Gastroenterology and Endoscopy News - August 2021 by McMahon Group

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The Independent Monthly Newspaper for Gastroenterologists

Volume 72, Number 8 • August 2021

Cause for Optimism In Stubborn Problem Of Intestinal Fibrosis

HEPATOLOGY IN FOCUS

ntestinal fibrosis, one of the most stubborn challenges in managing inflammatory bowel disease, may soon meet its match. A raft of research into intestinal antifibrotics, the launch of a global consortium tackling the problem, and the first clinical trial of a novel antifibrotic are some of many causes for optimism, experts say. “There’s a lot happening now, and the future is bright for the treatment and prevention of fibrosis,” said Florian Rieder, MD, who heads a lab at the Lerner Research Institute at Cleveland Clinic in Ohio. An estimated 30% of patients with Crohn’s disease and 5% of those with ulcerative colitis develop symptomatic fibrostenosis, often requiring hospitalization and surgery, which itself leads to a cycle of strictures and surgeries. However, research presented at the 2021 virtual Digestive Disease Week, and several other developments are providing hope for patients at risk for intestinal fibrosis. In one study presented at DDW (abstract Su479), Dr. Rieder and his colleagues examined the effects of recombinant human milk fat globule-EGF factor 8 (rhMFGE8), which has antifibrotic effects in the liver and heart, on fibrosing and nonfibrosing intestinal tissues. They used mesenchymal cells taken from patients with Crohn’s disease and ulcerative colitis, as well as from healthy controls. After exposing the extracellular matrix (ECM) that promotes fibrosis—and more specifically the human intestinal myofibroblasts (HIMFs) that make up the ECM—to rhMFGE8, they found that expression of MFGE8 in fibrotic Crohn’s disease tissue was significantly elevated, but it did not lead to an antifibrotic effect. “This suggests that in Crohn’s disease, sensitizing HIMF

ew research has found that nearly half of patients who receive care at Veterans Health Administration hospitals have risk factors for liver disease. Yet, fewer than 10% of patients with these risk factors and markedly abnormal fibrosis scoring or transient elastography receive a diagnosis of cirrhosis.

The investigators hope to use these data to encourage population-level screening for advanced liver disease, an effort they say may ultimately enable earlier intervention. “Unfortunately, many of our patients with cirrhosis see Undiagnosed, page 14

New Dialysis Machine May Reverse Liver Failure

ope may be on the horizon for people who have acute-on-chronic liver failure, according to results from an early-phase international, multicenter study. Researchers have found that DIALIVE, a novel liver dialysis device, is safe and effective in this group of patients, significantly increasing the proportion

see Fibrosis, page 38

of them who recover from organ failure and shortening the time required to do so. “DIALIVE is a mechanical liver device, which hits at the heart of what we believe are the two most important pathobiological mechanisms which drive see DIALIVE, page 8

IN THE NEWS

EXPERT PICKS

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Zeposia for the treatment of UC

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REVIEW ARTICLE Cases From the Frontiers Of Endoscopic Ultrasound in 2021

see insert at 20

FDA APPROVAL

For your appropriate adult patients with Crohn’s disease (CD) for whom other therapies

Entyvio works through a gut-selective MOA by speciﬁcally binding to the α4β7 integrin and blocking its interaction with MAdCAM-1, which is mainly expressed on gut endothelial cells.1-7 Remission was evaluated at Week 52.1 Individual results may vary.

NEW CD PATIENTS CHOOSE ENTYVIO 8* INDICATIONS Adult Ulcerative Colitis (UC) ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active UC. Adult Crohn’s Disease (CD) ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active CD.

IMPORTANT SAFETY INFORMATION • ENTYVIO (vedolizumab) for injection is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients. • Infusion-related reactions and hypersensitivity reactions including anaphylaxis, dyspnea, bronchospasm, urticaria, ﬂushing, rash, and increased blood pressure and heart rate have been reported. These reactions may occur with the ﬁrst or subsequent infusions and may vary in their time of onset from during infusion or up to several hours post-infusion. If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment. • Patients treated with ENTYVIO are at increased risk for developing infections. Serious infections have been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis,

It’s the fastest growing ﬁrst-line biologic in CD 9† Biologics included Entyvio, Humira® (adalimumab), Remicade® (inﬂiximab), and Stelara® (ustekinumab)‡

IMPORTANT SAFETY INFORMATION (continued) salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding ENTYVIO in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. • Progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the post marketing setting (e.g., human immunodeﬁciency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out. Monitor patients for any new or worsening neurological signs or symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if conﬁrmed, discontinue ENTYVIO dosing permanently.

moderately to severely active ulcerative colitis (UC) or have not worked well enough or cannot be tolerated

See what Entyvio is made for at

EntyvioHCP.com/CDdata

IMPORTANT SAFETY INFORMATION (continued)

MAdCAM-1 = mucosal addressin cell adhesion molecule-1; MOA = mechanism of action.

• There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. ENTYVIO should be discontinued in patients with jaundice or other evidence of signiﬁcant liver injury.

* This information is derived from Symphony database of Entyvio medical and pharmacy claims from January 2020 to December 2020. †Based on an analysis of data in SHA database comparing patient counts from year-toyear absolute growth information from December 2018 to November 2020 with “ﬁrst line” deﬁned as a new start in patients with UC or CD who had no UC or CD biologic drug claims for the past 3 years. ‡Humira® (AbbVie Inc. Chicago, IL); Remicade® (Janssen Biotech, Inc. Horsham, PA); Stelara® (Janssen Biotech, Inc. Horsham, PA).

• Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines and may receive live vaccines if the beneﬁts outweigh the risks. • Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo): nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, inﬂuenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities.

References: 1. Entyvio (vedolizumab) Prescribing Information. Takeda Pharmaceuticals USA, Inc. 2. Briskin M, Winsor-Hines D, Shyjan A, et al. Am J Pathol. 1997;151(1):97-110. 3. Fedyk E, Wyant T, Yang LL, et al. Inflamm Bowel Dis. 2012;18(11):2107-2119. 4. Milch C, Wyant T, Xu J, et al. J Neuroimmunol. 2013;264:123-126. 5. Soler D, Chapman T, Yang LL, et al. J Pharmacol Exp Ther. 2009;330(3):864-875. 6. Wyant T, Leach T, Sankoh S, et al. Gut. 2015;64(1):77-83. 7. Wyant T, Fedyk E, Abhyankar B. J Crohns Colitis. 2016;10(12):1437-1444. 8. Data on file. Symphony Health Analysis Claims, March 2021. Takeda Pharmaceuticals USA, Inc. 9. Data on file. Fastest-growing biologic, January 2021. Takeda Pharmaceuticals USA, Inc.

Please see Brief Summary of Full Prescribing Information on adjacent pages.

Rather hear from a rep? Schedule a visit at EntyvioHCP.com/Rep

ENTYVIO is a trademark of Millennium Pharmaceuticals Inc., registered with the U.S. Patent and Trademark Office and is used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners. ©2021 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. Printed in U.S.A. US-VED-0925v1.0 05/21

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION ENTYVIO (vedolizumab) for injection, for intravenous use

nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 2).

FULL PRESCRIBING INFORMATION

Table 2. Adverse Reactions in ≥3% of ENTYVIO-Treated Patients and ≥1% Higher than in Placebo (UC Trials I and II* and CD Trials I and III*)

INDICATIONS AND USAGE ENTYVIO is indicated in adults for the treatment of: • moderately to severely active ulcerative colitis. • moderately to severely active Crohn’s disease. CONTRAINDICATIONS ENTYVIO is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate) [see Warnings and Precautions].

ENTYVIO† (N=1434)

Placebo‡ (N=297)

Nasopharyngitis Headache

13% 12%

7% 11% 10%

Adverse Reaction

Arthralgia

12%

Nausea

Pyrexia

Upper respiratory tract infection

Fatigue

WARNINGS AND PRECAUTIONS Infusion-Related Reactions and Hypersensitivity Reactions Infusion-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate [see Adverse Reactions]. These reactions may occur with the first or subsequent infusions of ENTYVIO and may vary in their time of onset from during infusion or up to several hours post-infusion.

Inﬂuenza

Back pain

If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment.

Rash

Pruritus

Infections Patients treated with ENTYVIO are at increased risk for developing infections [see Adverse Reactions]. The most commonly reported infections in clinical trials occurring at a rate greater on ENTYVIO than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection). Serious infections have also been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding treatment in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution when considering the use of ENTYVIO in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. For progressive multifocal leukoencephalopathy (PML), see Warnings and Precautions.

Cough

Bronchitis

Sinusitis

Oropharyngeal pain

Pain in extremities

*Data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included. † Patients who received ENTYVIO for up to 52 weeks. ‡ Patients who received placebo for up to 52 weeks.

Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohn’s disease trial, are similar to those listed in Table 2.

Progressive Multifocal Leukoencephalopathy PML, a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the postmarketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out.

Infusion-Related Reactions and Hypersensitivity Reactions

Monitor patients on ENTYVIO for any new onset, or worsening, of neurological signs and symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue dosing permanently.

In UC Trials I and II and CD Trials I and III, 4% of patients treated with ENTYVIO and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with ENTYVIO (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria and vomiting (each of these adverse reactions occurred in <1% in all patients treated with ENTYVIO) and no individual adverse reaction reported occurred at a rate above 1%. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Less than 1% of patients treated with ENTYVIO had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1%.

Liver Injury There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury [see Adverse Reactions]. Live and Oral Vaccines Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks. There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO [see Adverse Reactions]. ADVERSE REACTIONS The following topics are also discussed in detail in the Warnings and Precautions section: • Infusion-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions] • Liver Injury [see Warnings and Precautions]

Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following ENTYVIO administration in clinical trials [see Warnings and Precautions]. In UC Trials I and II and Crohn’s Trials I and III, one case of anaphylaxis [one out of 1,434 patients treated with ENTYVIO (0.07%)] was reported by a Crohn’s disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone.

In clinical trials, for patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical treatment (e.g., antihistamine, hydrocortisone and/or acetaminophen) prior to next infusion. Infections In UC Trials I and II and CD Trials I and III, the rate of infections was 0.85 per patient-year in the patients treated with ENTYVIO and 0.7 per patient-year in the patients treated with placebo [see Warnings and Precautions]. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis and urinary tract infection. Two percent of patients discontinued ENTYVIO due to infections. In UC Trials I and II and CD Trials I and III, the rate of serious infections was 0.07 per patient-year in patients treated with ENTYVIO and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohn’s disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohn’s disease patients. Over 48 months, there was no increase in the rate of serious infections. In controlled- and open-label long-term extension trials in adults treated with ENTYVIO, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.

The data described below reflect exposure to ENTYVIO in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years.

In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock, was reported in four of 1,434 (0.3%) patients treated with ENTYVIO and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohn’s disease patients treated with ENTYVIO died due to reported sepsis or septic shock; both patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open-label, long-term extension trial, additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported. The rate of sepsis in patients with ulcerative colitis or Crohn’s disease receiving ENTYVIO was two per 1,000 patient-years.

The safety data described in Table 2 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included.

In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with ENTYVIO. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States, and none of the patients had extrapulmonary manifestations.

In these trials, 1,434 patients received ENTYVIO 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn’s disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III).

Liver Injury

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.

Adverse reactions were reported in 52% of patients treated with ENTYVIO and 45% of patients treated with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD Trials I and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with ENTYVIO compared to 4% of patients treated with placebo (UC Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with ENTYVIO and 9% with placebo). The most common adverse reactions (reported by ≥3% of patients treated with ENTYVIO in the UC Trials I and II and CD Trials I and III combined group and ≥1% higher than in combined placebo group) were

There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO [see Warnings and Precautions]. In UC Trials I and II and CD Trials I and III, three patients reported serious adverse reactions of hepatitis, manifested as elevated transaminases with or without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five ENTYVIO doses; however, based on case report information it is unclear if the reactions indicated drug-induced or autoimmune etiology. All patients recovered following discontinuation of therapy with some requiring corticosteroid treatment. In controlled trials, the incidence of ALT and AST elevations ≥3x ULN was <2% in patients treated with ENTYVIO and in patients treated with placebo. In the open-label trial, one additional case of serious hepatitis was observed.

Malignancies In UC Trials I and II and CD Trials I and III, malignancies (excluding dysplasia and basal cell carcinoma) were reported in six of 1,434 (0.4%) patients treated with ENTYVIO, including colon cancer (n=2), transitional cell carcinoma (n=1), breast cancer (n=1), carcinoid tumor of the appendix (n=1) and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%) patients treated with placebo (squamous cell carcinoma). Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open-label long-term extension trial included B-cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer and squamous cell carcinoma. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited. Live and Oral Vaccines There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO. In a placebo-controlled study of healthy volunteers, 61 subjects were given a single ENTYVIO 750 mg dose (2.5 times the recommended dose), and 62 subjects received placebo followed by intramuscular vaccination with Hepatitis B surface antigen and oral cholera vaccine. After intramuscular vaccination with three doses of recombinant Hepatitis B surface antigen, those treated with ENTYVIO did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to ENTYVIO did have lower seroconversion rates and anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in patients is unknown.

Lactation Risk Summary Available published literature suggests the presence of vedolizumab in human milk. The effects of local gastrointestinal exposure and expected low systemic exposure to vedolizumab on the breastfed infant are unknown. There are no data on the effects of vedolizumab on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENTYVIO and any potential adverse effects on the breastfed infant from ENTYVIO or from the underlying maternal condition. Pediatric Use Safety and effectiveness of ENTYVIO in pediatric patients have not been established. Geriatric Use Clinical trials of ENTYVIO did not include sufficient numbers of subjects aged 65 and over (46 Crohn’s and ulcerative colitis patients aged 65 and over were treated with ENTYVIO during controlled Phase 3 trials) to determine whether they respond differently from younger subjects. However, no overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Manufactured by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015

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 to vedolizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

U.S. License No. 1898

In UC Trials I and II and CD Trials I and III, in patients who received ENTYVIO, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than five half-lives after last dose). During treatment, 56 of 1,434 (4%) of patients treated with ENTYVIO had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive (at two or more study visits) for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody and available vedolizumab concentration data, six had undetectable and two had reduced vedolizumab concentrations. None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials.

For more information, go to www.ENTYVIO.com or call 1-877-TAKEDA-7 (1-877-825-3327).

Postmarketing Experience The following adverse reactions have been identified during post-approval use of ENTYVIO. 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. Immune system disorders: Anaphylaxis [see Warnings and Precautions] DRUG INTERACTIONS Natalizumab Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab. TNF Blockers Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers. Live Vaccines Live vaccines may be administered concurrently with ENTYVIO only if the benefits outweigh the risks [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENTYVIO during pregnancy. Information about the registry can be obtained by calling 1-877-TAKEDA7 (1-877-825-3327). Risk Summary Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified an ENTYVIO associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy (see Clinical Considerations). No fetal harm was observed in animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations 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 miscarriage is 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 (IBD) 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 ENTYVIO administered during pregnancy could affect immune responses in the in utero exposed newborn and infant. The clinical significance of low levels of ENTYVIO in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Data Animal Data A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100 mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100 mg/kg (about 20 times the recommended human dosage).

