptoms in the absence of alarm symptoms can prompt a 4- to 8-week trial of PPI therapy with assessment of response,27 GERD can lead to the formation of peptic strictures, mechanical narrowing that can cause dysphagia. Per the updated Lyon Consensus, the presence of LA Grades B/C/D EE, peptic stricture, and/or biopsy-proven Barrett’s esophagus represent conclusive evidence for a diagnosis of GERD (as in this case).28 If these findings are not present on endoscopy, a

diagnosis of GERD may be established with ambulatory reflux monitoring, with distal esophageal AETs more than 6% indicating the presence of pathologic GERD.27,28 If ambulatory reflux monitoring is inconclusive based on AET, then adjunctive evidence such as numbers of reflux episodes, reflux symptom association, and mean nocturnal baseline impedance may support a diagnosis of GERD.29-31 A personalized approach to management is warranted, with further evaluation and/or escalation of anti-reflux therapy, including invasive anti-reflux interventions, pursued thoughtfully with shared decision-making.27,32,33

Management The patient returned for follow-up endoscopy 2 months later on 40 mg of omeprazole twice daily. Although he reported partial improvement in his dysphagia, upper endoscopy demonstrated LA Grade C esophagitis and ongoing luminal narrowing at the EGJ. Given persistent and severe EE and stricture despite adherence with a high dose of omeprazole, the patient was switched to 20 mg of vonoprazan (Voquezna, Phathom) daily. After 1 month of vonoprazan therapy, upper endoscopy revealed resolution of his reflux esophagitis (Figure 3B). Across 2 endoscopies, the patient’s peptic stricture was successfully dilated to a diameter of 18 mm

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Figure 3A. Upper endoscopy image with

Figure 3C. Upper endoscopy image of through-the-

Los Angeles Grade D esophagitis and peptic stenosis.

scope balloon dilation of esophageal stenosis.

Figure 3B. Upper endoscopy image after vonoprazan therapy with healing of esophagitis and presence of stenosis.

using through-the-scope balloon dilators (Figure 3C). He reported resolution of his dysphagia and reflux symptoms at follow-up. In the setting of EE, optimized antisecretory therapy facilitates healing and can be followed by repeat upper endoscopy to document healing and exclude the presence of Barrett’s esophagus.34 High-dose PPIs are most commonly used as first-line therapy for the healing of EE given their effectiveness, accessibility, safety profile, and cost. 27 However, potassium-competitive acid

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blockers (P-CABs) such as vonoprazan, which received FDA approval for EE in November 2023, are a newer class of antisecretory medications that can provide more potent acid inhibition than PPI formulations, with faster onset of action and longer duration of effect and without premeal dosing requirements.35,36 Although P-CABs currently are less accessible and more costly than PPIs in the United States, they may be superior to PPIs for the healing and maintenance of healing of more severe (LA Grades C/D) EE and may be associated with more rapid healing.36,37 Beyond representing an effective therapeutic option for patients with more severe EE and those with documented reflux who fail twice-daily PPI therapy (as in this case), the rapid onset of acid inhibition of P-CABs raises their potential utility as on-demand therapy for reflux-related symptoms.36,38 For peptic strictures, endoscopic dilation, whether employing balloon or bougie techniques, is safe and effective.39,40

Conclusion Through these representative hypothetical cases, we have outlined practical approaches to the evaluation of esophageal dysphagia and the basic management of EoE, achalasia, and reflux esophagitis with peptic stenosis, incorporating clinical pearls and more recent esophageal diagnostic and therapeutic advances, such as dupilumab, FLIP, POEM, and vonoprazan. As demonstrated through these cases, we are fortunate as gastroenterology providers to be able to thoughtfully evaluate our patients with dysphagia with the assistance of insightful diagnostic modalities and also, when indicated, treat our patients with a growing arsenal of effective, patient-tailored management options.

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Almario CV, Ballal ML, Chey WD, et al. Burden of gastrointestinal symptoms in the United States: results of a nationally representative survey of over 71,000 Americans. Am J Gastroenterol. 2018;113(11):1701-1710.

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Alcala Gonzalez LG, Oude Nijhuis RAB, Smout A, et al. Normative reference values for esophageal high-resolution manometry in healthy adults: a systematic review. Neurogastroenterol Motil. 2021;33(1):e13954.

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Patel A, Posner S, Gyawali CP. Esophageal high-resolution manometry in gastroesophageal reflux disease. JAMA. 2018;320(12):1279-1280.

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Carlson DA, Kahrilas PJ, Lin Z, et al. Evaluation of esophageal motility utilizing the functional lumen imaging probe. Am J Gastroenterol. 2016;111(12):1726-1735.

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Ponds FA, Fockens P, Lei A, et al. Effect of peroral endoscopic myotomy vs pneumatic dilation on symptom severity and treatment outcomes among treatment-naive patients with achalasia: a randomized clinical trial. JAMA. 2019;322(2):134-144.

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Gyawali CP, Carlson DA, Chen JW, et al. ACG Clinical Guidelines: Clinical Use of Esophageal Physiologic Testing. Am J Gastroenterol. 2020;115(9):1412-1428.

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Yadlapati R, Kahrilas PJ, Fox MR, et al. Esophageal motilty disorders on high-resolution manometry: Chicago classification version 4.0. Neurogastroenterol Motil. 2021;33(1):e14058.

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Andolfi C, Fisichella PM. Meta-analysis of clinical outcome after treatment for achalasia based on manometric subtypes. Br J Surg. 2019;106(4):332-341.

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Carlson DA, Pandolfino JE, Yadlapati R, et al. A standardized approach to performing and interpreting functional lumen imaging probe panometry for esophageal motility disorders: the Dallas Consensus. Gastroenterology. Published online February 4, 2025. doi:10.1053/j.gastro.2025.01.234

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Yang D, Bechara R, Dunst CM, et al. AGA clinical practice update on advances in per-oral endoscopic myotomy (POEM) and remaining questions—what we have learned in the past decade: expert review. Gastroenterology. 2024;167(7):1483-1490.

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Nguyen A, Carlson D, Patel A, et al. American Gastroenterological Association (AGA) clinical practice update: incorporating functional lumen imaging probe (FLIP) into clinical esophageal practice: expert review. Gastroenterology. In press; 2025.

Yadlapati R, Gyawali CP, Pandolfino JE. AGA clinical practice update on the personalized approach to the evaluation and management of GERD: expert review. Clin Gastroenterol Hepatol. 2022;20(5):984-994.e1.

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Blonski W, Jacobs J, Feldman J, et al. The history and use of the timed barium esophagram in achalasia, esophagogastric junction outflow obstruction, and esophageal strictures. Neurogastroenterol Motil. 2025;37(1):e14928.

Gyawali CP, Yadlapati R, Fass R, et al. Updates to the modern diagnosis of GERD: Lyon consensus 2.0. Gut. 2024;73(2):361-371.

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Frazzoni M, Frazzoni L, Ribolsi M, et al. Applying Lyon Consensus criteria in the work-up of patients with proton pump inhibitory-refractory heartburn. Aliment Pharmacol Ther. 2022;55(11):1423-1430.

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Rengarajan A, Savarino E, Della Coletta M, et al. Mean nocturnal baseline impedance correlates with symptom outcome when acid exposure time is inconclusive on esophageal reflux monitoring. Clin Gastroenterol Hepatol. 2020;18(3):589-595.

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Hirano I, Moy N, Heckman MG, et al. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system. Gut. 2013;62(4):489-495.

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Aceves SS, Alexander JA, Baron TH, et al. Endoscopic approach to eosinophilic esophagitis: American Society for Gastrointestinal Endoscopy Consensus Conference. Gastrointest Endosc. 2022;96(4):576-592.e1.

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Dellon ES, Muir AB, Katzka DA, et al. ACG Clinical Guideline: Diagnosis and Management of Eosinophilic Esophagitis. Am J Gastroenterol. 2025;120(1):31-59.

Patel A, Wang D, Sainani N, et al. Distal mean nocturnal baseline impedance on pH-impedance monitoring predicts reflux burden and symptomatic outcome in gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2016;44(8):890-898.

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Dellon ES, Khoury P, Muir AB, et al. A clinical severity index for eosinophilic esophagitis: development, consensus, and future directions. Gastroenterology. 2022;163(1):59-76.

Patel A, Yadlapati R. Diagnosis and management of refractory gastroesophageal reflux disease. Gastroenterol Hepatol (N Y). 2021;17(7):305-315.

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Patel A, Gyawali CP. The role of magnetic sphincter augmentation (MSA) in the gastroesophageal reflux disease (GERD) treatment pathway: the gastroenterology perspective. Dis Esophagus. 2023;36(suppl 1):doad005.

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Dellon ES, Hirano I. Epidemiology and natural history of eosinophilic esophagitis. Gastroenterology. 2018;154(2):319-332.e3.

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Kiran A, Cameron B, Xue Z, et al. Increasing age at the time of diagnosis and evolving phenotypes of eosinophilic esophagitis over twenty years. Dig Dis Sci. 2024;69(2):521-527.

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Hanna S, Rastogi A, Weston AP, et al. Detection of Barrett’s esophagus after endoscopic healing of erosive esophagitis. Am J Gastroenterol. 2006;101(7):1416-1420.

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Muftah M, Bernstein D, Patel A. Eosinophilic esophagitis: lessons learned from its evolution. Dig Dis Sci. 2024;69(2):318-319.

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Mayerhofer C, Kavallar AM, Aldrian D, et al. Efficacy of elimination diets in eosinophilic esophagitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023;21(9):2197-2210.e3.

Wong N, Reddy A, Patel A. Potassium-competitive acid blockers: present and potential utility in the armamentarium for acid peptic disorders. Gastroenterol Hepatol (N Y). 2022;18(12):693-700.

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Dellon ES, Rothenberg ME, Collins MH, et al. Dupilumab in adults and adolescents with eosinophilic esophagitis. N Engl J Med. 2022;387(25):2317-2330.

Patel A, Laine L, Moayyedi P, et al. AGA clinical practice update on integrating potassium-competitive acid blockers into clinical practice: expert review. Gastroenterology. 2024;167(6):1228-1238.

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Chang JW, Rubenstein JH, Mellinger JL, et al. Motivations, barriers, and outcomes of patient-reported shared decision making in eosinophilic esophagitis. Dig Dis Sci. 2021;66(6):1808-1817.

Laine L, DeVault K, Katz P, et al. Vonoprazan versus lansoprazole for healing and maintenance of healing of erosive esophagitis: a randomized trial. Gastroenterology. 2023;164(1):61-71.

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Sauer BG, Barnes BH, McGowan EC. Strategies for the use of dupilumab in eosinophilic esophagitis. Am J Gastroenterol. 2023;118(5):780-783.

Fass R, Vaezi M, Sharma P, et al. Randomised clinical trial: efficacy and safety of on-demand vonoprazan versus placebo for non-erosive reflux disease. Aliment Pharmacol Ther. 2023;58(10):1016-1027.

39.

Desai M, Hamade N, Sharma P. Management of peptic strictures. Am J Gastroenterol. 2020;115(7):967-970.

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Josino IR, Madruga-Neto AC, Ribeiro IB, et al. Endoscopic dilation with bougies versus balloon dilation in esophageal benign strictures: systematic review and meta-analysis. Gastroenterol Res Pract. 2018;2018:5874870.

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Vaezi MF, Pandolfino JE, Yadlapati RH, et al. ACG Clinical Guidelines: Diagnosis and Management of Achalasia. Am J Gastroenterol. 2020;115(9):1393-1411.

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The Frontiers of Therapeutic Endoscopic Ultrasound in 2025:

Advances in EUS Scope Design ANDREW C. STORM, MD Chair, Gastrointestinal Endoscopy Co-Director, Developmental Endoscopy Unit Mayo Clinic Rochester, Minnesota

E

ndoscopic ultrasound has evolved from a purely diagnostic modality into a powerful therapeutic tool in interventional gastroenterology. Therapeutic EUS is increasingly used for a wide range of procedures, including fine-needle biopsy,

drainage of pancreatic and postoperative fluid collections, biliary access and drainage, gastroenterostomy, and novel nonsurgical bypass procedures, among others.

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Earlier this year, the American Society for Gastrointestinal Endoscopy published quality indicators for EUS that included ideal adverse event rate thresholds for diagnostic and therapeutic EUS procedures.1 This guidance aims to standardize the rapidly evolving practice of EUS by minimizing complications and ensuring high-quality gastrointestinal patient care through use of quality indicators, as well as EUS report standards, training and competency criteria, and a framework for multidisciplinary collaboration. Although these efforts are critically important for improving the safety and efficacy of EUS procedures worldwide, the design and functionality of the echoendoscope is another increasingly recognized factor in the successful and safe performance of EUS procedures. As therapeutic applications continue to expand, the importance of therapeutic echoendoscope design has become central to the efficacy, accessibility, and safety of EUS-guided interventions. Below, I explore several ideas related to how echoendoscope design affects therapeutic EUS procedures and why innovation in this area is essential for the future of minimally invasive EUS-guided gastroenterology procedures.

Evolution of EUS and the Role Of Endoscope Design EUS initially was developed to enhance diagnostic imaging of the gastrointestinal tract, providing highresolution visualization of the digestive organs and surrounding tissues. Traditional linear echoendoscopes offered limited maneuverability and working channel access, which restricted therapeutic capabilities mainly to EUS-guided

fine-needle aspiration (FNA) for sampling and injection. As interventional EUS procedures have gained popularity and the number of available devices to support these interventions has grown, the limitations of early scope design have become apparent. The need for more robust tools capable of combining precision imaging with therapeutic functionality has led to significant innovations in endoscope architecture, including some interesting new platforms through which endoscopists can offer EUS procedures in their practices.

Scope Design Affects Therapeutic Precision and Safety Precision and safety are 2 pillars of a successful therapeutic EUS practice, and advanced endoscope designs contribute significantly to both. First, improved maneuverability—specifically, better articulation and control— enables operators to access difficult-to-reach anatomic locations. Enhanced tip deflection and elevator mechanisms allow the endoscopist to align instruments more accurately with target lesions or ducts, reducing procedural time and minimizing trauma from repeated needle or device advancements. Fujisawa et al describe significant improvements in procedural and fluoroscopy time for therapeutic EUS cases using a novel interventional EUS scope design in a study that included 143 procedures in 120 patients.2 Their study compared procedures using an older conventional model (EG-580UT, Fujifilm) with a newer scope design (EG-740UT, Fujifilm). The newer model includes a bending segment curvature that improved from 27.9 to 25 degrees; enhanced elevator strength, allowing for an impressive increased

Conventional scope Max. angle: 35.2º

Figure 1. Comparison of the elevator function of the conventional and new scope designs. Note the enhanced angle of deflection capacity of the newer instrument. From J Clin Med. 2024;13(10):2840.

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New scope Max. angle: 76.7º

angle of deflection from 35.2 to 76.7 degrees (Figure 1); and a white light endoscopy camera that was relocated from distal to the working channel to a proximal location, allowing for better visualization of tools being deployed via the working channel (Figure 2).

From Our Case Files: ERCP With an EUS Scope A 64-year-old man presented with jaundice, biliary dilation, and a new mass lesion in the head of the pancreas. EUS was performed with the EG-740UT scope for staging and sampling of the primary mass lesion, which confirmed pancreatic adenocarcinoma. Using the same scope, the endoscopist was able to perform transpapillary endoscopic

retrograde cholangiopancreatography (ERCP) due to the strength and deflection of the elevator and view of the accessory channel allowed by this new scope design (Figure 3). A fully covered metal stent was deployed across the distal malignant biliary obstruction for palliation of the stricture after biliary sphincterotomy (Figure 4). Other recent EUS scope design features include the integration of high-frequency ultrasound probes with Doppler capabilities, which aids in identifying vascular structures and avoiding inadvertent vessel puncture. Also, innovations in imaging fidelity, such as contrast-enhanced EUS and elastography, are being integrated into many echoendoscope processor platforms, offering even more detailed assessments before intervention. Furthermore, the development of varying diameters and

Conventional scope (EG-580UT)

New scope (EG-740UT)

Figure 2. Comparison of the conventional and new scope designs. In the new model, the camera has been relocated from distal to the tool channel to a proximal position, which allows for visualization of tools such as lumen-apposing stent deployment. From J Clin Med. 2024;13(10):2840.

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rigidity in echoendoscopes can affect patient comfort, navigation ease, and procedural outcomes. Slimmer, more flexible scopes reduce the need for deep sedation or general anesthesia and may reduce the risk for complications, particularly in frail or smaller patients. Bang et al show that a slim linear echoendoscope significantly improved their practice of interventional and diagnostic EUS (Figure 5).3 In their reported experience of more than 2,000 procedures, complete EUS examination failed in 1.15% of cases (n=23) due to the diameter of the EUS scope. Complete examination was technically successful in 22 of those 23 failed cases (>95% successful rescue) using a slim EUS scope design (EG34J10U, Pentax). This further highlights the role of scope design in improving the diagnostic and therapeutic capabilities of physicians working on the frontiers of EUS.

From Our Case Files: Endobronchial Ultrasound Scope for GI Access A 2-year-old girl presented with failure to thrive and vomiting after meals. Evaluation included CT, which revealed a mass lesion in the pancreas. Percutaneous sampling was unsuccessful, so EUS-guided tissue sampling was requested to guide next steps in therapy. However, the patient’s weight of 10 kg made passage of an adult linear echoendoscope, which has an insertion tube diameter of 12.6 mm, challenging and ill-advised. Thus, we opted to use an endobronchial ultrasound (EBUS) scope (BF-UC180F, Olympus) with a 6.2-mm insertion shaft diameter. The imaging field with EBUS is smaller and quality of the image is reduced compared with larger EUS scopes (Figure 6).

Figure 3. ERCP using an EG-740UT (Fujifilm) EUS scope. Note the EUS transducer, seen at the 6 o’clock position in the image. Novel scope designs include improvements in elevator strength and angle of deflection, as well as movement of the camera from downstream to upstream of the accessory channel, which enhances therapeutic interventions, including ERCP-type maneuvers. ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound.

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A solid cystic lesion was seen in the neck of the pancreas, which was sampled using EBUS FNA. Final cytology from the sampling was consistent with pancreatoblastoma, which was resected with no evidence of tumor recurrence. This case serves as a reminder that “bigger” is not always “better,” and EUS scope platforms should consider smaller and abnormal anatomy, where a slim-scope design may permit life-changing diagnostic and therapeutic interventions.

Facilitating Access to EUS And Reducing the Learning Curve Therapeutic EUS remains a technically demanding skill that requires extensive training and experience. Poor scope design can compound difficulties that practicing physicians

may take for granted. These shortfalls in design likely increase the learning curve and raise the risk for complications in not only novice but also expert hands. User-friendly scope design with built-in guidance and safety mechanisms likely will be essential to democratize access to EUS across more centers and geographic regions. Simplified control systems, visual feedback related to tip orientation within a patient’s anatomy, and intuitive interfaces and image interpretation software already are being explored for future-generation endoscopes. Future designs might include real-time haptic feedback or automated safety locking systems to prevent failed access, unintended puncture, or stent maldeployment. These features improve training and help maintain consistency and safety among less experienced practitioners. Another limitation to improved access to EUS for patients

Figure 4. Fluoroscopic images showing transpapillary cannulation and cholangiogram (left) and palliative stent placement (right) during ERCP using the EG-740UT (Fujifilm) EUS scope. Shortening the bending segment, moving the camera, and improving the elevator function all contribute to improved scope function for these therapeutic maneuvers. ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound.

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across the globe is scope and processor cost, which may be prohibitive to new, smaller, or rural practices. In response to this issue, a novel platform called the EndoSound Vision System (EndoSound) is available in the United States as an add-on device that converts any flexible upper gastrointestinal video endoscope and most pediatric colonoscopes into a functional EUS system (Figure 7). This system is comprised of a compact ultrasound beamformer, reusable transducer, and disposable mounting kit and allows for advanced procedures, such as fine-needle biopsy, without the need for the elevator mechanism used in traditional reusable linear echoendoscopes. This system could improve access to safe and efficient EUS diagnostic and interventional procedures where expertise is available but access to modern EUS equipment is lacking. Finally, simulation-based training through virtual reality and simulated phantom (physical) models is becoming an integral part of many fields within medical education. Realistic, low-risk training opportunities are critical for developing the next generation of procedural providers who can keep up with the growing field of diagnostic and therapeutic EUS. Echoendoscopes that can be easily integrated with simulators and training devices could become critical for more realistic training, practice, and assessment of current and future EUS procedures, ultimately accelerating procedural proficiency and improving patient experiences and outcomes.

A Future of Robotic, AI-Guided, And Personalized Medical Interventions As therapeutic EUS continues to push boundaries— enabling procedures that were once the exclusive domain of surgery—the need for precision grows. Design elements of the future may include multiple accessory ports, enhanced water jet systems for clearing the field of view, and ergonomic control interfaces, such as potential integration with robotic-assisted technologies or motorized insertion systems. Robotic assistance may one day allow for even more accurate, less operator-dependent interventions aimed at further empowering the endoscopists of the future to perform high-end interventional procedures with confidence. In bronchoscopy, peripheral lung lesion assessment has been revolutionized by a robotic bronchoscopy platform (Ion, Intuitive Surgical), made possible through shape-sensing fibers, an ultrathin access catheter, and highly precise robotic control.4

Figure 6.

The EG34-J10U slim linear scope (Pentax) permits access in smaller, more narrow anatomy.