Revised: March 2020 ENTYVIO is a trademark of Millennium Pharmaceuticals Inc. and is used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners. ©2014 – 2020 Takeda Pharmaceuticals America, Inc. VMB245 R4_Brf04/20

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Vol. 72, No. 8

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EDITORIAL ADVISORY BOARD

Look for the compass rose for these potentially practice-altering articles.

Be alert to PVT in hospitalized cirrhotics ➣ See page 16

ANDREW ALBERT, MD, MPH Chicago, Illinois

HARISH K. GAGNEJA, MD Austin, Texas

MANOOP S. BHUTANI, MD Houston, Texas

FRANK G. GRESS, MD New York, New York

BROOKS D. CASH, MD Houston, Texas

VIVEK KAUL, MD, FACG, FASGE, AGAF Rochester, New York

ALINE CHARABATY, MD, AGAF Washington, D.C. AUSTIN CHIANG, MD, MPH Philadelphia, Pennsylvania ALAN F. CUTLER, MD Farmington Hills, Michigan

ACG issues new C. diff guidelines

➣ See page 26

Roughly one-third of IBD patients stop biologics within 18 months

➣ See page 29

GARY R. LICHTENSTEIN, MD Philadelphia, Pennsylvania JENIFER R. LIGHTDALE, MD, MPH Worcester, Massachusetts

KLAUS MERGENER, MD, PHD, MBA Tacoma, Washington SATISH RAO, MD, PHD Augusta, Georgia JOEL E. RICHTER, MD Tampa, Florida DAVID ROBBINS, MD New York, New York ELLEN J. SCHERL, MD New York, New York PRATEEK SHARMA, MD Kansas City, Kansas

DANA J. LUKIN, MD, PHD, FACG New York, New York

JEROME H. SIEGEL, MD New York, New York

PETER R. MCNALLY, DO Fort Carson, Colorado

ASHWANI K. SINGAL, MD, MS Sioux Falls, South Dakota

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Live Cell Bank Could Pinpoint Individualized IBD Therapies

esearchers at Weill Cornell Medicine in New York City believe their leading-edge repository of tissue samples can generate more answers for clinicians who treat children with inflammatory bowel disease. In place of snap-frozen samples, Weill Cornell’s IBD biobank uses cryopreservation to keep cell samples alive and study them over the long term. The team at Weill Cornell actually prefers to call their biobank a Live Cell Bank to distinguish it from other biobanks that don’t work with live cells, said Robbyn Sockolow, MD, the chief of the Division of Pediatric Gastroenterology and Nutrition. “The science behind what we do is really phenomenal. We have a true partnership with basic scientists,” she said. Established in 2015, the biobank now contains samples from over 2,000 patients, nearly 700 of them pediatric. Around 150 are returning donors, giving the team at Weill Cornell the ability to conduct longitudinal studies. The team collects a range of samples from donors during the colonoscopy, including peripheral blood and cryopreserved peripheral blood mononuclear cells, immune cells from the lamina propria for functional studies, and biopsy tissues from the intestinal epithelium for transcriptome and proteomic analyses. Stool samples also are collected for viral, fungal and bacterial microbiome analysis. “We can create a fairly comprehensive picture using all these platforms,” David Artis, PhD, the director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell, said. “On a number of levels, we’re getting a better understanding of the heterogeneity of the disease.” Until recently, gastroenterologists have had limited ability to profile IBD. Fresh samples had to be tested immediately, which prevented extensive profiling or more complicated study designs. Snap freezing preserved but also killed samples. The ability to preserve live cells means researchers have more time to study the nuances of an individual’s disease. There are three recognized types of pediatric IBD, but Dr. Artis said he expects that number to grow, thanks to research using the biobank. “The way this is being done at Weill really affords the ability to have patients’ samples studied in a very detailed way,” Scott Snapper, MD, PhD, the chief of gastroenterology, hepatology and nutrition at Boston Children’s Hospital, said. The team can essentially

‘We can create a fairly comprehensive picture using all these platforms. On a number of levels, we’re getting a better understanding of the heterogeneity of the disease.’ —David Artis, PhD, Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine

grow “mini guts” in a dish based on a single patient, he said, and learn the specific underpinnings of their disease. More than just understanding IBD, the biobank is a “resource that would allow us to do preliminary translational research with patient samples,” Dr. Artis said. That includes testing different treatments on a patient’s samples to identify the most effective treatment for their individual disease. “For IBD patients, it’s currently unclear what medicine to give what patient at what time,” Dr. Snapper, who is not directly involved in the project, said. Finding the right treatment for a given IBD patient is trial and error. It’s a physician’s best guess based on available trends and data. But Weill Cornell’s biobank could allow them to ascertain whether a patient has certain molecular signatures.

In Search of: Personalized IBD Therapies Researchers have already identified a few predictive genetic markers for certain IBD therapies. For instance, a 2017 study in Nature Medicine reported that oncostatin M predicted failure of anti–tumor necrosis factor agents. Another study in Gastroenterology found that in patients who didn’t respond to antiTNF agents, higher baseline serum concentrations of interleukin-22 were associated with a greater likelihood of response to MEDI2070. But these markers have never been studied as a part of treatment choice, Dr. Snapper said. The hope, however, is that Weill Cornell will soon be able to tell—based on a patient’s extensive profile of genetic markers, microorganisms, RNAs, proteins and metabolites—which treatment fits best. Getting the treatment right for patients early on could make all the difference in their long-term health, Dr. Sockolow said. The correct treatment in the first

ll the h inflammation i fl i few months of symptoms can quell and prevent damage, essentially restoring the patient’s health back to their pre-IBD state, she said. But if early treatments aren’t successful, fibroblasts can form and lead to more lasting damage. The same kind of translational research also may aid the investigation of nutritional interventions in IBD. “We would love for diet to participate way more in IBD treatment, but we are still in the infancy” stage, Dr. Sockolow said. She said parents would leap at the opportunity to employ nonpharmacologic interventions. But because of heterogeneity of the disease and the challenge of human nutritional studies, making broad nutritional recommendations is difficult. But certain strategies could be very effective on an individual basis. Dr. Artis is particularly interested in looking at different fiber types and contents. Highfiber diets have worked wonders in mouse models, he said, but such diets are controversial because many recommendations for IBD call for patients to avoid fiber. It’s likely that it comes down to the specific fiber type, because “some can activate the immune system and some can switch the immune system off,” he said. That’s something they could eventually examine on a patient-by-patient basis. Right now, the gastroenterologists and researchers at Weill Cornell are collecting samples and analyzing them extensively. There’s enormous potential for research and clinical practice, Dr. Snapper said, but “until you—in a prospective way—test your hypothesis, until you actually do the study, you don’t know.” Still, he expressed confidence in the team carrying the project forward: “They have a star-studded group of investigators and clinicians. There are maybe a half a dozen groups around the world that can do that sort of thing, and they’re one of them.” —Donavyn Coffey

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

DIALIVE continued from page 1

HEPATOLOGY IN FOCUS Parenteral nutrition and liver injury page 15 ‘The gut also serves as a major regulatory gateway controlling molecular trafficking, and seems intimately involved in systemic health and disease states via gutsystemic signaling.’ —Ajay Jain, MD, DNB, MHA

Postmenopausal Women and NAFLD Fibrosis page 17 ‘Postmenopausal women with NAFLD are a high-risk group of patients.’ —Maya Balakrishnan, MD

further organ failure in patients with acute-on-chronic liver failure,” said Banwari Agarwal, MBBS, MD, a consultant in critical care medicine at the Royal Free Hospital in London. “First, the device removes a patient’s dysfunctional albumin and infuses fresh albumin into the patient. Second, it adsorbs circulating endotoxin, which leads to a significant attenuation of systemic inflammation and has a direct impact on recovery of other organ failure.” To test the safety and efficacy of the DIALIVE device, Dr. Agarwal and his colleagues enrolled 32 patients with alcoholic cirrhosis into the trial. Participants in the DIALIVE group were required to undergo a minimum of three treatment sessions to be evaluable. In total, 17 patients (13 men; mean age, 49 years) were treated with the dialysis device. These patients had a mean CLIF-OF (Chronic Liver Failure Consortium–Organ Failure) score of 10.3 and a mean CLIF-C ACLF (Chronic Liver Failure Consortium–Acute-onChronic Liver Failure) score of 48.6. The remaining 15 participants (13 males; mean age, 49.1 years)—all of whom were treated with standard of care—had a mean CLIF-OF score of 9.9 and a mean CLIF-C ACLF score of 47.0. Liver dialysis therapy was administered for a median of three sessions (range, one to five) in first three days, for a median of eight hours (range, seven to 12) each. “I’m very glad to report that the overall safety data from the study have been quite promising, with serious adverse events very similar in the two arms,” Dr. Agarwal said in a presentation at the International Liver Congress 2021 (abstract GS-1997). Roughly two-thirds of patients (64.7%) in the treatment group experienced serious adverse events, compared with 53.3% of those in the standard-of-care group. Five patients in the dialysis group and four in the standardof-care group died after three months.

‘Fascinating and Fantastic’ Dr. Agarwal acknowledged that the study cohort was relatively small, but he said the efficacy data are a strong signal that patients treated with DIALIVE were significantly more likely to recover and return to the pre-illness levels of liver and other organ function. “The performance of the device and what it translated to in terms of clinical outcomes were fascinating and fantastic,” he said. The researchers found that at day 10, patients in the liver dialysis group experienced significant improvements in both liver (P=0.045) and brain (P< 0.001) subscores of the CLIF-OF scale. By comparison, those in the standard-of-care group had deterioration of the lung subscore (P=0.002), resulting in a significant positive overall treatment effect of the DIALIVE on CLIFOF (P=0.043). With respect to ACLF grade, 66.7% of DIALIVE patients reached ACLF 0, significantly more than the 33.3% of those receiving standard care (P=0.0357). Liver dialysis patients also reached ACLF 0 2.8 times faster than those who received standard care (P=0.059). Similar results were observed for CLIF-C ACLF

‘The device rremoves a patient’s d dysfunctional albumin a and infuses fresh a albumin into the p patient. [Then] it adsorbs circulating endotoxin, which leads to a significant attenuation of systemic inflammation and has a direct impact on recovery of other organ failure.’ —Banwari Agarwal, MBBS, MD, Royal Free Hospital, London

scores. The mean score for liver dialysis patients at day 10 was 5.4 points lower than for patients in the standard-care group (P=0.064), according to the researchers. Scores on the Model for End-Stage Liver Disease scale also were significantly lower among DIALIVE patients at both day 5 (P=0.049) and day 10 (P=0.028), they reported. The findings provide a springboard for later-phase clinical trials of the DIALIVE device, Dr. Agarwal said. “The short-term outlook for patients with acute-onchronic liver failure is abysmal with the current standard of care,” he said. “But with DIALIVE, two-thirds of patients achieved resolution to their baseline liver illness, along with significant improvement in extrahepatic organ function.” Tobias Böttler, MD, an attending physician at the University Hospital Freiburg, in Germany, said the new results were encouraging, “particularly since liver replacement therapies have largely failed in clinical trials so far. We need to test this device in larger patient cohorts with different disease etiologies and identify the specific characteristics of patients that benefit from this therapy.” —Michael Vlessides Drs. Agarwal and Böttler reported no relevant financial disclosures.

Don’t accept less—

choose VEMLIDY

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Not actual patients.

INDICATION VEMLIDY is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease.

IMPORTANT SAFETY INFORMATION BOXED WARNING: POSTTREATMENT SEVERE ACUTE EXACERBATION OF HEPATITIS B • %JTDPOUJOVBUJPO PG BOUJ IFQBUJUJT # UIFSBQZ JODMVEJOH 7&.-*%: NBZ SFTVMU JO TFWFSF BDVUF FYBDFSCBUJPOT PG IFQBUJUJT # )FQBUJD GVODUJPO TIPVME CF NPOJUPSFE DMPTFMZ XJUI CPUI DMJOJDBM BOE MBCPSBUPSZ GPMMPX VQ GPS BU MFBTU TFWFSBM NPOUIT JO QBUJFOUT XIP EJTDPOUJOVF BOUJ IFQBUJUJT # UIFSBQZ JODMVEJOH 7&.-*%: *G BQQSPQSJBUF SFTVNQUJPO PG BOUJ IFQBUJUJT # UIFSBQZ NBZ CF XBSSBOUFE

Please see Brief Summary of full Prescribing Information for VEMLIDY, including BOXED WARNING, on the following pages.

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Mean baseline plasma HBV DNA was 5.8 log10 IU/mL in Trial 108 and 7.6 log10 IU/mL in Trial 110.1 1SJNBSZ Fƍ DBDZ FOEQPJOU The proportion of patients with HBV DNA <29 IU/mL and noninferiority to TDF (10% margin; 95% CI approach) at Week 48 for both trials.1-3 5IF NPTU DPNNPO BEWFSTF SFBDUJPOT JODJEFODF Ƈ BMM HSBEFT BU 8FFL XFSF IFBEBDIF BCEPNJOBM QBJO DPVHI CBDL QBJO GBUJHVF OBVTFB arthralgia, diarrhea, and dyspepsia.4

IMPORTANT SAFETY INFORMATION 8BSOJOHT BOE 1SFDBVUJPOT • 3JTL PG %FWFMPQNFOU PG )*7 3FTJTUBODF JO )#7 )*7 $PJOGFDUFE 1BUJFOUT Due to this risk, VEMLIDY alone should not be used for the USFBUNFOU PG )*7 JOGFDUJPO 4BGFUZ BOE Fƍ DBDZ PG 7&.-*%: IBWF OPU CFFO FTUBCMJTIFE JO )#7 )*7 DPJOGFDUFE QBUJFOUT )*7 BOUJCPEZ UFTUJOH TIPVME CF PƊ FSFE UP BMM )#7 JOGFDUFE QBUJFOUT CFGPSF JOJUJBUJOH UIFSBQZ XJUI 7&.-*%: BOE JG QPTJUJWF BO BQQSPQSJBUF BOUJSFUSPWJSBM DPNCJOBUJPO regimen that is recommended for HBV/HIV-1 coinfected patients should be used. • /FX 0OTFU PS 8PSTFOJOH 3FOBM *NQBJSNFOU Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue VEMLIDY in patients who develop clinically TJHOJƋ DBOU EFDSFBTFT JO SFOBM GVODUJPO PS FWJEFODF PG 'BODPOJ TZOESPNF .POJUPS SFOBM GVODUJPO JO BMM QBUJFOUT Ŝ 4FF %PTBHF BOE "ENJOJTUSBUJPO • -BDUJD "DJEPTJT BOE 4FWFSF )FQBUPNFHBMZ XJUI 4UFBUPTJT Fatal cases have been reported with the use of nucleoside analogs, including tenofovir EJTPQSPYJM GVNBSBUF 5%' %JTDPOUJOVF 7&.-*%: JG DMJOJDBM PS MBCPSBUPSZ Ƌ OEJOHT TVHHFTUJWF PG MBDUJD BDJEPTJT PS QSPOPVODFE IFQBUPUPYJDJUZ develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations.

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%SVH *OUFSBDUJPOT • Coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and the risk of adverse reactions. • $PBENJOJTUSBUJPO PG 7&.-*%: JT OPU SFDPNNFOEFE XJUI UIF GPMMPXJOH PYDBSCB[FQJOF QIFOPCBSCJUBM QIFOZUPJO SJGBCVUJO SJGBNQJO SJGBQFOUJOF PS 4U +PIOşT XPSU 4VDI DPBENJOJTUSBUJPO JT FYQFDUFE UP EFDSFBTF UIF DPODFOUSBUJPO PG UFOPGPWJS BMBGFOBNJEF SFEVDJOH UIF UIFSBQFVUJD FƊ FDU PG 7&.-*%: %SVHT UIBU TUSPOHMZ BƊ FDU 1 HMZDPQSPUFJO 1 HQ BOE CSFBTU DBODFS SFTJTUBODF QSPUFJO #$31 BDUJWJUZ NBZ MFBE UP DIBOHFT JO 7&.-*%: absorption. $POTVMU UIF GVMM QSFTDSJCJOH JOGPSNBUJPO GPS 7&.-*%: GPS NPSF JOGPSNBUJPO PO QPUFOUJBMMZ TJHOJƋ DBOU ESVH JOUFSBDUJPOT JODMVEJOH DMJOJDBM comments.

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Median change from baseline to Week 96 in eGFRȾɂ was mL/min in the VEMLIDY group (n=790) and mL/min in those receiving TDF (n=390) in pivotal trials.1,4

The mean percentage change in BMD from baseline to Week 96 was with VEMLIDY (n=746) compared to with TDF (n=371) at the lumbar spine, and (n=740) compared to (n=369) at the total hip in pivotal trials.1,4

Median baseline eGFRȾɂ of 106 mL/min and 105 mL/min for VEMLIDY and TDF, respectively.1

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Mean changes from baseline in low-density lipoprotein cholesterol (LDL-C) (fasted) and triglycerides (TG) (fasted) at Week 96 were +7 mg/dL and +13 mg/dL for VEMLIDY, versus -10 mg/dL and -7 mg/dL for TDF.1 1JWPUBM USJBM EFTJHOT 5IF Fƍ DBDZ BOE TBGFUZ PG 7&.-*%: NH PODF EBJMZ JO UIF USFBUNFOU PG DISPOJD IFQBUJUJT # JO BEVMUT XJUI DPNQFOTBUFE MJWFS EJTFBTF XFSF FWBMVBUFE JO SBOEPNJ[FE EPVCMF CMJOE BDUJWF DPOUSPMMFE OPOJOGFSJPSJUZ USJBMT 5SJBM / )#F"H USFBUNFOU OB®WF BOE USFBUNFOU FYQFSJFODFE QBUJFOUT BOE 5SJBM / )#F"H USFBUNFOU OB®WF BOE USFBUNFOU FYQFSJFODFE QBUJFOUT a 5IF QSJNBSZ Fƍ DBDZ FOEQPJOU GPS CPUI USJBMT XBT the proportion of patients with plasma HBV DNA levels below 29 IU/mL at Week 48.1-3 a

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IMPORTANT SAFETY INFORMATION %PTBHF BOE "ENJOJTUSBUJPO • 5FTUJOH 1SJPS UP *OJUJBUJPO HIV infection. • 1SJPS UP PS 8IFO *OJUJBUJOH BOE %VSJOH 5SFBUNFOU On a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. • %PTBHF JO "EVMUT 1 tablet taken once daily with food. • 3FOBM *NQBJSNFOU Not recommended in patients with end stage renal disease (ESRD; eCrCl <15 mL/min) who are not receiving chronic hemodialysis; in patients on chronic hemodialysis, on hemodialysis days, administer VEMLIDY after completion of hemodialysis treatment. • )FQBUJD *NQBJSNFOU Not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment. Please see Brief Summary of full Prescribing Information for VEMLIDY, including BOXED WARNING, on the following pages. 3FGFSFODFT 7&.-*%: 1SFTDSJCJOH *OGPSNBUJPO 'PTUFS $JUZ $" (JMFBE 4DJFODFT *OD .BSDI Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of QBUJFOUT XJUI )#F"H OFHBUJWF DISPOJD IFQBUJUJT # WJSVT JOGFDUJPO B SBOEPNJTFE EPVCMF CMJOE QIBTF OPO JOGFSJPSJUZ USJBM Lancet Gastroenterol Hepatol Chan HLY, Fung S, Seto WK, et al; and the GS64 JOWFTUJHBUPST 5FOPGPWJS BMBGFOBNJEF WFSTVT UFOPGPWJS EJTPQSPYJM GVNBSBUF GPS UIF USFBUNFOU PG )#F"H QPTJUJWF DISPOJD IFQBUJUJT # WJSVT JOGFDUJPO B SBOEPNJTFE EPVCMF CMJOE QIBTF OPO JOGFSJPSJUZ USJBM Lancet Gastroenterol Hepatol 4 %BUB PO Ƌ MF (JMFBE 4DJFODFT *OD

VEMLIDY® (tenofovir alafenamide) 25 mg tablets, safety and efﬁcacy of VEMLIDY have not been established to receive blinded treatment through Week 120 was in patients coinfected with HBV and HIV-1. HIV antibody similar to that at Week 96. The safety proﬁle of VEMLIDY for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx only. WARNING: POSTTREATMENT SEVERE ACUTE EXACERBATION OF HEPATITIS B Discontinuation of anti-hepatitis B therapy, including VEMLIDY, may result in severe acute exacerbations of hepatitis B. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VEMLIDY. If appropriate, resumption of anti-hepatitis B therapy may be warranted [see Warnings and Precautions].

INDICATIONS AND USAGE VEMLIDY is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease.

DOSAGE AND ADMINISTRATION Also see Warnings and Precautions and Use in Speciﬁc Populations Testing: Prior to initiation, test patients for HIV-1 infection; VEMLIDY alone should not be used in patients with HIV-1 infection. Prior to or when initiating VEMLIDY, and during treatment with VEMLIDY on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Dosage in Adults: One tablet (25 mg) taken orally once daily with food. Renal Impairment: No dosage adjustment is required in patients with estimated creatinine clearance greater than or equal to 15 mL per minute, or in patients with end stage renal disease (ESRD; estimated creatinine clearance below 15 mL per minute) who are receiving chronic hemodialysis. On days of hemodialysis, administer VEMLIDY after completion of hemodialysis treatment. VEMLIDY is not recommended in patients with ESRD who are not receiving chronic hemodialysis. Hepatic Impairment: No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh A). VEMLIDY is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Also see BOXED WARNING and Drug Interactions Severe Acute Exacerbation of Hepatitis B after Discontinuation of Treatment: Discontinuation of anti-hepatitis B therapy, including VEMLIDY, may result in severe acute exacerbations of hepatitis B. Patients who discontinue VEMLIDY should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. Risk of Development of HIV-1 Resistance in Patients Coinfected with HBV and HIV-1: Due to the risk of development of HIV-1 resistance, VEMLIDY alone is not recommended for the treatment of HIV-1 infection. The

testing should be offered to all HBV-infected patients before initiating therapy with VEMLIDY, and, if positive, an appropriate antiretroviral combination regimen that is recommended for patients coinfected with HIV-1 should be used. New Onset or Worsening Renal Impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events. Patients taking tenofovir prodrugs who have renal impairment and those taking nephrotoxic agents, including NSAIDs, are at increased risk of developing renal-related adverse reactions. Prior to or when initiating VEMLIDY, and during treatment with VEMLIDY on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue VEMLIDY in patients who develop clinically signiﬁcant decreases in renal function or evidence of Fanconi syndrome. Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with VEMLIDY should be suspended in any individual who develops clinical or laboratory ﬁndings suggestive of lactic acidosis or pronounced hepatotoxicity, including hepatomegaly and steatosis in the absence of marked transaminase elevations.

ADVERSE REACTIONS Also see BOXED WARNING and Warnings and Precautions In Adults with Chronic Hepatitis B and Compensated Liver Disease: The safety assessment of VEMLIDY was based on pooled data through the Week 96 data analysis from 1298 subjects in two randomized, double-blind, active-controlled trials, Trial 108 and Trial 110, in adults with chronic hepatitis B and compensated liver disease. Further safety assessment was based on pooled data from Trials 108 and 110 from subjects who continued to receive their original blinded treatment through Week 120 and additionally from subjects who received open-label VEMLIDY from Week 96 through Week 120. Based on the Week 96 analysis, the most common adverse reaction (all Grades) reported in at least 10% of subjects in the VEMLIDY group was headache. The proportion of subjects who discontinued treatment with VEMLIDY or TDF due to adverse reactions of any severity was 1.5% and 0.9%, respectively. Adverse Reactions: Adverse reactions (All Grades) reported in ≥5% of subjects receiving VEMLIDY through week 96 were: headache (12%), abdominal pain (9%), cough (8%), back pain (6%), fatigue (6%), nausea (6%), arthralgia (5%), diarrhea (5%), and dyspepsia (5%). The safety proﬁle of VEMLIDY in subjects who continued

in subjects who remained on VEMLIDY in the open-label phase through Week 120 was similar to that in subjects who switched from TDF to VEMLIDY at Week 96. Renal Laboratory Tests: In a pooled analysis of Trials 108 and 110 in adult subjects with chronic hepatitis B and a median baseline estimated creatinine clearance between 106 and 105 mL per minute (for the VEMLIDY and TDF groups, respectively), mean serum creatinine increased by less than 0.1 mg/dL and median serum phosphorus decreased by 0.1 mg/dL in both treatment groups at Week 96. Median change from baseline to Week 96 in estimated creatinine clearance was -1.2 mL per minute in the VEMLIDY group and -4.8 mL per minute in those receiving TDF. In subjects who remained on blinded treatment beyond Week 96 in Trials 108 and 110, change from baseline in renal laboratory parameter values in each group at Week 120 were similar to those at Week 96. In the open-label phase, median change in estimated creatinine clearance by Cockcroft-Gault method from Week 96 to Week 120 was -0.6 mL per minute in subjects who remained on VEMLIDY and +1.8 mL per minute in those who switched from TDF to VEMLIDY at Week 96. Mean serum creatinine and median serum phosphorus values at Week 120 were similar to those at Week 96 in subjects who remained on VEMLIDY and in subjects who switched from TDF to VEMLIDY. The long-term clinical significance of these renal laboratory changes on adverse reaction frequencies between VEMLIDY and TDF is not known. Bone Mineral Density Effects: In a pooled analysis of Trials 108 and 110, the mean percentage change in bone mineral density (BMD) from baseline to Week 96 as assessed by dual-energy X-ray absorptiometry (DXA) was -0.7% with VEMLIDY compared to -2.6% with TDF at the lumbar spine and -0.3% compared to -2.5% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 11% of VEMLIDY subjects and 25% of TDF subjects at Week 96. BMD declines of 7% or greater at the femoral neck were experienced by 5% of VEMLIDY subjects and 13% of TDF subjects at Week 96. In subjects who remained on blinded treatment beyond Week 96 in Trials 108 and 110, mean percentage change in BMD in each group at Week 120 was similar to that at Week 96. In the open-label phase, mean percentage change in BMD from Week 96 to Week 120 in subjects who remained on VEMLIDY was 0.6% at the lumbar spine and 0% at the total hip, compared to 1.7% at the lumbar spine and 0.6% at the total hip in those who switched from TDF to VEMLIDY. The long-term clinical significance of these BMD changes is not known. Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3-4) occurring in ≥2% of subjects receiving VEMLIDY in Trials 108 and 110 through week 96 were: ALT >5x ULN (8%); LDL-cholesterol (fasted) (>190 mg/dL) (6%), glycosuria ≥3+ (5%); AST >5x ULN (3%); creatine kinase ≥10x ULN (3%); serum amylase >2x ULN (3%). The overall incidence of blinded treatment ALT flares was similar between VEMLIDY (0.6%) and TDF (0.9%) through Week 96. ALT flares generally were not associated with coincident elevations in bilirubin,

occurred within the ﬁrst 12 weeks of treatment, and resolved without recurrence. Based on the Week 120 analysis, the frequencies of lab abnormalities in subjects who remained on VEMLIDY in the open-label phase were similar to those in subjects who switched from TDF to VEMLIDY at Week 96. Amylase and Lipase Elevations and Pancreatitis: At Week 96, in Trials 108 and 110, eight subjects treated with VEMLIDY with elevated amylase levels had associated symptoms, such as nausea, low back pain; abdominal tenderness, pain, and distension; and biliary pancreatitis and pancreatitis. Of these eight, two subjects discontinued VEMLIDY due to elevated amylase and/or lipase; one subject experienced recurrence of adverse events when VEMLIDY was restarted. No subject treated with TDF had associated symptoms or discontinued treatment. From Week 96 to Week 120, one additional subject who continued openlabel VEMLIDY and none of the subjects who switched from TDF to VEMLIDY had elevated amylase levels and associated symptoms. Serum Lipids: Mean changes from baseline in fasting serum lipids in subjects receiving VEMLIDY through week 96 were: total cholesterol: -1 [n=742] (baseline 188 mg/dL [n=835]); HDLcholesterol: -5 [n=740] (baseline 60 mg/dL [n=835]); LDL-cholesterol: +7 [n=741] (baseline 116 mg/dL [n=835]); triglycerides: +13 [n=743] (baseline 102 mg/ dL [n=836]); total cholesterol to HDL ratio: 0 [n=740] (baseline 3 mg/dL [n=835]). In the open-label phase, lipid parameters at Week 120 in subjects who remained on VEMLIDY were similar to those at Week 96. In subjects who switched from TDF to VEMLIDY, mean change from Week 96 to Week 120 in total cholesterol was 23 mg/dL, HDL-cholesterol was 5 mg/dL, LDL-cholesterol was 16 mg/dL, triglycerides was 30 mg/dL, and total cholesterol to HDL ratio was 0 mg/dL. In Virologically Suppressed Adult Subjects with Chronic Hepatitis B: The safety of VEMLIDY in virologically suppressed adults is based on Week 48 data from a randomized, double-blind, active-controlled trial (Trial 4018) in which subjects taking TDF at baseline were randomized to switch to VEMLIDY (N=243) or to continue their TDF treatment (N=245). Adverse reactions observed with VEMLIDY in Trial 4018 were similar to those in Trials 108 and 110. Changes from baseline in renal function, BMD, and lipid parameters in the VEMLIDY and TDF groups at Week 48 were similar to those observed in Trials 108 and 110 at Week 96. In Virologically Suppressed Adult Subjects with Chronic Hepatitis B and Renal Impairment: In an open-label trial (Trial 4035) in virologically suppressed adult subjects with chronic hepatitis B switching to VEMLIDY 25 mg, the safety of VEMLIDY was assessed in 78 subjects with moderate to severe renal impairment (estimated creatinine clearance between 15 and 59 mL per minute by Cockcroft-Gault method; Part A, Cohort 1) and 15 subjects with ESRD (estimated creatinine clearance below 15 mL per minute) receiving chronic hemodialysis (Part A, Cohort 2). The safety of VEMLIDY, including changes from baseline in renal function, BMD, and lipid parameters, was similar to that observed in clinical trials of VEMLIDY in subjects with compensated liver disease but without renal impairment.