EUS using an EBUS scope for pediatric cases can be a challenge for the endosonographer because the imaging field and quality are more limited than in adult echoendoscopes.

Image courtesy of Pentax.

EBUS, endobronchial ultrasound; EUS, endoscopic ultrasound.

Figure 5.

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The intersection of endoscope design with artificial intelligence is another area poised for evolution in echoendoscope design. AI-enhanced EUS systems—those that can provide real-time feedback, recognize anatomic landmarks, and recommend diagnoses and/or procedural steps—will depend heavily on advanced data processing in development.5 The form factor and internal architecture of these future echoendoscopes must be engineered to support these improvements without compromising usability or safety, such as factors important to natural orifice translumenal endoscopic surgery, ensuring sterility. Furthermore, personalized medicine in EUS may someday require the ability to tailor instruments to individual patient anatomies and pathologies. Endoscope platforms with interchangeable working shafts, variable stiffness, and more complex patient-specific pre-procedural and intraprocedural planning for diagnostic and therapeutic intents

via 3D EUS (or dual cross-sectional modality) mapping will become more desirable. These goals necessitate rethinking our current scope designs, which were engineered as diagnostic-only tools, as the future likely will require more versatile, adaptable platforms.

Conclusion EUS has evolved from a diagnostic imaging modality to a keystone platform for therapeutic intervention in flexible endoscopy and gastroenterology. The future of the field hinges not only on procedural and device innovations but also on the scope platforms that make them possible. Therapeutic EUS has grown to encompass a wide array of procedures, from earlier biopsy and nerve blocks to newer and more advanced novel anastomosis creation and ablation procedures. The success and safety of these interventions may be intricately linked to echoendoscopic equipment

Figure 7. The EndoSound Vision System (EndoSound) permits the use of any standard video gastroscope and many pediatric colonoscopes to become an EUS platform, potentially improving efficient access to EUS procedures for many patients. A reusable ultrasound transducer is attached with a single-use mounting kit, permitting high-definition, on-demand EUS procedures where traditional EUS equipment may be unavailable. EUS, endoscopic ultrasound. Image courtesy of EndoSound.

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design. As the scope of therapeutic intent on the frontiers of EUS expands, it is difficult to overstate the importance of innovative design. Advanced scope designs can enhance safety, expand therapeutic options, reduce the learning curve, and may pave the way for robotic and AI integration. Newer EUS scope designs have involved significant improvements to the maneuverability, shaft size, camera view, and elevator function of therapeutic linear scopes. Early data suggest that procedure duration can be shortened by these improvements, and previously challenging interventions,

including ERCP maneuvers, using an EUS scope are made simpler, as shown in our case examples. Investment in therapeutic echoendoscope design and engineering should remain a strategic imperative for scope manufacturers and clinicians seeking to stay at the forefront of minimally invasive gastrointestinal care. In the coming decade, as therapeutic EUS becomes even more central to the management of complex gastrointestinal and hepatobiliary conditions, these advances in echoendoscope technology from the frontiers of EUS will allow us to reach the full potential of minimally invasive endoscopic therapy.

References 1.

Mishra G, Lennon AM, Pausawasdi N, et al. Quality indicators for EUS. Gastrointest Endosc. 2025;101(5):928-949.

2.

Fujisawa T, Ishii S, Nakai Y, et al. Dedicated echoendoscope for interventional endoscopic ultrasound: comparison with a conventional echoendoscope. J Clin Med. 2024;13(10):2840.

3.

Bang JY, Willems P, Navaneethan U, et al. Impact of slim linear echoendoscope on the practice of EUS. J Clin Gastroenterol. 2024;58(8):830-835.

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4.

Simoff MJ, Pritchett MA, Reisenauer JS, et al. Shape-sensing robotic-assisted bronchoscopy for pulmonary nodules: initial multicenter experience using the Ion Endoluminal System. BMC Pulm Med. 202116;21(1):322.

5.

Marya NB, Powers PD, Chari ST, et al. Utilisation of artificial intelligence for the development of an EUS-convolutional neural network model trained to enhance the diagnosis of autoimmune pancreatitis. Gut. 2021;70(7):1335-1344.

Table 1: Common Adverse Reactions Observed in at Least 2% of Patients Undergoing Colon Cleansing in Study 1 Split-Dose Regimen

BRIEF SUMMARY: Consult the Full Prescribing Information for complete product information. CLENPIQ (sodium picosulfate, magnesium oxide, and anhydrous citric acid) oral solution INDICATIONS AND USAGE CLENPIQ is indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS CLENPIQ is contraindicated in the following conditions: • Patients with severe renal impairment (creatinine clearance less than 30 mL/minute), which may result in accumulation of magnesium • Gastrointestinal obstruction or ileus • Bowel perforation • Toxic colitis or toxic megacolon • Gastric retention • Hypersensitivity to any of the ingredients in CLENPIQ WARNINGS AND PRECAUTIONS Serious Fluid and Electrolyte Abnormalities Advise patients to hydrate adequately before, during, and after the use of CLENPIQ. Use caution in patients with congestive heart failure when replacing fluids. If a patient develops significant vomiting or signs of dehydration including signs of orthostatic hypotension after taking CLENPIQ, consider performing post- colonoscopy lab tests (electrolytes, creatinine, and BUN) and treat accordingly. Approximately 20% of patients in both arms (sodium picosulfate, magnesium oxide, and anhydrous citric acid or 2 L of PEG + E plus two x 5-mg bisacodyl tablets) of clinical trials of another oral formulation of sodium picosulfate, magnesium oxide, and anhydrous citric acid product had orthostatic changes in blood pressure and/ or heart rate on the day of colonoscopy and up to seven days post colonoscopy. In a single study of patients 9 to 16 years of age, approximately 20% of patients who received another oral product of sodium picosulfate, magnesium oxide, and anhydrous citric acid had orthostatic changes (changes in blood pressure and/or heart rate) compared with approximately 7% of those who received the comparator (PEG). These changes occurred up to five days post colonoscopy. Fluid and electrolyte disturbances can lead to serious adverse reactions including cardiac arrhythmias, seizures, renal impairment, and syncope. Correct fluid and electrolyte abnormalities before treatment with CLENPIQ. Advise patients to consume a variety of clear liquids (e.g., balanced electrolyte solution), and not only water after each dose of CLENPIQ. In addition, use caution when prescribing CLENPIQ for patients who have conditions or who are using medications that increase the risk for fluid and electrolyte disturbances or that may increase the risk of seizure, arrhythmia, and renal impairment. Seizures There have been reports of generalized tonic-clonic seizures and/or loss of consciousness with the use of bowel preparation products in patients with no prior history of seizures. The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. The neurologic abnormalities resolved with correction of fluid and electrolyte abnormalities. Use caution when prescribing CLENPIQ for patients with a history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with known or suspected hyponatremia. Use in Patients with Renal Impairment CLENPIQ is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), accumulation of magnesium in plasma may occur. Use caution when prescribing CLENPIQ for patients with mild to moderate renal impairment or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal anti-inflammatory drugs). These patients may be at increased risk for renal injury. Advise these patients of the importance of adequate hydration before, during, and after the use of CLENPIQ. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. Cardiac Arrhythmias There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. Use caution when prescribing CLENPIQ for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Consider pre-dose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias. Syncope Syncope has been reported with CLENPIQ in the postmarketing setting. Some cases were serious events that included falls with associated head injuries or fractures requiring hospitalization. In some cases, electrolyte abnormalities were also present (e.g., hyponatremia and hypokalemia). Cases have been reported after one or two CLENPIQ doses and many of these cases occurred within 12 hours of dosing. Patients should be aware of the risk of syncope during treatment and adequately hydrate before, during, and after the use of CLENPIQ. Advise patients to consume a variety of clear liquids (e.g., balanced electrolyte solution), not only water after each dose of CLENPIQ and to get up gradually from a lying or sitting position. Colonic Mucosal Ulceration, Ischemic Colitis, and Ulcerative Colitis Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of additional stimulant laxatives with CLENPIQ may increase this risk. Consider the potential for mucosal ulcerations when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. Use in Patients with Significant Gastrointestinal Disease If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering CLENPIQ. Use with caution in patients with severe active ulcerative colitis. Aspiration Patients with impaired gag reflex are at risk for regurgitation or aspiration during the administration of CLENPIQ. Observe these patients during the administration of CLENPIQ. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Adults Clinical Study of CLENPIQ - Study 1 Table 1 displays the most common adverse reactions in a randomized, multicenter, assessor-blinded, non-inferiority trial of CLENPIQ for colon cleansing in adults (Study 1). CLENPIQ was compared to another oral sodium picosulfate, magnesium oxide, and anhydrous citric acid product, both administered according to the Split-Dose dosage regimen.

Adverse Reaction

CLENPIQ (N=448) %

Sodium picosulfate, magnesium oxide, and anhydrous citric acid1 (N=453) %

Nausea Headache Hypermagnesemia2 Abdominal pain3 Dehydration or dizziness

3 3 2 2

3 3 5 2

2

2

1

Powder for reconstitution 2 Magnesium levels returned to normal within one week after colonoscopy in all patients in the CLENPIQ group. 3 Abdominal pain included reports of abdominal pain, abdominal pain upper, and abdominal pain lower. Clinical Study of Another Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Product - Study 2 In a randomized, multicenter, investigator-blinded, active-controlled clinical trial for colon cleansing in adults, another oral formulation of sodium picosulfate, magnesium oxide, and anhydrous citric acid product was compared with a regimen of two liters (2 L) of polyethylene glycol plus electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets (Study 2). In this study the protocol specified that abdominal bloating, distention, pain/cramping, and watery diarrhea, which are known to occur in response to bowel preparation, were documented as adverse events only if they required medical intervention (such as a change in study drug or led to discontinuation, therapeutic or diagnostic procedures, met the criteria for serious adverse event) or showed clinically significant worsening during the study that was not in the frame of the usual clinical course, as determined by the investigator. The most common adverse reactions in Study 2 are shown in Table 2. Table 2: Common Adverse Reactions1 Observed in at Least 1% of Patients Undergoing Colon Cleansing2 in Study 2 Split-Dose Regimen Adverse Reaction

Sodium picosulfate, magnesium oxide, and anhydrous citric acid (N=305) %

2 L PEG + E3 with 2 x 5-mg bisacodyl tablets (N=298) %

Nausea

3

4

Headache Vomiting

2 1

2 3

1, 2

abdominal bloating, distention, pain/cramping, and watery diarrhea not requiring an intervention were not collected 3 2 L PEG + E = two liters polyethylene glycol plus electrolytes solution Electrolyte Abnormalities In Study 1, rates of abnormal electrolyte shifts were generally similar between CLENPIQ and another sodium picosulfate, magnesium oxide, and anhydrous citric acid product (Table 3). In general, these shifts were transient and not clinically significant. In Study 2, sodium picosulfate, magnesium oxide, and anhydrous citric acid was in general associated with numerically higher rates of abnormal electrolyte shifts on the day of colonoscopy compared to the control regimen (Table 3). These shifts were transient in nature and numerically similar between treatment arms at the Day 28 visit. Table 3: Shifts from Normal Baseline to Outside the Normal Range Post-Baseline Split-Dose Regimen Study 1 Split-Dose Regimen Study 2 Laboratory Parameter (direction of change)

Visit

Potassium (low)

Day of Colonoscopy 24-48 hours Day 7 Day 28 Sodium (low) Day of Colonoscopy 24-48 hours Day 7 Day 28 Chloride Day of (low) Colonoscopy 24-48 hours Day 7 Day 28 Magnesium Day of (high) Colonoscopy 24-48 hours

Day 7 Day 28 Calcium (low) Day of Colonoscopy 24-48 hours Day 7 Day 28 Bicarbonate Day of (low) Colonoscopy 24-48 hours Day 7 Day 28 Creatinine Day of (high) Colonoscopy 24-48 hours Day 7 Day 28

Sodium picosulfate, magnesium CLENPIQ oxide, and anhydrous citric acid1 n/N (%)

Sodium 2 L PEG+E picosulfate, with magnesium 2 x 5 mg oxide, and bisacodyl anhydrous tablets citric acid1 n/N (%)

34/422 (8.1)

10/423 (2.4)

19/260 (7.3)

11/268 (4.1)

13/417 (3.1) 7/420 (1.7) 3/421 (0.7)

3/423 (0.7) 6/425 (1.4) 7/423 (1.7)

3/302 (1.0) 11/285 (3.9) 11/284 (3.9)

2/294 (0.7) 8/279 (2.9) 8/278 (2.9)

4/426 (0.9)

23/443 (5.2)

11/298 (3.7)

3/295 (1.0)

6/423 (1.4) 6/423 (1.4) 8/427 (1.9)

9/441 (2.0) 9/440 (2.0) 9/439 (2.1)

1/303 (0.3) 2/300 (0.7) 2/299 (0.7)

1/295 (0.3) 1/292 (0.3) 3/291 (1.0)

23/437 (5.3)

16/444 (3.6)

11/301 (3.7)

1/298 (0.3)

3/434 (0.7) 3/434 (0.7) 4/438 (0.9) 112/431 (26.0) 23/427 (5.4)

3/442 (0.7) 1/303 (0.3) 2/441 (0.5) 1/303 (0.3) 1/440 (0.2) 2/302 (0.7) 143/440 34/294 (11.6) (32.5) 21/440 (4.8) 0/303 (0.0)

0/295 (0.0) 3/295 (1.0) 3/294 (1.0)

11/428 (2.6) 10/432 (2.3)

9/440 (2.0) 12/438 (2.7)

0/297 (0.0) 1/296 (0.3)

1/291 (0.3) 2/290 (0.7)

8/436 (1.8)

1/446 (0.2)

2/292 (0.7)

1/286 (0.3)

1/434 (0.2) 0/434 (0.0) 0/439 (0.0)

0/444 (0.0) 0/444 (0.0) 2/442 (0.5)

0/303 (0.0) 0/293 (0.0) 0/292 (0.0)

0/295 (0.0) 1/283 (0.4) 1/282 (0.4)

0/294 (0.0) 0/295 (0.0)

6/431 (1.4)

35/438 (8.0)

N/A2

N/A2

40/430 (9.3) 37/430 (8.6) 33/433 (7.6)

43/434 (9.9) 40/438 (9.1) 43/436 (9.9)

N/A2 N/A2 N/A2

N/A2 N/A2 N/A2

6/427 (1.4)

1/432 (0.2)

5/260 (1.9)

13/268 (4.9)

6/425 (1.4) 5/426 (1.2) 4/429 (0.9)

5/431 (1.2) 4/431 (0.9) 6/429 (1.4)

1/303 (0.3) 10/264 (0.4) 11/264 (4.2)

0/295 (0.0) 13/267 (4.8) 14/265(5.3)

N/A: not applicable. 1 Powder for reconstitution 2 Bicarbonate was not analyzed in Study 2.

Pediatrics In the pediatric patients aged 9 to 16 years who received another oral product of sodium picosulfate, magnesium oxide, and anhydrous citric acid, the most common adverse reactions (> 5%) were nausea, vomiting, and abdominal pain. Electrolytes abnormalities were observed in pediatric patients similar to those seen in adults. Three patients had abnormally low glucose levels (40 to 47 mg/dL). Two patients received sodium picosulfate, magnesium oxide, and anhydrous citric acid and one received the comparator (PEG). The abnormal values occurred at the colonoscopy visit for one patient (sodium picosulfate, magnesium oxide, and anhydrous citric acid) and at the 5-day follow up visit for the other two patients (sodium picosulfate, magnesium oxide, and anhydrous citric acid and PEG). All three patients were asymptomatic. Postmarketing Experience The following adverse reactions have been identified during post approval use of oral sodium picosulfate, magnesium oxide, and anhydrous citric acid products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity: rash, urticaria, and purpura Gastrointestinal: abdominal pain, diarrhea, fecal incontinence, proctalgia, vomiting, reversible aphthoid ileal ulcers, and ischemic colitis Neurologic: generalized tonic-clonic seizures with and without hyponatremia in epileptic patients, and syncope. DRUG INTERACTIONS Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Use caution when prescribing CLENPIQ for patients with conditions or who are taking other drugs that increase the risk for fluid and electrolyte disturbances or may increase the risk of renal impairment, seizures, syncope, arrhythmias or QT prolongation in the setting of fluid and electrolyte abnormalities. Potential for Reduced Drug Absorption CLENPIQ can reduce the absorption of other co-administered drugs: • Administer oral medications at least one hour before of the start of administration of CLENPIQ. • Administer tetracycline and fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, and penicillamine at least 2 hours before and not less than 6 hours after administration of CLENPIQ to avoid chelation with magnesium. Antibiotics Prior or concomitant use of antibiotics with CLENPIQ may reduce efficacy of CLENPIQ as conversion of sodium picosulfate to its active metabolite BHPM is mediated by colonic bacteria. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no data with CLENPIQ use in pregnant women to determine a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats when sodium picosulfate, magnesium oxide, and anhydrous citric acid were administered orally at doses 1.2 times the recommended human dose based on body surface area during organogenesis. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Reproduction studies with sodium picosulfate, magnesium oxide, and anhydrous citric acid have been performed in pregnant rats following oral administration of up to 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on body surface area) during the period of organogenesis. There was no evidence of harm to the fetus due to sodium picosulfate, magnesium oxide, and anhydrous citric acid. The reproduction study in rabbits was not adequate, as treatment- related mortalities were observed at all doses. A pre and postnatal development study with sodium picosulfate, magnesium oxide, and anhydrous citric acid in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses up to 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on body surface area). Published reproduction studies with sodium picosulfate in pregnant rats and rabbits during the period of organogenesis did not show evidence of harm to the fetus at doses up to 100 mg/kg (approximately 49 and 98 times, respectively, the recommended human dose of 10 mg sodium picosulfate based on body surface area). Lactation Risk Summary There are no data on the presence of magnesium oxide or anhydrous citric acid in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Published data on lactating women indicate that the active metabolite of sodium picosulfate, bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM) remained below the limit of detection (1 ng/mL) in breast milk after both single and multiple doses of 10 mg/day. There are no data on the effects of sodium picosulfate on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CLENPIQ and any potential adverse effects on the breastfed infant from CLENPIQ or the underlying maternal condition. Pediatric Use The safety and effectiveness of CLENPIQ have been established for cleansing of the colon as a preparation for colonoscopy in pediatric patients 9 years of age and older. Use of CLENPIQ in this age group is supported by evidence from adequate and well- controlled trials in adults and a single, dose-ranging, controlled trial in 78 pediatric patients 9 to 16 years of age all of which evaluated another oral product of sodium picosulfate, magnesium oxide, and anhydrous citric acid. The safety profile in this pediatric population was similar to that seen in adults. Monitor for possible hypoglycemia in pediatric patients, as CLENPIQ has no caloric substrate. The safety and effectiveness of CLENPIQ in pediatric patients less than 9 years of age have not been established. Geriatric Use Of the 448 adult patients in Study 1 who received CLENPIQ, 124 (28%) patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between elderly and younger patients. Elderly patients are more likely to have decreased hepatic, renal, or cardiac function and may be more susceptible to adverse reactions resulting from fluid and electrolyte abnormalities. Renal Impairment CLENPIQ is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), as accumulation of magnesium in plasma may occur. Patients with less severe renal impairment or patients taking concomitant medications that may affect renal function may be at increased risk for renal injury. Advise these patients of the importance of adequate hydration before, during, and after the use of CLENPIQ. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. OVERDOSAGE Overdosage of more than the recommended dose of CLENPIQ may lead to severe electrolyte disturbances, as well as dehydration and hypovolemia, with signs and symptoms of these disturbances. Monitor for fluid and electrolyte disturbances and treat symptomatically. Toll free number for providers and patients to call with questions: 1-(888)-FERRING (1-(888)-337-7464) Rx only Manufactured by: ASM Aerosol-Service AG, Industriestrasse 11, CH - 4313 Möhlin, Switzerland Manufactured for:

Ferring Pharmaceuticals Inc., Parsippany, N.J. 07054 Rev. 10/2024

CLENPIQ® (sodium picosulfate, magnesium oxide, and anhydrous citric acid) Oral Solution 10 mg/3.5 g/12 g per 175 mL bottle

A RIGHT TO A GOOD

START FINISH CLENPIQ is the first and only FDA-approved, ready-to-drink, low-volume bowel prep1—because completing the prep is an important step towards a successful colonoscopy

Split-dose CLENPIQ has established successful cleansing of the entire colon2* • 84% of patients successfully cleansed – overall colon (primary endpoint)1,2* • 90% of patients successfully cleansed – ascending colon (secondary endpoint)2* • Most common adverse reactions observed (*1% of patients) in the split-dose clinical trial were nausea (3%), headache (2%), and vomiting (1%)1*† Visit CLENPIQ.com to learn more and download savings for your patients. *Study Design: The safety and efficacy of CLENPIQ has been established based on clinical studies of another oral formulation of sodium picosulfate, magnesium oxide, and anhydrous citric acid. The efficacy of the split-dose regimen was evaluated for non-inferiority against a day-before comparator (2L PEG with electrolytes plus 2x5 mg bisacodyl tablets). The primary efficacy endpoint was the proportion of patients with successful cleansing of the overall colon, defined as “excellent” or “good” using the Aronchick scale. A secondary endpoint was the proportion of patients with successful cleansing of the ascending colon defined as “excellent,” “good,” or “fair” using the Ottawa scale. †Abdominal bloating, distension, pain/cramping, and watery diarrhea not requiring an intervention were not collected.