Postmarketing Experience: The following adverse reactions have been identiﬁed during post approval use of VEMLIDY or other products containing tenofovir alafenamide. Because postmarketing events 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. Skin and Subcutaneous Tissue Disorders: Angioedema, urticaria. Renal and Urinary Disorders: Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome.

DRUG INTERACTIONS Also see Warnings and Precautions Potential for Other Drugs to Affect VEMLIDY: VEMLIDY is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP may lead to changes in tenofovir alafenamide absorption. Drugs that induce P-gp activity are expected to decrease plasma concentrations of TAF, which may lead to loss of therapeutic effect of VEMLIDY. Coadministration of VEMLIDY with other drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentration of TAF. Drugs Affecting Renal Function: Because tenofovir is primarily excreted by the kidneys by a combination of glomerular ﬁltration and active tubular secretion, coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, which may increase the risk of adverse reactions. Established and Other Potentially Significant Interactions: The drug interactions described are based on studies conducted with TAF or are predicted drug interactions that may occur with VEMLIDY. Information regarding potential drug-drug interactions with HIV antiretrovirals is not provided (see the Prescribing Information for emtricitabine/tenofovir alafenamide for interactions with HIV antiretrovirals). The list includes potentially signiﬁcant interactions but is not all inclusive. Alteration in dose or regimen may be recommended for the following drugs when coadministered with VEMLIDY: • Anticonvulsants: When coadministered with carbamazepine, the TAF dose should be increased to two tablets once daily. Coadministration of VEMLIDY with oxcarbazepine, phenobarbital, or phenytoin is not recommended. • Antimycobacterials: Coadministration of VEMLIDY with rifabutin, rifampin or rifapentine is not recommended. • Herbal Products: Coadministration of VEMLIDY with St. John’s wort is not recommended. Consult the full Prescribing Information prior to and during treatment with VEMLIDY for potential drug interactions; this list is not all inclusive. USE IN SPECIFIC POPULATIONS Also see Dosage and Administration Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VEMLIDY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at

1-800-258-4263. Risk Summary: Available data from the APR show no significant difference in the overall risk of birth defects for TAF compared with the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. Human data: Based on prospective reports to the APR of exposures to TAF-containing regimens during pregnancy resulting in live births (including over 200 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 5.2% and 1.2% following first and second/ third trimester exposure, respectively, to TAF-containing regimens. Lactation: It is not known whether VEMLIDY and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. It is not known if tenofovir alafenamide can be present in animal milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VEMLIDY and any potential adverse effects on the breastfed infant from VEMLIDY or from the underlying maternal condition. Pediatric Use: Safety and effectiveness of VEMLIDY in pediatric patients less than 18 years of age have not been established. Geriatric Use: In clinical trials, VEMLIDY was administered to 89 subjects aged 65 and over. No clinically significant differences in safety or efficacy have been observed between elderly subjects and subjects between 18 and less than 65 years of age. Renal Impairment: No dosage adjustment of VEMLIDY is required in patients with mild, moderate, or severe renal impairment, or in patients with ESRD (estimated creatinine clearance below 15 mL per minute) who are receiving chronic hemodialysis. On days of hemodialysis, administer VEMLIDY after completion of hemodialysis treatment. VEMLIDY is not recommended in patients with ESRD (estimated creatinine clearance below 15 mL per minute by Cockcroft-Gault method) who are not receiving chronic hemodialysis as the safety of VEMLIDY has not been established in this population. Hepatic Impairment: No dosage adjustment of VEMLIDY is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of VEMLIDY in patients with decompensated cirrhosis (Child-Pugh B or C) have not been established; therefore, VEMLIDY is not recommended in patients with decompensated (ChildPugh B or C) hepatic impairment. OVERDOSAGE If overdose occurs, monitor the patient for evidence of toxicity. Treatment consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. 208464-GS-006 March 2021

H E PAT O L O G Y I N F O C U S

Undiagnosed continued from page 1

are discovered in the later stages of their disease process,” said Lauren Beste, MD, the director of data and analytics for the VA’s HIV, Hepatitis & Related Conditions Program office, in Seattle. “But when you look back, you often realize they had signs of cirrhosis that didn’t get picked up, sometimes for years. Our motivation for the study was to see how many patients have risk factors for liver disease as well as other corroborating findings that might indicate they have undiagnosed cirrhosis.” The population of interest comprised patients in VA care in 2018, who demonstrated risk factors for cirrhosis—chronic viral hepatitis, alcohol use disorder, obesity or diabetes—and had no prior diagnosis of the disease.

with liver disease risk factors and a high-risk screening score will end up truly having cirrhosis, but we strongly suspect it’s more than 9.7% of them.” One-third of patients who were formally diagnosed with cirrhosis decompensated in the first year after their diagnosis, she noted. Patients who received a diagnosis of cirrhosis were younger (66.3 vs. 73.4 years), more likely to have hepatitis C virus (30% vs. 11%) or alcohol use disorder (46 vs. 29%), and less likely to have diabetes or obesity (65% vs. 40%) than their counterparts without the diagnosis, according to the researchers. The findings point to the existence of a significant

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Fatty Liver Disease Common in U.S. Vets early 40% of veterans seeking treatment in the primary care setting have evidence of metabolic (dysfunction)-associated fatty liver disease (MAFLD), U.S. researchers have found. The study, named a Poster of Distinction at the 2021 virtual Digestive Disease Week (abstract Su374), included 174 men and women (mean age, 51.3 years; 41.4% white, 42.9% Black) who completed a lifestyle survey and underwent both blood testing and FibroScan (Echosens). Of those, 39.1% had MAFLD—a new term for non-alcoholic fatty liver disease—and 13.2% had evidence of clinically significant fibrosis, according to the researchers (Table).

Table. Prevalence of Fatty Liver Disease Among Veterans By Characteristic in Primary Care Characteristic MAFLD (n=68)

No MAFLD (n=106)

P Value

Female

67 (63.2%)

0.01

30 (44.1%)

Race

‘Certainly not everyone with liver disease risk factors and a high-risk screening score will end up truly having cirrhosis, but we strongly suspect it’s more than 9.7% of them.’ —Lauren Beste, MD, Veterans Health Administration, Seattle

Dr. Beste and her colleagues also examined the proportion of patients who underwent liver-related testing in the preceding 24 months, including imaging, transient elastography or laboratory components of the FIB-4 score. They defined potential cirrhosis in two ways: liver stiffness greater than 12 kPa or a FIB-4 score above 3.25. The researchers also identified patients who received a diagnosis of cirrhosis or experienced a decompensation event in the 2018-2019 period. The analysis found 6,658,875 patients in 2018 who did not have a prior diagnosis of cirrhosis. Of these, 45.4% had at least one risk factor for liver disease (diabetes or obesity, 70%; alcohol use, 26%).

High Risk, High Concern Of the 3,023,074 patients with such risk factors, 87.5% (n=2,644,952) underwent liver-related testing. Of this group, 133,636 had markedly abnormal FIB-4 or transient elastography results. Despite these findings, only 9.7% of patients with risk factors and abnormal screening results received a diagnosis of cirrhosis. “These are really high-risk patients, yet less than 10% received a formal diagnosis of cirrhosis,” Dr. Beste told Gastroenterology & Endoscopy News. “This is concerning to us because it’s likely that many of the patients who have these abnormal scores also have unrecognized cirrhosis. Certainly not everyone

pool of patients who likely have cirrhosis and require further evaluation and referrals, said Dr. Beste, who added that population-level screening may help identify many of them. “We need to raise awareness of what constitutes a concerning result,” she said. “The next step is to figure out how to bring this to the forefront of providers’ attention when they’re seeing patients in their office. We have an opportunity to help providers recognize patients at high risk for cirrhosis and encourage further workup.” Heather M. Patton, MD, the director of population management and hepatology at the VA San Diego Healthcare System, called the study “important” for several reasons. “Timely recognition and referral of patients with cirrhosis is imperative in order to offer opportunity to impact disease progression and long-term outcomes,” said Dr. Patton, who expressed dismay that so few patients received a diagnosis of cirrhosis. “This, along with the high rate of decompensation in the year following diagnosis, indicates that we are routinely missing opportunities to treat liver disease before morbidity and mortality are imminent.” Dr. Patton also expressed concern that so many veterans had at least one risk factor for liver disease. “The extremely high prevalence of risk factors for liver disease in our veterans should serve as a strong impetus

0.05

White

34 (50%)

43 (40.6%)

Black

20 (29.4%)

50 (47.2%)

Other

14 (20.6%)

13 (12.2%)

Hispanic

12 (18.2%)

14 (13.6%)

0.42

Age, mean (standard deviation)

55.3 (10)

48.6 (12)

<0.01

Diabetes

29 (42.7%)

16 (15.1%)

<0.01

Normal

0 (0%)

30 (28.3%)

Overweight

14 (20.6%)

34 (32.1%)

Obese

54 (79.4%)

42 (39.6%)

High triglycerides

19 (28%)

14 (13.2%)

0.02

Low HDL

3 (4.4%)

2 (1.9%)

0.38

High cholesterol

42 (61.8%)

50 (47.2%)

0.06

Hypertension

38 (55.9%)

39 (36.8%)

0.01

E score median >7

9 (13.2%)

5 (4.7%)

0.04

BMI

E score, liver elasticity score; HDL, high-density lipoprotein; MAFLD, metabolic (dysfunction)-associated fatty liver disease

to develop mechanisms for population-based screening to identify patients with advanced liver disease,” she said. —Michael Vlessides The study was presented at The Liver Meeting Digital Experience 2020 (abstract 661). Drs. Beste and Patton reported no relevant financial disclosures. Both Drs. Beste and Patton noted that the views expressed in the article are those of the interviewees and do not necessarily reflect the position or policy of the Department of Veterans Affairs.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

H E PAT O L O G Y I N F O C U S

Unlocking the Mechanisms Behind PN-Associated Liver Injuries New research brings focus to details of this intricate system

or years, gastroenterologists have been aware that parenteral nutrition (PN), while lifesaving, can damage the liver. Now, researchers are beginning to gain an understanding of the underlying mechanisms in this complex process. The gut responds and adapts to antigens and antibodies, and is constantly exposed to environmental toxins that challenge the barrier function, said Ajay Jain, MD, DNB, MHA, the associate division chief of pediatric gastroenterology, section head of pediatric nutrition and a professor of pediatrics at Saint Louis University, in Missouri, during a keynote address at the ASPEN 2021 Nutrition Science and Practice Conference. “Enteral nutrients and trillions of bacteria modulate luminal targets along complicated signaling pathways, maintaining and challenging normal homeostasis,” Dr. Jain said. “The gut also serves as a major regulatory gateway controlling molecular trafficking, and seems intimately involved in systemic health and disease states via gut-systemic signaling.” Strategically targeting gut–systemic cross talk “could bring a paradigm change in current therapeutics mitigating PN-associated injury, which remains a major research focus,” he said. The interaction between farnesoid X receptor (FXR) and fibroblast growth factor 19 (FGF19) has been one area studied in how the gut regulates liver health in the context of PN, Dr. Jain said. FXR is thought to be present throughout the gut and particularly in the terminal ileum. As bile acids travel down from the gastrointestinal tract during regular food intake, they activate FXR, which results in the release of the metabolic hormone FGF19. This hormone then travels through the portal circulation to the liver and binds to its receptor, FGFR4. Another function of FGF19 is to regulate the enzyme CYP7A1, which is a rate-limited step in the synthesis of bile acid. In addition, FGF19 has been shown to regulate the homeostasis of lipids and blood sugar. Parenteral feeding, which bypasses the gut, has been associated with complications of liver disease as well as atrophy of the gut mucosa and inflammation. The term intestinal failure–associated liver disease (IFALD)— hepatobiliary dysfunction secondary to intestinal failure—is increasingly used to describe PN-associated injury. Potential drivers of IFALD include prematurity, with premature infants’ immature hepatic transport and metabolism of bile acids partly contributing to injury. Additional drivers are toxicity of the PN solution, such as from lipids or other PN constituents like metals, which can impair hepatobiliary transporters, and sepsis, which can cause cytokine-mediated liver injury.

The Gut–Liver Connection A novel idea that is being proposed is that the lack of luminal nutrients in patients on PN can disrupt bile acid and other signaling ligands along gut–systemic signaling pathways essential for health, Dr. Jain said. Indeed, IFALD has been shown to be minimal if enteral support

Linchpins Between The Gut and Body he portal vein is not only a conduit for blood flow to the liver, but is increasingly believed to carry key signaling molecules originating from the gut for hepatic uptake and systemic disease modulation, Dr. Jain said. Emerging data suggest that the intricate system linking these components presents a major relationship between the gut and the body, regulating normal health and disease. Some factors at play include:

can be provided. In the absence of enteral nutrition, gut FXR remains inactive, resulting in altered FGF19 signaling and liver disease. “Our gut feeling is that the gut really controls liver health during PN,” he said. Dr. Jain’s laboratory has been studying this field for more than a decade. The researchers have created a novel ambulatory PN in piglets using miniature pumps and tunneled catheters. Comparing animals fed enteral nutrition, a PN diet, and PN plus enteral bile acids to Microbiome. The gut microbiota is activate gut‒liver signaling, the group noted that enteral individually adapted and involved with the bile acids prevented hepatic injury, and both histologic processing of nutrients and production of and serologic liver injury markers were closer to those vitamins, metabolites and toxins. Every seen in the enteral feeding group (Am J Physiol Gastroperson contains about 100 trillion intest Liver Physiol 2012;302[2]:G218-G224). symbiotic microbes. More recent studies in animals from his lab, and in humans from other labs, have demonstrated dramatic Enterohepatic circulation. Bile salts differences in gut microbiota between those fed enteral secreted by the liver are largely reabversus parenteral diets. Animals receiving enteral nutrisorbed by the gut. The process is now tion had a predominance of the Firmicutes phylum understood to involve more than merely while those receiving PN had clonal shifts toward the recycling. Rather, it forms a key Bacteroidetes phylum. Indeed, other studies have noted signaling link between the gut and the that humans with intestinal failure had an 18-fold overliver, and a key target in gut–systemic abundance of bacilli compared with healthy controls signaling. and lacked bacteria belonging to the Firmicutes phylum (JPEN 2017;41[2]:238-248). Hepatobiliary receptors and transOver the years, different components of PN therapy porters along the gut systemic axis. have been implicated in the development of IFALD These contribute to the secretion and in pediatric patients, said Jeffrey Rudolph, MD, the reabsorption of bile acid. medical director of intestinal care and rehabilitation at UPMC Children’s Hospital, in Pittsburgh. —K.B. “What [Dr. Jain’s] talk really did was give insight into the complex interplay between the components of PN, the factors in the host recipient and even potentially the microbiome, and how that interplays all through FXR and FGF19 signaling,” Dr. Rudolph said. Giving PN alone versus enteral nutrition seems to aggravate liver disease, Dr. Rudolph added, and Dr. Jain’s talk focused on the complex gut–liver axis that contributes to this process: “As a GI thinking about why it’s important to provide enteral nutrition, other than the idea of just weaning the PN, using nutrition as a therapeutic to help prevent liver disease and having some idea into the basic mechanisms of how that potentially works is very helpful and increased my understanding of how Novel ambulatory model of total parenteral nutrition. PN in IFALD is affected by things like sepsis, prema—Karen Blum turity and other physiologic components of the host.” Drs. Jain and Rudolph reported no relevant financial disclosures.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