INDICATION CLENPIQ oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Please see brief summary of Prescribing Information following this advertisement. References: 1. CLENPIQ® [Prescribing Information]. Parsippany, NJ: Ferring Pharmaceuticals Inc. 2. Rex DK, Katz PO, Bertiger G, et al. Split-dose administration of a dual-action, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study. Gastrointest Endosc. 2013;78(1):132-141. © 2025 Ferring. CLENPIQ, Ferring and the Ferring Pharmaceuticals logo are trademarks of Ferring. US-CLEN-2500011 08/25

A Gastroenterologist’s Guide To Bowel Preparation

JONATHAN BEARD, MD Division of Gastroenterology Duke University Medical Center Durham, North Carolina

AUDREY H. CALDERWOOD, MD, MS Center for Digestive Health Dartmouth-Hitchcock Medical Center Dartmouth Institute for Health Policy and Clinical Practice Dartmouth Geisel School of Medicine Lebanon, New Hampshire

A

s the leading gastrointestinal procedure in the United States, colonoscopy is an important tool for colorectal cancer screening, post-polypectomy surveillance, guidance in managing inflammatory bowel disease, and diagnosis of symptoms.1

High-quality colonoscopy depends on several factors, including cecal intubation and adequate inspection of the mucosa for adenomas and other pathology, which, in turn, are dependent on adequate withdrawal time and bowel preparation quality. An updated 2024 guideline from the American College of Gastroenterology/American Society for Gastrointestinal Endoscopy (ACG/ASGE) continues to emphasize the importance of bowel preparation by raising the target for optimal cleansing from 85% to 90%, while also increasing the minimum adenoma detection rate (ADR) to 35% and setting a new 6% benchmark for sessile serrated lesion detection.2,3

However, approximately 20% to 25% of the more than 15 million colonoscopies performed annually are limited by inadequate preparation, which has consequences for patients and the healthcare system.4 Patients may suffer from increased pain, missed adenomas, subsequent cancers, repeat colonoscopies with associated missed days of work and lost wages, and increased complications.5-12 System implications include increased intraprocedural time, reduced ability to perform other procedures, and increased costs.5,13 This article reviews currently available bowel purgative agents for colonoscopy and other bowel preparation–related procedures.

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Table 1. FDA-Approved Agents for Bowel Cleansing Before Colonoscopy Name

Total volume/instructions

Average retail price without discountsa

PEG-based regimens CoLyte (Mylan) Gavilyte-G (generic) Gavilyte-N (generic) GoLytely (Braintree) (PEG + electrolytes)

4L Large 4-L container with slight variations of powdered electrolytes depending on the product; patient fills container with lukewarm water and shakes until powder dissolves; flavor packets also can be added; 240 mL of solution is ingested every 10 min, either in 1 sitting the morning of the exam or in split-prep fashion (2 L evening before, 2 L morning of exam)

CoLyte: $40.50 Gavilyte-G: $28.86 Gavilyte-N: $41.47 GoLytely: $40.50

SUFLAVE (Braintree) (PEG-3350, sodium sulfate, potassium chloride, magnesium sulfate + sodium chloride)14,15

3L 2 1-L bottles and 2 “flavor-enhancing” packets; patient empties 1 packet into 1 bottle and then fills bottle with lukewarm water and shakes until powder dissolves; store in refrigerator until ready to drink; solution is ingested at 240 mL every 15 min until empty; patient then consumes an additional 475 mL of water. Process is repeated with second packet the morning of the procedure

$158.52

MoviPrep (Salix) (PEG-3350, sodium ascorbate, sodium sulfate, sodium chloride, potassium chloride + ASC [PEG-ELS + ASC])

3L 4 packets labeled A (2) and B (2) and a 1-L container; evening before exam: mix contents of pouch A and pouch B (1 each) in container; ingest 240 mL every 15 min until complete, then drink additional 500 mL of clear liquid (1.5 L total); repeat process morning of exam

$117.13

Plenvu (Salix) (PEG-3350, sodium ascorbate, sodium sulfate, sodium chloride, potassium chloride + ascorbic acid [PEG-ELS + ASC])

$209.34 2L 1 pouch labeled dose 1, and 2 additional pouches (dose 2 pouch A and dose 2 pouch B) and 500-mL container; evening before exam: mix pouch labeled dose 1 in the container and drink solution over 30 min; then drink an additional 500 mL of clear fluid over 30 min; repeat process morning of exam with packets labeled dose 2

Sodium sulfate–based regimens SUPREP (Braintree) (sodium sulfate, potassium sulfate, magnesium sulfate)

3L 2 small (180 mL) flavored bottles; evening before exam: dilute 1 bottle with water to 500 mL and drink; then drink 1 L of water over the next hour; repeat process morning of exam

$115.66

SUTAB (Braintree) (sodium sulfate, magnesium sulfate, potassium chloride)

3L 24 tablets; evening before exam: take 12 tablets followed by 1.5 L of water over the next 2.5 h; repeat morning of exam

$214.65

Sodium phosphate regimen OsmoPrep (Salix) (sodium phosphate)

$319.02 ~1.9 L (2 quarts) 32 tablets; evening before exam: take 4 tablets with 240 mL of water every 15 min until 20 tablets are taken (5 doses); morning of exam: take 4 tablets every 15 min with 240 mL of water until 12 tablets are taken (3 doses)

Sodium picosulfate–based regimen Clenpiq (Ferring) (sodium picosulfate, magnesium oxide, citric acid [SPMC])

~2.5 L 2 bottles; night before exam: drink the first bottle (160 mL), followed by 1.2 L of water; morning of exam: drink the second bottle (160 mL) followed by 945 mL of water

$218.42

a Prices are before discounts, coupons, and/or insurance and, thus, actual cost may be less than prices listed. For potential savings, go to moviprep.salix.com, plenvu.copaysavingsprogram.com, suflave.com/savings, suprepkit.com, sutab.com/savings, and clenpiq.com/hcp/savings.

Sources: Drug information, including dietary considerations, obtained via Lexicomp. Price information obtained from GoodRx “average retail price” and drugs.com.

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Contraindications/cautions

Palatability

Dietary considerations

Contraindicated in obstruction, perforation, gastric retention, ileus, toxic colitis/megacolon; caution in heart failure, CKD, end-stage liver disease, IBD, and with certain medications (diuretics, ACEIs, ARBs, NSAIDs)

Rapid drinking preferred to small amounts; can put on ice, use straw, or suck on lemon/sugar-free candy to improve tolerability

Ideally NPO 3-4 h before starting prep, but absolutely no solid intake 2 h before

CoLyte: can be obtained in flavored options; Gavilyte-N: sulfate-free for improved, less salty, taste Lemon-lime–flavored

A low-residue breakfast on day of prep; clear liquids permitted up to 2 h before colonoscopy

Contraindicated in obstruction, perforation, gastric retention, ileus, toxic colitis/megacolon; caution in G6PD deficiency due to the presence of sodium ascorbate/ASC; avoid in phenylketonuria due to the presence of phenylalanine; caution in heart failure, CKD, end-stage liver disease, IBD, those aged >65 y, and with certain medications (diuretics, ACEIs, ARBs, NSAIDs)

Rapid drinking preferred to small amounts; can put on ice, use straw, or suck on lemon/sugar-free candy to improve tolerability

Can eat clear liquids, soup, plain yogurt for dinner before starting prep; finish eating 1 h before start of prep

First half of prep is mango flavored; second half of prep is fruit punch flavored

If using split dose, light lunch to be completed 3 h before starting prep; for morning-only dose, NPO after 8 PM

Contraindicated in obstruction, perforation, gastric retention, ileus, toxic colitis/megacolon; caution in heart failure, CKD, end-stage liver disease, IBD, and those aged >65 y, or taking certain medications (diuretics, ACEIs, ARBs, NSAIDs); may increase uric acid and precipitate gout flare

Berry/cherry flavored

Light breakfast or clear liquids allowed morning before starting prep

Contraindicated in obstruction, perforation, gastric retention, ileus, toxic colitis/megacolon; caution in heart failure, CKD, end-stage liver disease, IBD, and those aged >65 y, or taking certain medications (diuretics, ACEIs, ARBs, NSAIDs)

No flavor; patient must be able to swallow 24 pills

Low-residue breakfast or clear liquids allowed day before exam

Contraindicated in obstruction, perforation, gastric bypass, ileus, toxic colitis/megacolon; boxed warning of rare but serious acute phosphate nephropathy; caution in seizure disorders, hypovolemia, active colitis, CKD, and those aged >65 y or taking certain medications (diuretics, ACEIs, ARBs, NSAIDs)

No flavor; patient must be able to swallow 32 pills

Clear liquid diet before and during tablet administration; rehydrate before and after exam

Cranberry-flavored ready-to-drink Contraindicated in obstruction, perforation, gastric retention, ileus, toxic colitis/megacolon, severe renal impairment; caution solution in heart failure, CKD, end-stage liver disease, and those at risk for electrolyte imbalances, aged >65 y, or taking certain medications (diuretics, ACEIs, ARBs, NSAIDs)

Do not ingest solid food, dairy, red or purple liquids, alcohol, or other laxatives while taking Clenpiq

ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; ASC, ascorbic acid; CKD, chronic kidney disease; G6PD, glucose-6-phosphate dehydrogenase; IBD, inflammatory bowel disease; NPO, nothing by mouth; NSAIDs, nonsteroidal anti-inflammatory drugs; PEG-ELS, polyethylene glycol electrolyte solution.

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Table 2. Non–FDA-Approved Agents Used for Bowel Cleansing Before Colonoscopy Name

Total volume/instructions

Magnesium 2.5 L (3 bottles + 1.5 L water) citrate No standard dosing, but experts suggest 1-1.5 bottles (300-450 mL) followed by 720 mL water; repeat same day (if single-day dosing) or morning of exam (if split dosing) PEG-3350 + sports drink + bisacodyl

Average Contraindications/ retail pricea cautions $22.98 ($7.66 per bottle)

$14.86 1.9 L (64 oz) 238 g (8.3-oz bottle), mixed into 64 oz of sports drink (do NOT use red) until dissolved; generally, bisacodyl delayed-release oral tablet to be taken before PEG-3350

Palatability

Avoid in heart failure, CKD, end-stage liver disease, and in those at risk for electrolyte imbalances

Bitter taste may be improved if chilled before use

Avoid with known or suspected bowel obstruction; possible increased rates of hyponatremia

Generally preferred over PEG-ELS; chill in refrigerator to increase palatability

Dietary considerations None given; off-label use

CKD, chronic kidney disease; PEG-3350, polyethylene glycol-3350; PEG-ELS, PEG electrolyte solution. a

Prices are before discounts, coupons, and/or insurance and, thus, actual cost may be less than prices listed.

Sources: Drug information, including dietary considerations obtained via Lexicomp. Price information obtained from GoodRx “average retail price” and drugs.com.

Choosing an Agent An ideal bowel preparation regimen should be maximally efficacious, safe, and tolerable, as well as affordable and easy to use.3 Tables 1 and 2 list available FDA-approved and non–FDA-approved regimens, respectively.14,15 All US gastroenterology societies advise individualizing the preparation regimen for each patient, taking into consideration comorbidities, medications, and patient preferences and not endorsing any specific regimen (Table 3).3,16,17 The lack of endorsement of any single agent likely is due to comparable performance among bowel purgatives when they have been compared head to head. This was well demonstrated in a large prospective comparative effectiveness study of more than 4,000 patients in which investigators compared bowel preparation regimens with respect to efficacy and tolerability.18 Adequate cleansing (defined as a Boston Bowel Preparation Scale [BBPS] score of >6, with each segment BBPS >2) was found in 92.5% of patients using polyethylene glycol-3350 (PEG-3350) with a sports drink; 91.7% with sodium phosphate; 91.1% with PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid for oral solution (MoviPrep, Salix); 90.7% with sodium picosulfate, magnesium oxide, and anhydrous citric acid (Prepopik/Clenpiq, Ferring); 90.6% with sodium sulfate, potassium sulfate, and magnesium sulfate (SUPREP, Braintree); 90.6% with magnesium citrate; and 84% with PEG-3350 and electrolytes oral solution (GoLytely, Braintree). After adjusting for various preparation, procedure, endoscopist, and patient-level factors, PEG-3350 with a sports drink was the only agent that demonstrated statistically significant superior cleansing compared with GoLytely. In terms of tolerability (defined as the percentage of patients who reported finishing the entire regimen), Prepopik/Clenpiq (99.1%); magnesium citrate (98.1%); SUPREP (94.4%); sodium phosphate monobasic

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monohydrate and sodium phosphate dibasic anhydrous (Osmoprep, Salix) (92.7%); PEG-3350 with a sports drink (92.6%); and MoviPrep (91.4%) were rated as more tolerable than GoLytely (82.9%). Multivariable logistic regression analysis found that patients were less likely to complete GoLytely than any other option.18 Further studies have continued to demonstrate comparable efficacy among purgative agents, indicating that most agents likely will result in adequate cleanliness if adhered to properly.19-22

Patient Safety Safety is a crucial factor in the selection of a bowel prep regimen because risk profiles vary based on the mechanism of action, with agents typically classified as isotonic, hypertonic, or hypotonic. Isotonic options such as GoLytely work by retaining fluid within the bowel lumen and generally cause minimal fluid shifts.23 Despite the challenges typically associated with drinking large volumes of PEG, these agents generally are considered the preferred option for patients who cannot tolerate fluid or electrolyte shifts (eg, patients with congestive heart failure or chronic kidney disease).24 In contrast, hypertonic options such as sodium phosphate and magnesium citrate work by causing large paracellular fluid shifts into the bowel lumen.23 These agents traditionally have been avoided in patients with comorbid renal disease, cardiac disease, hepatic disease, and those who are advanced in age.25 Sodium phosphate, in particular, has been documented as a cause of acute phosphate nephropathy, for which it carries an FDA black box warning. For this reason, sodium phosphate should not be used as a routine preparation option.26,27 Although caution should be used when considering a hypertonic preparation, some of the newer agents in this class, such as Clenpiq, have not demonstrated any significant effects on cardiac conduction,

magnesium levels, renal function, or glucose levels, even when used in populations with chronic kidney disease and diabetes.28,29 Further research on hypertonic agents highlights their comparable safety profiles and favorability among patients, suggesting the potential for increased use in the future.30 Although hypotonic PEG-3350 with a sports drink is considered safe, there have been documented reports of prepinduced hyponatremia occurring at higher rates than with traditional PEG, albeit infrequently and possibly with minimal clinical consequence.31 Although PEG-3350 with a sports drink lacks a significant amount of long-term safety data because it is not FDA approved, historically, gastroenterologists have preferred this option before colonoscopy in pregnant patients, and it may be considered, if necessary.

Special Populations There is limited literature guiding bowel preparation selection in special populations, such as patients with IBD, older adults, and pregnant and lactating women.

Inflammatory Bowel Disease Most bowel preparation studies exclude patients with IBD. Furthermore, patients with a history of ulcerative colitis frequently are evaluated with flexible sigmoidoscopy and receive minimal oral preparation, and those with Crohn’s disease can have additional challenges related to active inflammation, bowel resections, and stricturing disease.32 The few studies that compare different preparatory agents in IBD patients found minimal difference in efficacy, and lower volume options were associated with increased compliance, tolerance, and willingness to repeat the preparation in the future.33,34 Many of these studies are limited by the exclusion of patients with active or severe IBD, previous colonic resection, and recent or active GI bleeding, thus limiting any generalization of the results across a heterogeneous population of patients with IBD.35 An important consideration is knowing which agents to avoid in these patients. In trials of patients without IBD, preparation-induced mucosal lesions increased 10-fold with sodium phosphate or sodium picosulfate, magnesium, and citric acid regimens compared with PEG.36 This potential for strong osmotic laxatives to cause minor mucosal damage, potentially mimicking Crohn’s disease, has been well documented, leading to their scant use in patients with IBD.37 However, as newer agents continue to demonstrate safety, there may be a paradigm shift toward their use in patients with IBD whose inflammation is well controlled.38

Older Patients Older adults have higher rates of inadequate preparation, possibly related to diet, colonic transit time, increased comorbidities, and medications. 39 When comparing agents in this population, multiple studies seem to suggest improved success in older patients who are given the option of a lower-volume agent, with otherwise similar safety outcomes.40,41 One insightful study recommended a combined strategy for older adults at risk for inadequate preparation that includes a low-fiber diet for 3 days, a

split-dose regimen, and completion of preparation within 5 hours of colonoscopy start. This technique resulted in successful cleansing in 87.4% to 91.7% of patients, versus 45.6% when these strategies were not used.42

Pregnant and Lactating Patients Careful consideration also is needed when selecting a bowel purgative for pregnant and lactating patients, given the potential for fetal hypoxia, premature labor, trauma, and teratogenesis secondary to endoscopic evaluations.43 When feasible, clinicians should postpone exams until the postpartum period, although certain clinical situations such as GI bleeding, refractory diarrhea, or suspicion of a colon mass require urgent evaluation, as outlined by the 2012 ASGE guidelines.44 No comparative efficacy trials exist, but in light of the physiologic volume changes associated with pregnancy, avoiding fluid shifts is encouraged, so isotonic solutions such as PEG are more appropriate for these patients.45,46 Even the efficacy and safety of well-established prep regimens such as GoLytely have not been studied extensively in animal reproduction models, and it is not known whether these agents cause fetal harm or are excreted in human milk.47 Although the FDA is rolling out new categories for medication pregnancy and lactation labeling, according to the old nomenclature, both PEG and sodium phosphate are Category C (shows potential adverse effects on fetus but insufficient data exist for pregnant women).3,48 Nonetheless, PEG in particular has long been safely used in pregnancy to improve constipation and could be considered, if necessary.49 Historical trends show gastroenterologists prefer recommending PEG-based solutions before colonoscopy.50 For now, recommendations from GI societies are limited to tap water enemas before flexible sigmoidoscopy pending further large-scale studies.3,16

Bowel Preparation Timing Although the literature does not support one best agent, there are ample data to support split-dose preparation, a process in which half to three-fourths of the purgative is ingested the night before the procedure, with the remaining half to one-fourth completed the morning of the procedure. Split-dose preparation is associated with higher rates of adequate preparation, increased patient tolerance (less nausea and vomiting), improved detection of colonic lesions, and lower rates of incomplete or aborted exams.51-57 Despite its superiority in cleaning, a split-dose approach may not be acceptable for all patients, particularly those worried about sleep disturbance, travel interruption, or fecal incontinence on the way to the procedure. 58 Another option is sameday preparation, a process in which the entire purgative is ingested in the morning before an afternoon colonoscopy. Multiple large studies have demonstrated comparable cleanliness, cecal intubation rates, and ADR with same-day prep and split-dose regimens.59,60 Ultimately, the biggest timing consideration with either split-dose or same-day preparation is the “runway time,” defined as the interval between the last dose of laxative and the initiation of the exam. A large meta-analysis that included 20 studies and 10,341 patients found higher rates

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Table 3. Guidelines on Colonoscopy Preparation From Selected Professional Societies Parameter

US Multi-Society Task Force (2014)

Agent selection

• Selection should consider medical history, medications, and, if available, adequacy of bowel prep in prior colonoscopies • Split-dose 4 L PEG-ELS provides high-quality cleansing • In healthy nonconstipated patients, 4 L PEG-ELS is not superior to lower-volume PEG • OTC agents have variable efficacy depending on the agent, dose, timing, etc

Timing/dosing

• Use of a split-dose regimen is strongly recommended; second dose of split regimen should begin 46 h before exam with completion 2 h before start • Same-day regimens are acceptable alternatives for patients undergoing afternoon exams • Regardless of OTC selected, efficacy and tolerability are enhanced with split-dose regimen

Diet

• When using split dose, low-residue or full liquids until the evening before exam

Tolerability

• Split dose is associated with greater willingness to repeat regimen compared with day-before regimen • Low-volume agents are associated with greater willingness to undergo repeat colonoscopy

Education

• Oral and written patient instructions for all components of the prep, with emphasis on the importance of compliance, should be provided

High risk for prep failure/special populations

• Additional bowel purgatives should be considered in patients with risk factors for poor prep • Use low-volume prep or extended time delivery for high-volume prep after bariatric surgery • Tap water enemas should be used before sigmoidoscopy in pregnant women

Safety

• Although OTC regimens are generally safe, exercise caution when using these agents in certain populations (ie, magnesium-based preps should be avoided in patients with CKD) • Sodium phosphate regimens should be avoided in older patients, children <12 y, and in patients with known or suspected IBD

Adjunctive agents

• Routine use of adjunctive agents is not recommended

CKD, chronic kidney disease; IBD, inflammatory bowel disease; OTC, over the counter; PEG-ELS, polyethylene glycol electrolyte solution. Based on references 3, 16, and 17.

of adequate cleanliness with shorter runway times: less than 5 hours before the exam (94%), 6 to 10 hours prior (92%), and more than 11 hours before (85%). Shorter runway times also were associated with higher polyp detection rates compared with longer runway times (47% vs 30%).61 Practices should instruct patients to complete their preparation with “5 golden hours” of runway time and no later than 2 hours before the start of the procedure to minimize aspiration risk, according to guidelines by the American Society of Anesthesiologists (ASA).56,62

Diet Considerations Dietary recommendations related to bowel preparation typically involve using a clear liquid diet (CLD) or a low-residue diet (LRD) in the days leading up to the exam. An LRD is neither clearly defined nor consistently applied in clinical studies, but is loosely characterized as a low-fiber diet that restricts dietary fiber to fewer than 10 g per day.63-66 A large meta-analysis including 13 randomized controlled trials and 2,587 patients reported no difference between the adequacy of bowel prep with CLD versus LRD.67 Of note, patients reported fewer adverse effects and improved tolerability with LRD. In terms of duration of LRD, a metaanalysis of 6 randomized controlled trials including 2,469

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subjects compared 1-day LRD versus multiple-day LRD.68 They found no improvement in bowel prep, ADR, or withdrawal time in the extended LRD, so endoscopy units should consider 1-day LRD.