NAFLD Outcomes Worse for Blacks

lack patients hospitalized with nonalcoholic fatty liver disease are significantly more likely to die in the hospital or suffer acute liver disease than white patients hospitalized with NAFLD, according to a retrospective analysis presented at the 2021 virtual Digestive Disease Week (poster Sa346). Black patients also experienced longer hospital stays than white patients, and came from families with more modest incomes on average. Geneticists have established that Black and white people are less likely to have a genetic predisposition to NAFLD than Native Americans, Hispanics or Asians. Despite this similarity, research has suggested that Black patients with NAFLD face different prognoses than whites with

the condition. The new study aimed to document whether there were indeed health outcome differences between the two groups in hospital settings. “There is definitely a difference in clinical outcomes between African Americans and whites in my anecdotal experience, so I decided to look into this question,” said David U. Lee, MD, who led the research. Dr. Lee, who completed this research as a fellow at Tufts University, in Boston. Dr. Lee and his colleagues analyzed seven years of data (2011-2017) from the National Inpatient Sample, a data set collected by the U.S. government to enable longitudinal research of health outcomes in hospitals across the country. They examined the health records

of approximately 50,000 adults with NAFLD (47,503 white and 2,816 Black patients) hospitalized during this period, to determine whether the health status of these patients was broadly similar or diverged appreciably. These health indicators ranged from in-hospital mortality to having other concomitant conditions, such as ascites or cirrhosis. The researchers excluded people younger than 18 years of age from the analysis, as well as those with other liver diseases such as infection with either the hepatitis B or C virus. Relatively few NAFLD patients of any race died in the hospital, although Black patients died at a significantly higher rate than white patients (5.58% vs. 4.64%). More than 10% of Black patients experienced acute liver failure in the hospital, which was not the case as frequently for white patients (13.5% vs. 7.92%), Dr. Lee’s group found. However, Black patients were less likely to experience cirrhosis (45.8% vs. 64.9%), ascites (22.7% vs. 32.4%) or variceal bleeding (1.85% vs. 4.38%). Compared with white patients, Black patients were more likely to have modest incomes and to be insured through Medicaid. Dr. Lee acknowledged that these data are observational, and not definitive proof of any link between genetics,

economics and NAFLD outcomes. “It’s always a pivotal step to make these observational studies,” he said, because they can serve as a conduit to more definitive research later. Nicole Rich, MD, a gastroenterologist at UT Southwestern Medical Center, in Dallas, who studies racial, ethnic and sex disparities in liver disease, called the latest results “hypothesis-generating,” but noted that data from administrative databases such as the National Inpatient Sample can be fraught. On one hand, the sheer numbers of patients are rarely seen in multicenter cohort studies. On the other hand, these data sets lack granularity, such as details on liver function and other comorbidities, making it difficult to reach firm conclusions. More work is needed to tease out the relative contribution of modifiable and nonmodifiable factors to the severity of NAFLD, she said, from genetics, which cannot be changed, to lifestyle and environment, over which patients have some control. Dr. Rich hypothesized that modifiable neighborhood-level factors, such as limited access to healthy food, may contribute to disparities in the incidence and outcomes of NAFLD. However, more detailed data on neighborhood food patterns—as a complement to the national data—would be necessary to test this premise. —Marcus Banks

Early PVT Detection Crucial for Hospitalized Cirrhosis Patients With Liver Cancer

atients with cirrhosis who also have primary liver cancer face a higher risk for complications and death when they have portal vein thrombosis (PVT), new research confirms. The findings highlight the need for early detection and treatment of PVT in these high-risk patients, according to study author David U. Lee, MD, an advanced hepatology fellow at Tufts Medical Center, in Boston, at the time of the study. “This study strengthens the known association between PVT and adverse outcomes in cirrhosis patients with liver cancer using a national registry,” Dr. Lee told Gastroenterology & Endoscopy News. He and his colleagues presented the findings at the 2021 virtual Digestive Disease Week, where the research was named a Poster of Distinction (abstract Su344). Dr. Lee’s team compared hepatic events, hospital length of stay, hospital costs and mortality between patients with and without PVT, using data from nearly 39,000 patients with cirrhosis and primary liver cancer (hepatocellular carcinoma or cholangiocarcinoma) from the National Inpatient Sample for 2011-2017. The 4,226 patients with PVT in the database were

younger (61.9 vs. 62.5 years; P<0.01) and more likely to be men (79.8% vs. 75.6%; P<0.01) than those without the condition. Multivariate analyses controlling for age, sex, race, liver covariates and hepatic events confirmed the associations between PVT and hospital mortality, ascites and other complications (Table). “As indicated by the odds ratios, the odds of adverse events were elevated between 10% to 90%,” Dr. Lee said. Nancy Reau, MD, the section chief of hepatology at Rush Medical College in Chicago, said the findings effectively reinforce the need for early detection of PVT in hospitalized cirrhosis patients with primary liver cancer, but that providers should use caution when choosing the appropriate treatment. “This study did not report anticoagulation use in the group with PVT and thus could not assess for the benefit of anticoagulation,” Dr. Reau said. “Given that there was a risk for variceal bleeding in those with PVT, anticoagulation must be used with trepidation.” She added that patients with bland PVT may have different needs from those with tumor thrombosis. “This distinction is important for both prognosis as well as therapeutic options,” she said.

Table. Multivariate Comparison of Liver Patients With and Without PVT Dependent Variable Mortality

Independent Adjusted Variable Odds Ratio PVT 1.15

Ascites

PVT

1.82

Spontaneous PVT bacterial peritonitis Variceal PVT bleeding Hepatorenal PVT syndrome

1.36

1.73 1.38

95% CI

P Value

1.031.28 1.701.94 1.181.55

0.012

1.551.94 1.221.56

<0.01 <0.01

PVT, portal vein thrombosis

Dr. Lee agreed that more research is needed to better prognosticate outcomes and evaluate therapy options that will improve overall and disease-free survival. —Adam Leitenberger Drs. Lee and Reau reported no relevant financial disclosures.

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Postmenopausal Women Face Highest Risk For Advanced NAFLD Fibrosis

mong patients with nonalcoholic fatty liver disease, postmenopausal women have the highest risk for advanced fibrosis, new research shows. “Postmenopausal women with NAFLD are a high-risk group of patients,” study author Maya Balakrishnan, MD, an assistant professor of gastroenterology at Baylor College of Medicine, in Houston, told Gastroenterology & Endoscopy News. “This is a paradigm shift in how we

think of liver disease, which has traditionally been thought of as something that affects men more than women.” Because advanced fibrosis is the strongest predictor of progression to cirrhosis, decompensated liver disease and liver-related mortality, it is critical that providers identify NAFLD patients with advanced fibrosis for timely

treatment to resolve NASH and reverse fibrosis, she said. In an earlier meta-analysis, Dr. Balakrishnan and her colleagues showed that, in the general population, women had a lower risk for NAFLD than men (Clin Gastroenterol Hepatol 2021;19[1]:61-71.e15). But among those diagnosed with NAFLD, women

around age 50 years had a higher risk for advanced fibrosis than men of the same age. Animal models of hepatic steatosis show that loss of estrogen may hasten progression of liver fibrosis, and some clinical studies have linked menopause with increased visceral fat, type 2 diabetes and NAFLD. see Postmenopausal, page 18

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THE U.S. PREVENTIVE SERVICES TASK FORCE (USPSTF) NOW RECOMMENDS SCREENING PATIENTS AT AVERAGE RISK FOR CRC STARTING AT AGE 45 (Grade B recommendation)3§|| Learn more at CologuardHCP.com/recommendations Indications and Important Risk Information Cologuard is intended for the qualitative detection of colorectal neoplasia associated DNA markers and for the presence of occult hemoglobin in human stool. A positive result may indicate the presence of colorectal cancer (CRC) or advanced adenoma (AA) and should be followed by diagnostic colonoscopy. Cologuard is indicated to screen adults of either sex, 45 years or older, who are at typical average risk for CRC. Cologuard is not a replacement for diagnostic colonoscopy or surveillance colonoscopy in high-risk individuals. Cologuard is not for high-risk individuals, including patients with a personal history of colorectal cancer and adenomas; have had a positive result from another colorectal cancer screening method within the last 6 months; have been diagnosed with a condition associated with high risk for colorectal cancer such as IBD, chronic ulcerative colitis, Crohn’s disease; or have a family history of colorectal cancer, or certain hereditary syndromes. Positive Cologuard results should be referred to diagnostic colonoscopy. A negative Cologuard test result does not guarantee absence of cancer or advanced adenoma. Following a negative result, patients should continue participating in a screening program at an interval and with a method appropriate for the individual patient. False positives and false negatives do occur. In a clinical study, 13% of patients without colorectal cancer or advanced adenomas received a positive result (false positive) and 8% of patients with cancer received a negative result (false negative). The clinical validation study was conducted in patients 50 years of age and older. Cologuard performance in patients ages 45 to 49 years was estimated by sub-group analysis of near-age groups. Cologuard performance when used for repeat testing has not been evaluated or established. Rx only. * In the pivotal study, screening colonoscopy was the reference method.2 †Cologuard specificity: 87% overall specificity, excluding CRC and advanced adenomas, and including all nonadvanced adenomas, nonneoplastic findings, and negative results on colonoscopy. There was 90% specificity in participants with no lesions biopsied on colonoscopy.2 Negative predictive value (NPV) is defined as the probability that disease is absent in those with a negative result; it is highly dependent on the prevalence of the disease. NPV was derived from the patient population evaluated in the lmperiale et al publication.2

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References: 1. Chen RC, Haynes K, Du S, Barron J, Katz AJ. Association of cancer screening deﬁcit in the United States with the COVID-19 pandemic. JAMA Oncol. doi:10.1001/jamaoncol.2021.0884. 2. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297. 3. Davidson KW, Barry MJ, Mangione CM, et al. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238. EXACT SCIENCES CORPORATION | 5505 Endeavor Lane, Madison, WI 53719 ExactSciences.com | ExactLabs.com | 1-844-870-8870 Cologuard is a registered trademark of Exact Sciences Corporation. ©2021 Exact Sciences Corporation. All rights reserved. US.CG.3201-3 May 2021

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Postmenopausal continued from page 17

Taken together, these data suggest that menopause may be driving the increased risk for advanced fibrosis in women with NAFLD, Dr. Balakrishnan said. To test this hypothesis, she and her colleagues conducted a cross-sectional study of 108 postmenopausal women, 107 premenopausal women and 55 men, all of whom had biopsy-proven NAFLD. The group’s average age was

47.4 years, and 27% had advanced fibrosis. Most of the people in this cohort— the Harris County NAFLD Cohort in Houston, which began prospective recruitment in 2015—were of Mexican or Central American descent. The investigators compared the presence of advanced fibrosis among premenopausal women, postmenopausal women and men, and determined

menopausal status using a baseline questionnaire when available (they assumed menopausal status for women ages 50 or older who did not complete a questionnaire). After adjusting for type 2 diabetes and hypertension, the risk for advanced fibrosis was 2.3 times higher in postmenopausal versus premenopausal women (odds ratio [OR], 2.34; 95% CI, 1.20-4.57). The risk for advanced

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fibrosis was also 2.5 times higher in women older than 50 than in younger women (95% CI, 1.23-5.13). Older and younger men showed similar risk levels, as did men compared with premenopausal women. The findings have important implications for how physicians counsel women with NAFLD, Dr. Balakrishnan said. “In my practice, I discuss with women the possibility of more rapid disease progression as they approach age 50.” Clinicians should be vigilant in their systematic stratification of fibrosis risk in these patients, and in educating patients about the importance of lifestyle modifications, she said. “Lifestyle modification and weight loss are the main interventions for NAFLD and should be aggressively pursued among postmenopausal women, though they may need to be specifically adapted for the needs of postmenopausal women with NAFLD,” Dr. Balakrishnan said. “As medications become approved for NASH [non-alcoholic steatohepatitis], their effect among postmenopausal women, in particular, will need to be addressed.” “This study helps clarify why women have a higher risk for NAFLD-associated fibrosis compared to men, and suggests that adding menopausal state to our risk stratification will better improve screening strategies to identify those with the highest risk for liver events,” said Nancy Reau, MD, the section chief of hepatology at Rush Medical College, in Chicago. Still, she said the relationship between sex hormones and NAFLD risk is far from clear. Women with polycystic ovarian syndrome also have a higher risk for NASH, Dr. Reau said, which suggests that testosterone—not just loss of estrogen—may play a role in hepatic risk for women. Drs. Balakrishnan and Reau reported no relevant financial disclosures.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Resilience, a Modifiable Quality, Reduces Risk for IBD Hospitalizations

eople with inflammatory bowel disease can learn to become more resilient when it comes to their condition, and dramatically reduce their use of health services, researchers have found. Over a one-year period, graduates of a program for resilience-based care coordination “saw a 90% reduction in emergency room visits and an 88% reduction in hospitalizations related to IBD,” reported Laurie Keefer, PhD, the director of psychobehavioral research with the Division of Gastroenterology at the Icahn School of Medicine at Mount Sinai, in New York City. Resilience is being increasingly recognized as a potentially modifiable factor in a host of chronic conditions, such as cancer, diabetes and chronic obstructive pulmonary disease. In a previous study led by Dr. Keefer, a high degree of resilience was associated with lower IBD activity and better quality of life (Inflamm Bowel Dis 2020 Jul 12. [epub ahead of print]). The new study assessed whether resilience is modifiable. Dr. Keefer and her colleagues evaluated 126 men and women participating in a program she developed called Gaining Resilience Through Transitions (GRITT-IBD). The program builds on the principles of positive psychology to improve optimism and self-regulation skills, among other components of resilience. The 126 participants were drawn from more than 300 consecutive patients with low GRITT-IBD scores, meaning they had low levels of resilience in an algorithm measuring factors such as management skills and the experience of both physical and psychological symptoms. Two hundred six patients who did not opt to enter into a six-month personalized care plan served as controls. The personalized care plan included strategies to build resilience, including psychological, nutritional and educational support for the goals of therapy. One year after enrollment, health care use was compared between those who entered the program and the controls, only 24% of whom declined participation due to lack of interest. Other reasons for not participating included an unacceptable distance to the treatment facility and lack of adequate insurance. In the group receiving resilience

training, women outnumbered men and had a higher percentage of Crohn’s disease. The baseline GRITT-IBD score was lower in the treatment group (45.8 vs. 54.2), but the difference did not reach statistical significance. Resilience training led to significant gains over time, with the GRITT-IBD score rising by 33 points (P<0.001) relative to baseline in the treatment group, Dr. Keefer reported. When compared with the 12 months prior to the study period, emergency department visits in the treatment group fell from 102 to 10 (90%; P<0.001) and hospitalizations fell from 70 to eight (88%; P<0.001). In the control group, emergency department visits over the study period were effectively unchanged, dropping from 89 to 85. Hospitalizations climbed from 23 to 38, an increase of 45%. Dr. Keefer said she is now working to improve the approach, including efforts to “scale care coordination” and improve strategies to engage patients. Resilience in IBD has already attracted the attention of other investigators, including a multicenter and multidisciplinary group that published a review on the topic (Intern Emerg Med 2020;15:211223). The paper supported resilience as a potential therapeutic target in IBD. “Low resilience is associated with poor coping skills and increased health care usage. If we find therapeutic approaches that reproducibly lead to better resilience, many IBD patients could benefit directly,” according to Christian Selinger, MD, the senior author of the review and a consultant gastroenterologist in the IBD service at Leeds Teaching Hospitals NHS Trust, in England. “In addition, by providing more proactive care [to improve resilience], IBD services might actually be able to prevent disease flares in some cases rather than just treat reactively.” Dr. Selinger cautioned that his remarks serve as “more of a vision than a statement based on solid evidence” until more prospective studies confirm clinical benefits. —Ted Bosworth Dr. Keefer reported an ownership interest in Trellus Health, a company that is now developing a connected care platform based on the GRITT-IBD method. Dr. Selinger reported no relevant financial disclosures. The study was presented at the 2020 virtual meeting of the American College of Gastroenterology (abstract 7).