Patient and Provider Education In addition to patient-friendly educational handouts that are written at no higher than a sixth-grade level, visual presentations and reminder calls have been shown to significantly affect the adequacy of bowel prep and cecal intubation.69,70 Technology-based tools also appear to have a role in enhancing bowel preparation education, with computer-based education demonstrating noninferiority compared with nursing education.71 One pragmatic benefit of using computer- or internet-based strategies is lower time and cost burdens on clinical staff, with similar outcomes.72 Another approach already in the palm of patients’ hands includes smartphone apps and artificial intelligence, which may significantly improve bowel prep, ADR, and polyp detection.73,74 Any form of enhanced patient education (eg, cartoons, phone calls, mobile apps, etc) results in improved rates of detection of polyps, adenomas, and sessile serrated lesions.75 With an understanding that bowel cleanliness among

American Society for Gastrointestinal Endoscopy (2015)

European Society of Gastrointestinal Endoscopy (2019)

• Prep should be individualized based on efficacy, cost, safety, and tolerability balanced with the patient’s overall health, comorbid conditions, and preferences

• High- or low-volume PEG and non–PEG-based agents that have been clinically validated are acceptable

• Split-dose regimen for all patients • Same-day preps are acceptable for afternoon exams if taken within 38 h of exam

• Split-dose regimen for elective exams • For afternoon exams, same-day prep is acceptable • Start last dose within 5 h of exam, and complete at least 2 h before start of exam

• Low-residue diet

• Low-fiber diet day before exam

• Split dosing or same-day prep may enhance patient tolerance

• Tolerance not addressed directly

• Verbal counseling should be provided along with simple and easy-to-follow written instructions

• Enhanced instructions for bowel prep • Specific verbal or written instructions to patients and clinic staff caring for hospitalized patients to improve prep

• Consider intensive education more aggressive than standard prep for patients with predictors for inadequate prep

• No specific prep recommendations in patients with constipation • PEG-based regimen in IBD • PEG-based regimen vs tap water enemas in pregnancy

• Do not use sodium phosphate and magnesium citrate prep routinely • Do not use sodium phosphate or magnesium citrate in older adults with renal disease or those taking meds that alter renal blood flow or electrolyte excretion

• In patients at risk for hydroelectrolyte disturbances, choice of laxative should be individualized • Recommends against routine use of oral sodium phosphate

• No adjunctive agents routinely recommended

• Add oral simethicone to prep • Recommends against routine use of enemas for prep

inpatients preparing for colonoscopy is generally suboptimal to that of outpatients, targeting education toward inpatient providers and patients may improve outcomes.76 This could include the usage of a standardized dot phrase and/or targeted education of ward nurses and physicians in the form of leaflets and lectures.77,78 Ideally, all patients and providers could benefit from receiving enhanced education, but tailoring of resources to patients with lower education levels should be prioritized.79

Improving the Odds Recognizing which patients are at risk of having inadequate preparation and tailoring strategies accordingly will help increase rates of adequate bowel preparation above the 90% target. Older age, male sex, inpatient status, type 2 diabetes, hypertension, cirrhosis, narcotic use, chronic constipation, history of stroke, and tricyclic agent use all were associated with inadequate prep in a metaanalysis of 50,000 patients.80 Specifically, in older patients, a history of abdominal surgery, constipation, diabetes, dietary noncompliance, incomplete purgative intake, and inadequate exercise during preparation independently predicted inadequate bowel cleanliness.81 Several other well-documented risk factors include lower socioeconomic

class, afternoon colonoscopy, ASA class greater than III, pre-procedure nausea and vomiting, and obesity.82,83 Given the significant increase in use of glucagon-like peptide-1 receptor agonists, these agents also were recently found to negatively affect the BBPS.84 Several prediction tools accounting for many of these factors have been developed.85-87 Although early models had disappointing performance, with receiver operating characteristic curves in the 60s, more tools are emerging with improved results that may become more widespread in clinical use.88-90 A prospective, multicenter study of 1,000 patients in 10 Italian hospitals evaluated factors associated with negative symptoms during the bowel preparation process. According to a 36-question survey, being female (odds ratio [OR], 3.64), heavier working hours (OR, 1.13), previous GI symptoms (OR, 7.81), somatic symptoms (OR, 2.19), and a daybefore regimen (OR, 2.71) were associated with negative symptoms, whereas age older than 60 years and a baseline good mood were protective factors against negative symptoms.91 Recognizing these potential risk factors may help in the selection of the purgative agent and allow for extra education about what to expect during the preparation process.

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Conclusion Achieving high-quality bowel preparation is possible. When choosing an agent, discuss the various options with the patient and engage in a shared decisionmaking process, allowing them to help select a preparation that best aligns with their goals (taste, volume, cost). Use a split-dose regimen when possible, reserving

same-day preparation for afternoon exams only. Don’t forget the 5 golden hours or the low-fiber diet when counseling patients. Finally, be sure to leverage endoscopy unit staff and technology to enhance patient education, particularly in patients at high risk for inadequate preparation or a negative preparation experience based on known risk factors.

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Shaukat A, et al. Am J Gastroenterol. 2021;116(3):458-479.

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Rex DK, et al. Gastrointest Endosc. 2024;100(3):352-381.

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Johnson DA, et al. Gastroenterology. 2014;147(4):903-924.

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Joseph DA, et al. Cancer. 2016;122(16):2479-2486.

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Chan WK, et al. BMC Gastroenterol. 2011;11:86.

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Moein HR, et al. Cureus. 2021;13(6):e16065.

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Calderwood AH, et al. Gastrointest Endosc. 2015;81(3):691-699.

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Kluge MA, et al. Gastrointest Endosc. 2018;87(3):744-751.

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Kaminski MF, et al. N Engl J Med. 2010;362(19):1795-1803.

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Kaminski MF, et al. Gastroenterology. 2017;153(1):98-105.

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Clark BT, et al. Am J Gastroenterol. 2014;109(11):1714-1724.

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Dong MH, et al. Dig Dis Sci. 2011;56(7):2114-2119.

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Rex DK, et al. Am J Gastroenterol. 2002;97(7):1696-1700.

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SUFLAVE. Accessed February 10, 2025. https://www.suflave.com/

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Bhandari R, et al. J Clin Gastroenterol. 2023;57(9):920-927.

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European Society of Gastrointestinal Endoscopy (ESGE). Accessed February 10, 2025. https://www.esge.com/assets/downloads/pdfs/ guidelines/2019_a_0959_0505.pdf

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ASGE Standards of Practice Committee, et al. Gastrointest Endosc. 2015;81(4):781-794.

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Gu P, et al. Am J Gastroenterol. 2019;114(2):305-314.

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Jung Y, et al. J Korean Med Sci. 2024;39(48):e301.

20. Park JH, et al. J Clin Med. 2024;13(23):7493. 21.

Maida M, et al. Dig Liver Dis. Published online December 14, 2024. doi:10.1016/j.dld.2024.11.019

22. Serradesanferm A, et al. Gastrointest Endosc. 2025;101(1):158-167.

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Collatuzzo G, et al. Dig Liver Dis. 2022;54(11):1554-1560.

New Guidance Issued On HLD and Sterilization

Q

uestions about endoscope reprocessing abound: Will putting simethicone in an endoscope impede cleaning? Do duodenoscopes need two rounds of high-level disinfection in a row? What about sterilizing semi-critical devices associated with higher infection transmission risk, such as duodenoscopes? To address some of these common concerns, new multi-society guidance reviews and clarifies evidence on sterilization and HLD of reusable medical devices, accessories and patient care items, including lumened endoscopes.

‘This document can serve as a guide on what the evidence says is necessary to do, required to do and where is the evidence lacking.’ —Audrey Calderwood, MD, MS Geisel School of Medicine at Dartmouth, Lebanon, N.H.

Developed by the Society for Healthcare Epidemiology of America (SHEA) in partnership with seven professional organizations, including the American Society for Gastrointestinal Endoscopy (ASGE), Society of Gastroenterology Nurses and Associates (SGNA) as well as The Joint Commission (Infect Control Hosp Epidemiol. Published online 2025 Apr 28), the guidance follows the 2024 update of the 2008 CDC Guideline for Disinfection and Sterilization in Healthcare Facilities (doi:10.1017/ice.2025.41; cdc.gov/infection-control/hcp/disinfection-sterilization/updates.html). “Sometimes clinical practice just develops because of local culture or because someone heard something, or they thought this is what you’re supposed to do,” said guideline co-author Audrey Calderwood, MD, MS, who represented the ASGE in the partnership. “This document can serve as a guide on what the evidence says is necessary to do, required to do and where is the evidence lacking,” added Dr. Calderwood, a professor of medicine and the director of the Comprehensive Gastroenterology Program at Geisel School of Medicine at Dartmouth, in Lebanon, N.H. New recommendations include advice on interpreting manufacturers’ instructions for use (IFUs), point-of-use treatment, HLD of semi-critical devices, defoaming agents, storage and alternatives to HLD. The authors revised recommendations on assessing the effectiveness of reprocessing. “There’s a lot of misinterpretation … when you have these standards out there: Well, what do I follow? What is a must, what is a should, what is a think-about?” said Aaron Preston, RN, BSN, AL-CIP, CIC, a senior coordinator of infection prevention at Emory University Hospital Midtown, in Atlanta, who was not involved in developing the guidance. However, he said, a section detailing The Joint Commission’s hierarchical approach to infection prevention and control compliance was explained in an understandable way. In addition to the SHEA, ASGE and SGNA, organizations represented were the Association for Professionals in Infection Control and Epidemiology (APIC), the Association for the Advancement of Medical Instrumentation (AAMI), the Association of periOperative Registered Nurses (AORN), the Healthcare Sterile Processing

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Association (HSPA), and the Infectious Diseases Society of America (IDSA). The SHEA, APIC, ASGE, SGNA and IDSA endorsed the guidance, and the AAMI, AORN, HSPA and The Joint Commission did not. An AAMI spokesperson replied that its status as a “neutral convener” prohibited comment, and a Joint Commission spokesperson cited its policy not to endorse evidence-based guidelines of specialty societies or other organizations. The AORN and HSPA did not reply to an email from this publication requesting comment.