Insurance Problems Take Toll On IBD Patients he loss of or disruption in insurance coverage can trigger potentially “devastating” physical and psychological consequences for people with inflammatory bowel disease, according to Laurie Keefer, PhD, the director of psychobehavioral research with the Division of ‘I had to declare Gastroenterology at the Icahn bankruptcy … I owed over School of Medicine at Mount Sinai, in New York City, and her $100,000 for Remicade colleagues. In a study presented at the treatments.’ 2021 virtual Digestive Disease Week (abstract Sa568), Dr. Keefer and her colleagues detailed the fallout for 29 IBD patients who had lost their health care coverage or faced another issue with their insurance that threatened to derail their care. Of those, 21% reported feeling “overwhelmed” by the setback, and 41% said they didn’t think they could manage a lapse in coverage. Nearly half (45%) said they’d resigned themselves to not getting their health insurance reinstated. In addition to the emotional insecurity, patients reported ‘I forgot to pay … a variety of physical problems linked to the loss of coverage. and I have anxiety, so Nearly six in 10 (58%) said they sometimes when a experienced a flare of their disease as a result of the lapse, problem comes, I shut and 14% said they required down … and I was like, surgery. Fourteen percent also I guess I’m just not said they developed antibodies to their medication. going to have insurance Although most patients anymore.’ reported having a support system of friends and family, nine (31%) said they had no such structure in place. Eleven patients (38%) said they did not inform their health care team about their lapse in insurance coverage, according to the researchers. “Insurance issues can have devastating physical and psychological effects on IBD patients,” Dr. Keefer’s group wrote. “A large proportion of ‘I didn’t feel like our cohort chose not to inform their provider of their insurance issue, felt a doctor calling incapable of managing it on their own, saying, “Hey, how and gave up on resolving it. … Our study highlights the need to further supcome she doesn’t port IBD patients with insurance issues have insurance?” by identifying them, encouraging them to inform their providers, and making was really going to easily accessible advocates available to do anything.’ avoid consequences of periods without access to the health care system.” —GEN Staff

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Dr. Sharma’s Endoscopy Insights: Improving Colonoscopy Quality his month, my focus is on studies highlighting strategies to improve the quality of colonoscopy, including improving the adenoma detection rate (ADR), reducing bleeding after polypectomy and optimizing optical evaluation to predict invasive cancer in large non-pedunculated colorectal polyps (LNPCPs). Colorectal polyps typically are evaluated by optical methods, including high-definition white light endoscopy and virtual chromoendoscopy. The first study I chose shows that successful optical evaluation is dependent on lesion morphology, and flat lesions can be evaluated efficiently by endoscopy to rule out submucosal invasion (SMI). Lesions larger than 2 cm, on the other hand, may be difficult to evaluate for SMI using optical techniques.

The second study is a systematic review and metaanalysis that addresses the question of whether prophylactic clipping should be routinely used after polyp resection. The results suggested that routine clipping does not reduce delayed bleeding after polyp resection. However, in patients with proximally located polyps, a polyp size of 2 cm or larger, and in those on anticoagulation or dual antiplatelet agents, prophylactic clipping is effective. Finally, the authors of the third study evaluated whether the monitoring of withdrawal time or use of report cards for physicians affected ADR. They found that a physician colonoscopy quality report card, but not monitoring of withdrawal time, was associated with a significant improvement in ADR.

Is Optical Evaluation of LNPCPs Reliable? (Clin Gastroenterol Hepatol 2021 May 12. https://doi.org/10.1016/j. cgh.2021.05.017)

Consider Prophylactic Clipping for Specific Groups (Clin Gastroenterol Hepatol 2021 May 2. https://doi. org/10.1016/j.cgh.2021.05.012)

This analysis included 1,583 large (≥2 cm) LNPCPs that were evaluated as part of a prospective, multicenter, observational cohort study. The median polyp size was 35 mm, and 855 were flat and 728 were nodular. Seven endoscopists with a median of 15 years of experience conducted the initial procedures and used established features, such as Kudo V pit pattern, depressed morphology, rigidity and fixation, and ulceration to determine the likelihood of submucosal invasive cancer (SMIC).

This meta-analysis included 13 studies looking at delayed bleeding within 30 days of prophylactic clipping after polypectomy of LNPCPs. The data included 5,380 patients who had 8,948 polyps resected and clipped.

SMIC was observed in 9.2% (95% CI, 7.9%-10.8%) of the lesions, and the overall sensitivity and specificity of optical evaluation was 67.1% and 95.1%, with a high negative predictive value of 96.6%, according to the researchers. Overall, SMIC was missed in 3% (95% CI, 2.3%-4%) of lesions. SMIC was more likely to be missed in mixed lesions (5.2%) compared with granular (3.2%) or nongranular (2.2%) lesions. Several variables independently predicted missed SMIC, including a polyp size of 4 cm or larger (odds ratio [OR], 2; 95% CI, 1-3.8), rectosigmoid location (OR, 2; 95% CI, 1.1-3.7) and nodular morphology (OR, 7.2; 95% CI, 2.8-18.9) (P<0.039 for all).

Overall, prophylactic clipping led to no significant effect on delayed bleeding (OR, 0.94; 95% CI, 0.76-1.17), according to the researchers, although it reduced delayed bleeding for proximal polyps of 2 cm or larger (OR, 0.62; 95% CI, 0.44-0.88). The effect was greatest in patients receiving antithrombotic agents, in whom delayed bleeding decreased from 10.8% to 6.4% with prophylactic clipping (OR, 0.59; 95% CI, 0.35-0.99; number needed to treat [NNT], 23). Similarly, in patients receiving anticoagulants or double platelet inhibitors, delayed bleeding decreased from 14.6% to 6.3% when clips were applied prophylactically (OR, 0.40; 95% CI, 0.16-1.01; NNT, 12).

Prateek Sharma, MD Professor of medicine at the University of Kansas School of Medicine, in Kansas City

Physician Report Cards Increase ADRs (2021 Virtual Digestive Disease Week; abstract Sa089)

The authors of this metaanalysis examined the impact of withdrawal time monitoring and physician report cards on ADRs. They included over 55,000 colonoscopies documented in 13 randomized controlled trials or observational studies published through 2018. Physician report cards were associated with a 31% increase in ADRs (OR, 1.31; 95% CI, 1.151.5; P<0.0001), while slower withdrawal time did not increase ADRs (OR, 1.02; 95% CI, 0.861.22; P=0.81).

—Compiled and written by David Wild

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Expert Picks From the 2021 DDW: Bariatric Therapies n this installment of “Expert Picks,” Shelby Sullivan, MD, the director of the Gastroenterology Metabolic and Bariatric Program at the University of Colorado School of Medicine Anschutz Medical Campus, in Aurora, highlights important research on bariatric therapies presented at the 2021 virtual Digestive Disease Week.

Abstract 2. Black patients suffer significantly higher adverse events from bariatric surgery despite better 30-day decrease in BMI—An analysis of the MBSAQIP data registry (Badurdeen D, et al)

EXPERT PICKS 53. Endoscopic Versus Surgical Gastrojejunal Revision for Weight Regain In Roux-En-Y Gastric Bypass Patients ‘[E]ndoscopic RYGB

Disparities in surgical outcomes across racial lines are well documented. While the technical aspects of bariatric surgical procedures have improved over the years, rates of adverse events (AEs) vary considerably between Black and white patients. Badurdeen and colleagues looked at disparities in outcomes among white patients (n=341,380) and Black patients (n=107,449) undergoing bariatric procedures, including Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG), by reviewing five years of data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database. The researchers found that from 2015 to 2019, Black patients had a 24% higher risk for serious morbidity and AEs even after correcting for baseline

characteristics, type of surgery and use of a robot. At 30 days, the mean decrease in BMI was 2.68 versus 2.53 kg/m2 (P<0.001) for Black and white patients, respectively, and 2.64 versus 2.55 kg/m2 (P<0.001) after RYGB and LSG. Dr. Sullivan: Racial disparities are apparent throughout medicine, and it is crucial that these are addressed. The first step of addressing disparities is understanding how race affects medical treatments. Dr. Badurdeen and colleagues’ findings of greater risk for serious morbidity and AEs in Black patients provides a foundation that will inform future research investigating the underlying causes of these differences in serious morbidity and AEs and how to reduce them.

revision resulted in less weight loss in the first year of therapy, but had significantly less risk for serious AEs than surgical RYGB revision.’

Su548. Semaglutide in Association to Endoscopic Sleeve Gastroplasty ‘The holy grail of endoscopic bariatric therapies and weight loss medications is to reach the level of weight loss seen with bariatric surgery with fewer AEs and shorter recovery time for patients.’

Abstract 53. Endoscopic Versus Surgical Gastrojejunal Revision for Weight Regain In Roux-En-Y Gastric Bypass Patients: 5-year Safety and Efficacy Comparison (Dolan RD, et al) Dilated gastrojejunal anastomosis (GJA) is an anatomic cause of weight regain following RYGB that can be corrected with diameter reduction through endoscopic or surgical revision. The transoral outlet reduction (or TORe) endoscopic revision technique

is associated with an 8.8% total weight loss at five years with few AEs, but no studies have directly compared this technique with surgical revision. Dolan et al compared rates of serious AEs and see Bariatrics, page 24

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Bariatrics continued from page 22

weight loss profiles between endoscopic and surgical revisional techniques over a five-year period. The retrospective matched cohort study included RYGB patients who underwent endoscopic or surgical revision for weight regain that was at least partly attributable to an enlarged GJA (>12 mm) at two tertiary referral centers. Endoscopic patients were matched 1:1 to surgical revision patients based on age, sex, BMI and weight regain. The study included 122 RYGB patients with weight regain and an enlarged GJA who underwent endoscopy (n=61) or surgical revision (n=61). Patients in the endoscopy group were more likely to complete the five-year follow-up (n=53 vs. 28). Pre-revision age, sex, time since RYGB, percent weight regain from initial weight loss, weight, BMI and GJA diameter were similar between groups. Patients who underwent surgical revision were more likely to experience serious AEs (26.2% vs. 4.9%; P=0.002), according to the researchers. Serious

AEs in the endoscopic group included GJA stenosis requiring balloon dilation (n=1), esophageal perforation requiring endoscopic clip closure (n=1), and gastrointestinal bleeding (n=1). Serious AEs in the surgical group included leak (n=3), GJA stenosis requiring balloon dilation (n=2), intraabdominal infection (n=2), superficial wound infection (n=2), ulcer (n=3), severe abdominal pain (n=3), GI bleeding (n=2), high-grade small bowel obstruction (n=1), pancreas injury causing pancreatitis (n=1), subcutaneous neck emphysema (n=1), and postoperative pulmonary embolism (n=1). The surgical group lost significantly more weight at one year post-procedure (44.3 vs. 23.7 lb; P=0.003), but no significant differences were observed at three and five years. Dr. Sullivan: Although RYGB is one of the most successful treatments for obesity, significant weight regain can occur in up to 20% to 30% of patients over time. This has negative effects on obesity-related

comorbidities and quality of life. Both endoscopic and surgical revisions have been studied for the treatment of weight regain after RYGB, but no studies have directly compared safety and efficacy between surgical and endoscopic revisions in patients with weight regain after RYGB. Although this study was retrospective, the authors matched patients for comparison and found that endoscopic RYGB revision resulted in less weight loss in the first year of therapy, but had significantly less risk for serious AEs than surgical RYGB revision. Moreover, there was no significant difference in weight loss between the groups at three and five years. The reasons for the similar weight loss efficacy at three and five years are not clearly understood, but there was a high rate of follow-up in the endoscopic revision group, which may have resulted in more contact with the weight loss team, which is known to increase weight loss.

Abstract 757. Barrett’s Esophagus After Sleeve Gastrectomy: An Analysis of Incidence and Diagnostic Upper Endoscopy Rates Using Statewide Claims Data (Swei E, et al) Recent studies have suggested that laparoscopic sleeve gastrectomy (LSG) is associated with the development of Barrett’s esophagus, even when symptoms of gastroesophageal reflux disease (GERD) are absent. Despite this, no consensus exists on the use of upper endoscopy (by EGD) to screen for Barrett’s in patients who have undergone LSG. This study aimed to shed light on this issue by assessing the rates of upper endoscopy and incidence of new Barrett’s esophagus diagnoses in patients undergoing LSG. The researchers identified 5,562 obese patients who underwent LSG during 2012-2017 while enrolled in the Colorado All Payer Claims Database. Of this group, 35.5% had at least one diagnostic record of

EGD. The researchers found that the incidence of EGD was highest in the year immediately before surgery (22.1%) and decreased to 5.67% by one year after LSG. The median annual incidence of EGD was 2.21% before surgery and 4.41% after surgery. Over the entire study period, 81 patients had a new diagnosis of Barrett’s esophagus within one year of an EGD, for a cumulative incidence of 1.45% among all patients and 4.11% among only patients who underwent EGD. The cumulative incidence of a new diagnosis of Barrett’s esophagus after LSG was 1.6% at two years and 6.0% at five years, according to the researchers. Dr. Sullivan: Increased rates of GERD have

been seen after sleeve gastrectomy; however, studies have only recently reported increased rates of Barrett’s esophagus after sleeve gastrectomy regardless of GERD symptoms. Dr. Swei and colleagues found that there was an increasing cumulative incidence of new diagnoses of Barrett’s esophagus over time after sleeve gastrectomy in a large database, which is consistent with the current published literature on Barrett’s esophagus after sleeve gastrectomy. Possibly more importantly, however, they found that there was a low rate of diagnostic EGD after sleeve gastrectomy, which is worrisome for missing the diagnosis of Barrett’s esophagus in patients who have undergone sleeve gastrectomy.