Reprocessing Duodenoscopes Double HLD became more common after mid-2010s outbreaks of carbapenem-resistant Enterobacteriaceae among patients who had undergone endoscopic retrograde cholangiopancreatography with duodenoscopes, but current evidence does not support policies requiring duodenoscopes to undergo double HLD or sterilization, the authors concluded. “People have been doing that out of caution to prevent risk of infection,” Dr. Calderwood said. “That’s probably not necessary.” The document takes a nuanced approach, recommending that facilities “begin developing an institutional process for converting from HLD to sterilization” for these devices. Furthermore, it states that facilities “may choose to evaluate sterilization along with other alternatives to HLD,” such as sterile single-use devices. “I think endoscopy units can feel safe and secure knowing that if high-quality, regular, high-level disinfection, which includes all the things—manual inspection, mechanical cleaning, putting it in the machine, etc.—if all of that is done in a high-quality way, at this time, no evidence suggests benefit from doing double, extra or something different,” Dr. Calderwood said.

Points of Contention Medical device safety expert Lawrence Muscarella, PhD, said the guidance was “fairly good” but expressed some misgivings. “A lot of the guidance made sense to me,” said Dr. Muscarella, who has published on outbreaks linked to contaminated reusable devices. “There were, though, a number of sections that did not.” Dr. Muscarella expressed concerns about what struck him as an unclear relationship between this document and the CDC guidelines. He also said he disagreed with the decision not to invite public comments or to issue a recommendation relating to testing the quality of water used in device processing. He cited a passage that stated that Pseudomonas was among several organisms cultured during pseudooutbreaks linked to contaminated rinse water but, according to the guidance, none were found to be clinically significant. “Endoscopes contaminated with waterborne gramnegative bacteria, including Pseudomonas, following reprocessing have been linked to multiple true patient infections. That is not consistent with what’s written in this paragraph,” Dr. Muscarella said. To be sure, he added, the problem has been reduced because hospitals generally filter the rinse water to remove

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‘I don’t want people to read that if there’s no recommendation, that means you don’t do the practice at all. I think what it means is that there’s more to be understood about frequency and impact to outcomes.’ —Aaron Preston, RN, BSN, AL-CIP, CIC Emory University Hospital Midtown, Atlanta

bacteria, “but filters don’t have alarms on them or bells that go off when they’re failing, so it can be unclear when they require changing unless periodic microbiological testing is performed.” In contrast, he said, the AAMI and his own publications have recognized “the importance of water quality across all stages of endoscope reprocessing.” Dr. Muscarella also expressed concerns with several other recommendations, including one deeming parts of semicritical instruments to be not critical for reprocessing purposes and some relating to immediate-use steam sterilization.

Knowledge Gaps and Unanswered Questions The authors did not find evidence to indicate that special drying cabinets prevent transmission of infection. “They might; they may not,” Dr. Calderwood said. “I think as long as the scopes are stored in a safe, clean and dry place and can be locked, that’s the main thing.” The committee made no recommendation regarding how long an endoscope can be stored before it should be processed again or replaced beyond following specific manufacturer IFUs, nor did it make a recommendation about routine monitoring with microbial cultures to assess HLD effectiveness. As for adding simethicone to a lumened semi-critical reusable device such as a colonoscope, the authors recommended following the IFUs and avoiding putting simethicone into the irrigation water bottle. In an appendix, the document lists knowledge gaps, including questions about lubricating agents and infection risk; removing non−water-soluble lubricants; boroscopes; and optimal retraining for staff who clean, process and maintain scopes. Mr. Preston pointed out that there aren’t enough data yet linking some interventions to patient outcomes and cautioned against automatically abandoning a practice about which the multisociety panel made no recommendation. “I don’t want people to read that if there’s no recommendation, that means you don’t do the practice at all,” he said. “I think what it means is that there’s more to be understood about frequency and impact [on] outcomes.” —Jenny Blair Dr. Calderwood and Mr. Preston reported no relevant financial disclosures. Dr. Muscarella reported a financial relationship with Ambu.

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Highlights of Updated EGD Quality Indicators Emphasis on documentation, including photodocumentation

T

he American Society for Gastrointestinal Endoscopy and American College of Gastroenterology Task Force on Quality in Endoscopy recently released updated

quality indicators for esophagogastroduodenoscopy, with new priority indicators related to photodocumentation of key landmarks and appropriate documentation metrics for EGD procedures used in an expanding list of disease states and conditions (Am J Gastroenterol 2024;119[9]:1781-1791).

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Lead author Rena Yadlapati, MD, the medical director of the Center for Esophageal Diseases at the University of California San Diego Health, told Gastroenterology & Endoscopy News that an update was needed because the care paradigms for EGD performance have evolved since the last iteration of the quality indicators. “EGD procedures are costly, require patients to take a day off of work and often to secure transportation, and carry the potential for risk,” she noted. “It is critical to ensure that EGDs are performed for an appropriate indication and that the optimal steps are taken during endoscopy to optimize diagnostic yield and therapeutic outcomes, all while minimizing risk.”

Dr. Yadlapati and her co-authors noted that while “there is little evidence to support the practice of photodocumentation in EGD, it is intuitive that this practice is a surrogate metric for mucosal cleaning, mucosal inspection including endoscopist blind spots, and a complete endoscopic examination, and serves as a reference in serial examinations and lesions referred for an endoscopic resection.” They added that photodocumentation is “well established” as a key indicator in colonoscopy and has been recommended in EGD by international organizations, including the European Society of Gastrointestinal Endoscopy and the World Endoscopy Organization.

Table. ASGE/ACG Task Force Priority Indicators for EGD Quality indicator

Performance target, %

Level of evidence

Frequency of photodocumentation of the esophagus, gastroesophageal junction, gastric cardia/fundus, corpus, incisura, antrum/pylorus, second portion of duodenum, and detected lesions in patients undergoing EGD

>90

3

Frequency of Los Angeles classification documentation when erosive esophagitis is present

>98

2C

Frequency with which the presence of at least 1 cm of endoscopically evident columnar mucosa is documented while obtaining biopsy samples to evaluate for BE

>95

1C

Frequency with which the extent of suspected or confirmed BE is documented using the Prague criteria in cases of suspected or confirmed BE

>95

1C+

Frequency with which, during EGD examination revealing peptic ulcers, at least 1 of the following stigmata is noted: active bleeding, nonbleeding visible vessels (pigmented protuberance), adherent clot, flat spot, or clean based

>98

1A

Frequency of endoscopic treatment delivered to ulcers with active spurting or oozing or with nonbleeding visible vessels

>90

1A

Frequency with which achievement of primary hemostasis in cases of attempted hemostasis of nonvariceal upper GI bleeding lesion is documented

>90

2A

Frequency of systematic biopsy sampling of the gastric corpus, antrum, and incisura in patients with known GPMCs, patients at high risk for gastric cancer or patients with an endoscopic appearance concerning for GPMCs

>90

2C

Frequency of administering high-dose proton pump inhibitor therapy (continuous or intermittently for 3 d) after successful endoscopic hemostatic therapy of a bleeding ulcer in patients without allergy or contraindication to the medication

>95

1A

Recommendations are graded from 1A to 3 based on methodologic strength supporting the evidence and clarity of benefit. Grade 1A implies a strong recommendation that can be applied to most clinical settings; grade 1C+ implies a strong recommendation that can apply to most practice settings in most situations; grade 1C implies an intermediate-strength recommendation that may change when stronger evidence is available; grade 2A implies an intermediate-strength recommendation in which the best action may differ depending on circumstances or patients’ or societal values; grade 2C implies a weak recommendation in which alternative approaches are likely to be better under some circumstances; and grade 3 implies a weak recommendation likely to change as data become available. BE, Barrett’s esophagus; EGD, esophagogastroduodenoscopy; GPMCs, gastric premalignant conditions. Based on Am J Gastroenterol 2024;119[9]:1781-1791.

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“Endoscopists should be mindful of cleansing and inspecting throughout the entire EGD exam and photodocument the landmark sites,” Dr. Yadlapati said, reflecting a similar evolution in colonoscopy practice. In addition to photodocumentation, the priority indicators include recommendations specific to common conditions, including erosive esophagitis, Barrett’s esophagus, peptic ulcer disease, upper GI bleeding and gastric premalignant conditions (Table).

‘It is critical to ensure that EGDs are performed for an appropriate indication and that the optimal steps are taken during endoscopy to optimize diagnostic yield and therapeutic outcomes, all while minimizing risk.’ —Rena Yadlapati, MD University of California San Diego Health

“In particular,” Dr. Yadlapati said, “there is a focus on high-quality screening and surveillance of pre-neoplastic conditions, including inspection with white light and chromoendoscopy, adherence to specific biopsy protocols, and emphasis on designating appropriate surveillance intervals.” Although it is not a priority indicator, she emphasized the recommendation that EGDs should be performed for an appropriate indication. “Ultimately, endoscopists should consider the goal outcome,” she explained. “For instance, eosinophilic esophagitis should be considered for a patient with dysphagia. For patients with gastric premalignant conditions, it is imperative to risk-stratify in order to guide the need for and timing of surveillance endoscopy, as well as to biopsy thoroughly, as these are associated with gastric cancer. For patients with upper GI bleeding, successful hemostasis is associated with reduced risk of recurrent GI bleeding and mortality.”

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Dr. Yadlapati said feedback on the updated quality indicators has been “very positive,” noting that the group has received questions about whether practices should modify their workflows to measure adherence. “In some cases, endoscopy software systems may need to be updated, for instance,” she said. The task force considered including new quality indicators focused on procedure and inspection time and neoplasia detection rate, Dr. Yadlapati added, but said the body of evidence was not able to support them. The group anticipates including these topics in future iterations, she said, “as well as … endobariatrics, third space endoscopy and the role of artificial intelligence,” which were beyond the scope of the present updates. Rajesh Keswani, MD, MS, the director of quality for Northwestern Medicine Digestive Health Center, in Chicago, described the update as “fantastic” and said it will guide clinical practice for years to come. “These indicators are comprehensive and, when possible, supported by high-quality data with references,” Dr. Keswani said. “I am very happy to see this update, as it has been many years since [quality indicators] were last published, and it is important that our indicators reflect the volume of research that has taken place since they were last developed.” Dr. Keswani praised the updated guidelines’ “strong emphasis” on using a consistent nomenclature when documenting findings, such as for eosinophilic esophagitis, erosive esophagitis and peptic ulcer disease. “This, unfortunately, still does not occur in practice,” he said. “The authors correctly emphasize that using these validated grading systems impacts both treatment and the prediction of future outcomes.” Dr. Keswani highlighted that the guidelines include “a nice cohort of quality metrics surrounding peptic ulcer bleeding” that run the gamut from pre-procedure management to postprocedure care. “Taken together, these indicators can inform a great quality improvement project,” he said. “For example, the indicators to avoid epinephrine monotherapy for bleeding peptic ulcer disease, ensure Helicobacter pylori testing and adhere to appropriate acid-suppression therapy can have both clinical and economic impacts.” —Ajai Srinivas Drs. Keswani and Yadlapati reported no relevant financial disclosures.

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