Abstract Su548. Semaglutide in Association to Endoscopic Sleeve Gastroplasty: Taking Endoscopic Bariatric Procedures Outcomes to the Next Level (Hoff AC, et al) This clinical prospective double-blind study involved patients who underwent ESG with the same suturing patterns, and diet and exercise prescriptions. One cohort received semaglutide (Wegovy, Novo Nordisk) and the other received a placebo after the fifth month of ESG completion. Doses were adjusted to symptoms, with an initial dose of 0.25 mg and maximum dose of 1.5 mg. Among the 27 patients who received semaglutide, the mean age was 34 years and 20 were women. In the placebo group of 28 patients, the mean age was 36 years and 21 were women. The researchers found that loss of body weight was greater in the semaglutide group than the placebo group (26.7% vs. 19.6%; P<0.0001), as were the percent extra weight loss (86.3% vs. 60.4%; P<0.001), change in body fat mass (12.7% vs. 9%; P<0.001), and change in HbA1c (0.95% vs. 0.61%;

P=0.0394). All doses of the drug were generally well tolerated, with no new safety concerns, according to the researchers. The most common AEs were doserelated GI symptoms, particularly nausea. Dr. Sullivan: The holy grail of endoscopic bariatric therapies and weight loss medications is to reach the level of weight loss seen with bariatric surgery with fewer AEs and shorter recovery time for patients. While no individual medication or endoscopic bariatric therapy has reached this level of weight loss effectiveness, combination therapy has that potential. Endoscopic sleeve gastroplasty has demonstrated short-term weight loss benefit in large meta-analyses and medium-term weight loss at five years at a single center. Semaglutide has been approved in the United States and abroad for the treatment of diabetes, and was

Gastro & Endo News

just recently approved for the treatment of obesity in the United States. Currently, semaglutide is the most effective medication to treat obesity. The study by Dr. Hoff and colleagues evaluates in a double–blind, randomized controlled trial the effects of ESG alone or in combination with semaglutide. Although the study was small, the authors were able to demonstrate significantly more weight loss in the combination therapy group than with ESG alone. Moreover, the amount of weight loss achieved is closer to the weight loss achieved with sleeve gastrectomy and RYGB, suggesting that reaching surgical levels of weight loss with the combination therapy of endoscopic bariatric therapies and weight loss medications may be within our grasp. —Compiled and written by Kate O’Rourke Dr. Sullivan was a co-author of abstract 757.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Hospitalized IBD Patients With NAFLD Have More Readmissions, Longer Stays

he combination of inflammatory bowel disease and fatty liver has been linked to worse outcomes for hospitalized patients, in a new study. In research presented at the 2021 Crohn’s and Colitis Congress (abstract 3494541), a group from the University of California, Los Angeles reported that hospitalized patients with IBD and nonalcoholic fatty liver disease have longer stays and are twice as likely to be readmitted as those without the liver condition. Rajiv Chhabra, MD, an associate professor at the University of Missouri Kansas City School of Medicine, who was not involved in the new work, said the study highlights “the pressing need to better understand the complex interaction between IBD and NAFLD, or hepatic steatosis. While previous research has reported that severity of IBD impacts the degree of hepatic steatosis, these researchers looked at the topic the other way around, to see how the presence of NAFLD impacts specific outcomes of IBD.” NAFLD has been documented in as much as one-third of IBD patients (Inflamm Bowel Dis 2016;22[8]:19371944). Whereas the typical risk factors for NAFLD are obesity, type 2 diabetes mellitus and dyslipidemia, people with IBD seem to have other risk factors, said lead researcher Shaya Noorian, MD, a resident in internal medicine at the UCLA Medical Center. “Medication hepatotoxicity, systemic inflammation related to IBD disease activity, history of IBD surgery and gut dysbiosis have all been linked to risk of NAFLD in the IBD population,” Dr. Noorian said. To document the effect that NAFLD has on hospitalized IBD patients, Dr. Noorian and his coinvestigators analyzed data from the Nationwide Readmissions Database from 2016 to 2017. Their analysis included 11,197 hospitalized patients with Crohn’s disease and 6,120 patients with ulcerative colitis, approximately 2% of whom had NAFLD. Those with NAFLD were matched with IBD patients without the liver disorder on age, sex, type of bowel disease, metabolic syndrome and diabetes mellitus. The researchers also adjusted for the presence of obesity and dyslipidemia. According to Dr. Noorian, multivariate

Shaya Noorian, MD, UCLA Medical Center

analyses revealed that NAFLD doubled the risk for readmission in patients with Crohn’s disease (hazard ratio [HR], 1.98; 95% CI, 1.8-2.17; P<0.001) and ulcerative colitis (HR, 1.97; 95% CI, 1.672.32; P<0.001). Having NAFLD also was associated with longer average stays in the hospital for patients with Crohn’s disease (0.74 days longer; P<0.01) and ulcerative colitis (0.84 days longer) (P<0.01). The average cost of care for patients with Crohn’s disease and NAFLD was $7,766 higher than for those with Crohn’s alone (P<0.01), and was $11,496 higher for people with ulcerative colitis and NAFLD than for their counterparts without NAFLD (P<0.01). In contrast, NAFLD did not significantly increase the risk for death, Dr. Noorian’s team found. Delineating which specific factors contribute to the development of NAFLD in IBD patients would be an important direction for future research, he said. “Perhaps if reversible or preventable causes of NAFLD are identified, such factors can be targeted to improve outcomes in patients with coexisting NAFLD and IBD,” Dr. Noorian told Gastroenterology & Endoscopy News. However, Dr. Chhabra urged that “caution should be used when interpreting results based off a database. There can be coding bias, misclassification bias, missed diagnoses, [issues with] external validity, all of which can limit the ability to generalize the results to a wider population.” —David Wild Drs. Chhabra and Noorian reported no relevant financial disclosures.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

C. Diff Roundup

C. difficile Rates Higher forr Hospitalized Hispanics With IBD th IB BD

ACG Issues New Guidelines on C. difficile Management

he American College of Gastroenterology has issued new guidelines on the management of Clostridioides difficile infection (CDI), with recommendations reflecting developments from the availability of biologics to the growing use of fecal microbiota transplantation (FMT). “These guidelines are a step forward in our understanding of C. difficile,” said Sahil Khanna, MBBS, MS, a professor of medicine at Mayo Clinic in Rochester, Minn., who was not involved in the guideline development. “For the practicing provider, there are some big changes in the treatment and testing of the disease.” For example, although the 2013 ACG guidelines on the topic recommended metronidazole or vancomycin for treatment of a first mild to moderate episode of CDI, he said, the new guidelines now suggest vancomycin or fidaxomicin (Dificid, Merck) for a first episode of non-fulminant CDI. Metronidazole now is suggested only as treatment for initial non-severe CDI in very low-risk patients. “Metronidazole has already been on the decline in clinical use, and I think these guidelines will lead to further reduction of its use,” he said. A notable update in the new guidelines is a recommendation that bezlotoxumab (Zinplava, Merck) be considered for the prevention of CDI recurrence in patients at high risk for recurrence, he said. “This is the first time bezlotoxumab has made it into a major society guideline for the gastroenterology and infectious disease community, and I think it will help get the drug covered more often by payors and make it available more widely to the

practicing clinician,” Dr. Khanna said. Another update that reflects the evolving body of evidence that has emerged over the past several years is a strong recommendation that FMT be considered for use after two CDI recurrences, or in patients with severe and fulminant CDI refractory to antibiotic therapy, particularly when they are poor surgical candidates, Dr. Khanna said. “The previous recommendation in 2013 was to consider FMT, but the body of research has grown to demonstrate its efficacy,” he said. The guideline authors recommend that FMT be repeated for patients experiencing a recurrence of CDI within eight weeks of an initial FMT. In addition, for patients with recurrent CDI who are not candidates for FMT, have relapsed after FMT, or require ongoing or frequent courses of antibiotics, the guidelines suggest using long-term suppressive oral vancomycin. For patients with a first recurrence of CDI, the guidelines suggest use of tapering or pulsed-dose vancomycin or fidaxomicin if patients were previously administered vancomycin or metronidazole. The guidelines recommend testing only of patients with symptoms suggestive of active CDI and use of a highly sensitive and specific CDI testing algorithm to help distinguish between colonization and active infection. According to the guidelines, severe CDI is diagnosed if the white blood cell count is 15,000 cells/mm3 or higher or serum creatinine is greater than 1.5 mg/dL, and fulminant CDI should be diagnosed if the patient has hypotension, shock, ileus or megacolon in the presence of typical CDI symptoms. For patients with fulminant CDI, the guideline authors urge adequate volume resuscitation and oral vancomycin for the first 48 to 72 hours, with the possible addition of IV metronidazole, and use of

ispanic patients with IBD aree 50% % Hismore likely than white non-Hisn panic patients to have CDI during an IBD-related hospitalization, according to an analysis of over 3,600 IBD inpatients in Florida. “Patients admitted with IBD and CDI have different demographic and clinical characteristics, depending on their racial background,” d lead researcher Giovanni Roldan, MD, an internal medicine resident at Jackson Memorial Hospital, Miami, and University of Miami Miller School of Medicine, said during a virtual poster presentation at the 2021 virtual Digestive Disease Week (abstract Sa565). Dr. Roldan and his colleagues have been examining the course of IBD and the prevalence of IBD-related complications, such as CDI, among Hispanic and racial minorities. Their current findings were based on an analysis of 3,608 patients in the Florida State Inpatient Database with an IBD-related admission in 2016. The investigators found 172 CDI diagnoses during the IBD-related hospitalizations. Among white patients hospitalized for IBD, 4.2% had a CDI diagnosis during their stay; that number was 6.5% among Hispanic patients (P<0.05). Among Black patients with IBD, the rate of CDI was 5.3%, which was not significantly higher. The researchers also found that Black and Hispanic patients with IBD and CDI were younger, aged 32 and 35 years, respectively, compared with 42.5 years for white patients (P<0.05). Hispanic and white patients with IBD and CDI had lower Elixhauser Comorbidity Index scores than their Black counterparts (1.54 and 2.19 for Hispanics and whites vs. 3.19 for Blacks) (P<0.05). The authors found no differences in rates of colectomy, lengths of hospital stay or mortality between the racial and ethnic groups.

vancomycin enemas for patients with an ileus. The panel also recommends against discontinuing antisecretory therapy when it is indicated in patients with CDI. They also recommend against the use of probiotics to prevent CDI or recurrent CDI. There are several recommendations specifically targeted to the IBD population, including CDI testing of IBD patients presenting with an acute flare and diarrhea. Other population-specific recommendations target patients who are pregnant, lactating or immunocompromised.

Preliminary Findings Confirm Suspicions About Pouch Failure in Peds

hildren who have a history of ulcerative colitis and ileal-pouch anal-anastomosis experience a more rapid progression to pouch failure than adults and historical controls, new research shows. Pediatric patients undergoing colectomy and their families are often

counseled based on adult data. But the new, single-center, retrospective study of 53 patients who received a pouchoscopy at the University of Chicago Medical Center between 1980 and 2019 suggests the adult data might be misleading for pediatric patients. The results do not change which

children need surgery, but they should help guide how IBD specialists counsel and follow up with pediatric patients to provide informed expectations about how long their pouches are likely to last, said Joseph Runde, DO, a pediatric gastroenterologist at the University of Chicago, who led the study.

see C. Diff Roundup, page 28

“I think there’s been a thought in IBD doctors’ minds that the children that present for colectomy now are different from the children that presented in 1980 or 1990,” Dr. Runde said. Dr. Runde’s team found that 41% of pediatric patients required a colectomy after treatment with anti‒tumor necrosis factor (TNF) agents, compared with 22% of adults. An analysis by decade revealed that while five-year see Pouch, page 33

THE TABLET CHOICE FOR BOWEL PREPARATION

• NO SODIUM PHOSPHATE1 • SAFE AND EFFECTIVE1,2 • ACG-RECOMMENDED SPLIT-DOSE REGIMEN3 – Two SUTAB doses are required for a complete preparation1 Dose 1 consists of 12 tablets and 16 oz of water Dose 2 consists of 12 tablets and 16 oz of water Each dose is followed by two additional 16 oz of water

92% OF PATIENTS IN TWO PIVOTAL TRIALS ACHIEVED SUCCESSFUL BOWEL CLEANSING WITH SUTAB1,2* 91% OF PATIENTS IN ONE PIVOTAL TRIAL RATED SUTAB AS TOLERABLE TO VERY EASY TO CONSUME2† • 52% of all SUTAB and MoviPrep® patients reported at least one selected gastrointestinal adverse reaction1,2‡ r /QTG 576#$ RCVKGPVU TGRQTVGF GZRGTKGPEKPI PCWUGC CPF XQOKVKPI VJCP EQORGVKVQT YKVJ Ű QH VJGUG TGRQTVU considered severe2‡

78% OF PATIENTS IN ONE PIVOTAL TRIAL WOULD REQUEST SUTAB AGAIN FOR A FUTURE COLONOSCOPY2† I -ÕVViÃÃ Ü>Ã Ì i «À >ÀÞ i `« Ì > ` Ü>Ã `iw i` >Ã > ÛiÀ> V i> Ã } >ÃÃiÃÃ i Ì v Î } `® À { iÝVi i Ì® LÞ the blinded endoscopist; scores were assigned following completion of colonoscopy. † Patients completed a preference questionnaire following completion of study drug to capture their perceptions of the preparation experience. This questionnaire has not undergone formal validation. ‡ Patients were queried for selected gastrointestinal adverse reactions of upper abdominal pain, abdominal distension, nausea, and vomiting following completion of study drug, rating the intensity as mild, moderate, or severe.1,2 ACG=American College of Gastroenterology Packaging and tablets MoviPrep® is a registered trademark of Velinor AG.

not shown actual size.

IMPORTANT SAFETY INFORMATION SUTAB® (sodium sulfate, magnesium sulfate, potassium chloride) tablets for oral use is an osmotic laxative indicated for cleansing of the colon in preparation for colonoscopy in adults. DOSAGE AND ADMINISTRATION: A low residue breakfast may be consumed. After breakfast, only clear liquids may be consumed until after the colonoscopy. Administration of two doses of SUTAB (24 tablets) are required for a complete preparation for colonoscopy. Twelve (12) tablets are equivalent to one dose. Water must be consumed with each dose of SUTAB and additional water must be consumed after each dose. Complete all SUTAB tablets and required water at least 2 hours before colonoscopy. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention. WARNINGS AND PRECAUTIONS: , Ã v yÕ ` > ` i iVÌÀ ÞÌi >L À > Ì iÃ: Encourage adequate hydration, assess concurrent medications and consider laboratory assessments prior to and after each use; Cardiac arrhythmias: Consider pre-dose and post-colonoscopy ECGs in patients at increased risk; Seizures: Use caution in patients with a history of seizures and patients at increased risk of seizures, including medications that lower the seizure threshold; Patients with renal impairment or taking concomitant medications that affect renal function: Use caution, ensure adequate hydration and consider laboratory testing; Suspected GI obstruction or perforation: Rule out the diagnosis before administration. ADVERSE REACTIONS: Most common gastrointestinal adverse reactions are: nausea, abdominal distension, vomiting and upper abdominal pain. DRUG INTERACTIONS: Drugs that increase risk of yÕ ` > ` i iVÌÀ ÞÌi L> > Vi° Please see Brief Summary of Prescribing Information on reverse side. See Full Prescribing Information and Medication Guide at SUTAB.com.

From the makers of SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution for adults—

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

C. Diff Roundup continued from page 26

Using Omadacycline for CABP Could Save Over $530 Million

reating community-acquired bacterial pneumonia (CABP) with the aminomethylcycline antibiotic omadacycline instead of fluoroquinolones and third-generation cephalosporins could save the U.S. health care system up to $531 million annually in costs for treatment-related CDI, a

recent modeling study predicted. The estimate is based on results from the OPTIC study comparing omadacycline (Nuzyra, Paratek) and moxifloxacin in the treatment of patients with CABP (N Engl J Med 2019;380:517-527). In the study, 2.1% of moxifloxacin-treated patients

(n=388) developed CDI overall, but among those at high risk for CDI, as measured by the Davis Risk score, the rate was 14%. In contrast, none of the 386 patients treated with omadacycline—whether low or high risk— developed CDI. In the modeling study, researchers

BRIEF SUMMARY: Before prescribing, please see Full Prescribing Information and Medication Guide for SUTAB® (sodium sulfate, magnesium sulfate, potassium chloride) tablets for oral use. INDICATIONS AND USAGE: An osmotic laxative indicated for cleansing of the colon in preparation for colonoscopy in adults. DOSAGE AND ADMINISTRATION: Split Dose (2-Day) Regimen: Dose 1 – On the day prior to colonoscopy: A low residue breakfast may be Packaging and consumed. After breakfast, only clear liquids may be consumed until after the tablets not shown colonoscopy. Early in the evening prior to colonoscopy, open one bottle of actual size. £Ó Ì>L iÌÃ° Ì i «À Û ì` V Ì> iÀ Ü Ì £È Õ ViÃ v Ü>ÌiÀ Õ« Ì Ì i w i®° Swallow each tablet with a sip of water and drink the entire amount over 15 to 20 minutes. Approximately one hour after the last tablet Ã }iÃÌi`] w Ì i «À Û ì` V Ì> iÀ > ÃiV ` Ì i Ü Ì £È Õ ViÃ v Ü>ÌiÀ Õ« Ì Ì i w i® > ` `À Ì i i Ì Ài > Õ Ì ÛiÀ Îä ÕÌiÃ° Ƃ««À Ý >Ìi Þ Îä ÕÌiÃ >vÌiÀ w Ã } Ì i ÃiV ` V Ì> iÀ v Ü>ÌiÀ] w Ì i «À Û ì` V Ì> iÀ Ü Ì £È Õ ViÃ v Ü>ÌiÀ Õ« Ì Ì i w i® > ` `À Ì i i Ì Ài > Õ Ì ÛiÀ Îä ÕÌiÃ° Dose 2 - Day of colonoscopy: Continue to consume only clear liquids until after the colonoscopy. The morning of colonoscopy (5 to 8 hours prior to the colonoscopy and no sooner than 4 hours from starting

Ãi £®] «i Ì i ÃiV ` L ÌÌ i v £Ó Ì>L iÌÃ° Ì i «À Û ì` V Ì> iÀ Ü Ì £È Õ ViÃ v Ü>ÌiÀ Õ« Ì Ì i w i®° -Ü> Ü i>V tablet with a sip of water and drink the entire amount over 15 to 20 minutes. Approximately one hour after the last tablet is ingested, w Ì i «À Û ì` V Ì> iÀ > ÃiV ` Ì i Ü Ì £È Õ ViÃ v Ü>ÌiÀ Õ« Ì Ì i w i® > ` `À Ì i i Ì Ài > Õ Ì ÛiÀ Îä ÕÌiÃ° Ƃ««À Ý >Ìi Þ Îä ÕÌiÃ >vÌiÀ w Ã } Ì i ÃiV ` V Ì> iÀ v Ü>ÌiÀ] w Ì i «À Û ì` V Ì> iÀ Ü Ì £È Õ ViÃ v Ü>ÌiÀ Õ« Ì Ì i w i® > ` `À Ì i i Ì Ài > Õ Ì ÛiÀ Îä ÕÌiÃ° « iÌi > -1/Ƃ Ì>L iÌÃ > ` ÀiµÕ Ài` Ü>ÌiÀ >Ì i>ÃÌ Ó ÕÀÃ Liv Ài V ÃV «Þ° CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention. WARNINGS AND PRECAUTIONS: Serious Fluid and Electrolyte Abnormalities: Ƃ`Û Ãi > «>Ì i ÌÃ Ì Þ`À>Ìi >ìµÕ>Ìi Þ Liv Ài] `ÕÀ }] > ` >vÌiÀ Ì i ÕÃi v -1/Ƃ ° v > «>Ì i Ì ìÛi «Ã Ã } wV> Ì Û Ì } À signs of dehydration after taking SUTAB, consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN). Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment. Correct yÕ ` > ` i iVÌÀ ÞÌi >L À > Ì iÃ Liv Ài ÌÀi>Ì i Ì Ü Ì -1/Ƃ ° 1Ãi -1/Ƃ Ü Ì V>ÕÌ «>Ì i ÌÃ Ü Ì V ` Ì Ã] À Ü >Ài ÕÃ } i` V>Ì Ã] Ì >Ì VÀi>Ãi Ì i À Ã v À yÕ ` > ` i iVÌÀ ÞÌi ` ÃÌÕÀL> ViÃ À >Þ VÀi>Ãi Ì i À Ã v >`ÛiÀÃi iÛi ÌÃ v Ãi âÕÀi] >ÀÀ ÞÌ >Ã] and renal impairment; Cardiac arrhythmias: Use caution when prescribing SUTAB 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; Seizures: Use caution when prescribing SUTAB for patients with a history of seizures and in patients at increased risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, or patients with known or suspected hyponatremia; Use in Patients with Risk of Renal Injury: Use SUTAB with caution in patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting i âÞ i L Ì ÀÃ] > } Ìi Ã ÀiVi«Ì À L V iÀÃ] À ÃÌiÀ `> > Ì y> >Ì ÀÞ `ÀÕ}Ã®° / iÃi «>Ì i ÌÃ >Þ Li >Ì À Ã v À Ài > ÕÀÞ° Advise these patients of the importance of adequate hydration with SUTAB and consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients; Colonic Mucosal Ulcerations and Ischemic Colitis: Osmotic laxative products may produce colonic mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of stimulant laxatives and SUTAB may increase these risks. Consider the potential for mucosal Õ ViÀ>Ì Ã ÀiÃÕ Ì } vÀ Ì i L Üi «Ài«>À>Ì Ü i ÌiÀ«ÀiÌ } V ÃV «Þ w ` }Ã «>Ì i ÌÃ Ü Ì Ü À ÃÕÃ«iVÌ y> >Ì ÀÞ bowel disease (IBD); 1Ãi *>Ì i ÌÃ Ü Ì - } wV> Ì >ÃÌÀ ÌiÃÌ > Ãi>Ãi: If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering SUTAB. Use with caution in patients with severe active ulcerative colitis. ADVERSE REACTIONS: Most common gastrointestinal adverse reactions are: nausea, abdominal distension, vomiting and upper abdominal pain. POTENTIAL FOR DRUG ABSORPTION: SUTAB can reduce the absorption of other co-administered `ÀÕ}Ã° Ƃ` ÃÌiÀ À> i` V>Ì Ã >Ì i>ÃÌ i ÕÀ Liv Ài ÃÌ>ÀÌ } i>V ` Ãi v -1/Ƃ ° Ƃ` ÃÌiÀ ÌiÌÀ>VÞV i > ` yÕ À µÕ i antibiotics, iron, digoxin, chlorpromazine, and penicillamine at least 2 hours before and not less than 6 hours after administration of each dose of SUTAB to avoid chelation with magnesium. Pregnancy: There are no available data on SUTAB use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No reproduction or developmental studies in animals have been conducted with sodium sulfate, magnesium sulfate, and potassium chloride (SUTAB). Lactation: There are no available data on the presence of SUTAB in human or animal milk, the effects on the breastfed child, or the effects on milk production. Pediatric Use: Safety and effectiveness in pediatric patients has not been established. Geriatric Use: Of the 471 patients who received -1/Ƃ « Û Ì> V V> ÌÀ > Ã] £xä ÎÓ¯® ÜiÀi Èx Þi>ÀÃ v >}i À ìÀ] > ` Óx x¯® ÜiÀi Çx Þi>ÀÃ v >}i À ìÀ° ` vviÀi ViÃ safety or effectiveness of SUTAB were observed between geriatric patients and younger patients. Elderly patients are more likely to >Ûi ìVÀi>Ãi` i«>Ì V] Ài > À V>À` >V vÕ VÌ > ` >Þ Li Ài ÃÕÃVi«Ì L i Ì >`ÛiÀÃi Ài>VÌ Ã ÀiÃÕ Ì } vÀ yÕ ` > ` i iVÌÀ ÞÌi abnormalities. STORAGE: Store at 20º to 25°C (68º to 77°F). Excursions permitted between £x¨ Ì Îäc x ¨ Ì nÈc ®° -ii 1-* V ÌÀ i` À Ìi «iÀ>ÌÕÀi° ,Ý Þ° > Õv>VÌÕÀi` LÞ Braintree Laboratories, Inc. Braintree, MA 02185 See Full Prescribing Information and Medication Guide at SUTAB.com. References: 1. SUTAB® [package insert]. Braintree, MA; 2020. 2. Di Palma JA, Bhandari R, Cleveland M, et al. A safety and ivwV>VÞ V «>À Ã v > iÜ ÃÕ v>Ìi L>Ãi` Ì>L iÌ L Üi «Ài«>À>Ì ÛiÀÃÕÃ > * > ` >ÃV ÀL>Ìi V «>À>Ì À >`Õ Ì ÃÕL iVÌÃ undergoing colonoscopy. Am J Gastroenterol° ÓäÓ£Æ££ÈÓ®\Î£ ÎÓn° ` \£ä°£{Îä É> }°ääääääääääää£äÓä 3. Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM; ACG. American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol. Óää Æ£ä{Î®\ÇÎ Çxä° 4. IQVIA. National Prescription Audit Report. May 2021.

—David Wild Dr. Khanna reported financial relationships with Finch, GSK, Jetson, Probiotech, Rebiotix, Seres, Shire/Takeda and Vedanta. Some of the investigators on the omadacycline study are employees of Paratek.

from Paratek, in King of Prussia, Pa., and Albany College of Pharmacy and Health Sciences, in New York, used the OPTIC data to forecast the economic impact of substituting omadacycline for fluoroquinolones and third-generation cephalosporins in the treatment of CABP in hospitalized patients with a high Davis Risk score for CDI. As per national prevalence data, they assumed 100,000 annual hospital admissions for CABP patients with a high Davis Risk score. Extrapolating from the OPTIC data, they estimated 14,000 cases of CDI among these high-risk patients if they were treated with a fluoroquinolone or third-generation cephalosporin and no cases of CDI if they were treated with omadacycline. The economic analysis included only excess treatment costs, such as cost per episode of hospital-onset CDI and CDI recurrence. The investigators accounted for the cost of omadacycline treatment, which they estimated at $2,070 for a fiveday in-hospital course of omadacycline, amounting to $207 million for 100,000 patients. According to the researchers, administering omadacycline instead of fluoroquinolones or third-generation cephalosporins in patients with CABP at high risk for CDI would save roughly $404 million annually in excess costs, assuming a 0% CDI recurrence rate, and $531 million annually, assuming a 20% CDI recurrence rate. The team noted that the findings “are not unique to omadacycline and could be applied to any antibiotic that confers a lower risk of CDI relative to current CABP treatments.” Additional research “is needed to validate the model findings,” according to the researchers, but they concluded that the “results can serve as the basis of antibiotic stewardship initiatives for health care institutions aspiring to reduce hospital CDI rates for associated costs.”

201-289-v2-C

June 2021

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Nearly 1 in 3 IBD Patients Stops Biologic Therapy Within 18 Months

lmost one-third of people followed in an inflammatory bowel disease registry stopped biologic therapy within 1.5 years, most often due to loss of response. The findings highlight the real-world impact of biologic discontinuation on IBD care and the importance of optimizing therapy to avoid loss of response, according to Edward L. Barnes, MD, MPH, an assistant professor of gastroenterology and hepatology at the University of North Carolina at Chapel Hill. “Secondary loss of response, particularly due to antibody formation, remains a critical issue in the long-term effectiveness and durability of biologic therapy for the treatment of Crohn’s disease and ulcerative colitis,” Dr. Barnes said. To better understand the factors associated with discontinuation of biologic agents in a real-world cohort, Dr. Barnes and his colleagues analyzed data on 856 IBD patients (39% with ulcerative

‘Secondary loss of response, particularly due to antibody formation, remains a critical issue in the long-term effectiveness and durability of biologic therapy for the treatment of Crohn’s disease and ulcerative colitis.’ —Edward L. Barnes, MD, MPH, UNC Chapel Hill

colitis, 61% with Crohn’s disease) who received care at 34 community and academic practices across the United States. These patients were enrolled in the TARGET-IBD observational registry between July 2017 and August 2020, and began treatment with a biologic

therapy during the study period. Overall, more than 30% of patients stopped treatment within 18 months (median time to discontinuation, 10 months). Discontinuation of treatment was somewhat more common with anti–tumor necrosis factor agents than anti-integrin and interleukin (IL)-12/ IL-23 inhibitor therapies, the researchers found. Loss of response to treatment was the most common reason for discontinuation (31%), followed by side effects (23%) and initial lack of response during induction therapy (primary nonresponse; 21%). Dr. Barnes noted that development of drug antibodies led to treatment discontinuation in 10% of patients. “Given that secondary loss of response is often due to factors such as antibody formation, there should be a continued focus on optimizing therapy,” he said. Strategies for optimizing biologic therapy, he said, can include: • combination therapy when appropriate; • assessment of drug and antibody levels when loss of response is suspected, followed by dose optimization or combination therapy; and • personalized approaches to treatment choices or regimens. “Additionally, I think addressing expectations of therapy with patients will always be critical, including time to expected effectiveness or clinical response, potential adverse effects, and factors that would necessitate discontinuation of therapy,” Dr. Barnes said. Given that almost one-third of patients in this cohort stopped therapy, Dr. Barnes said he believes this study may prompt a reexamination of the

factors associated with a lack of durability or earlier discontinuation. “Although our options for the treatment of Crohn’s disease and ulcerative colitis continue to increase, these are not infinite, and thus there is a need for strategies to improve the durability of biologic therapies in patients with IBD,” he said. “These may emerge in the form of more targeted or personalized approaches to biologic therapies in future years, but currently, a continued assessment of an individual’s risk for early discontinuation may be the best approach, including risk factors such as number of prior biologics and potential need for combination therapy.” David T. Rubin, MD, the Joseph B. Kirsner Professor of Medicine and chief of the Section of Gastroenterology, Hepatology and Nutrition at the University of Chicago, agreed it is crucial to better understand the reasons patients discontinue biologic therapy so that gastroenterologists can continue to improve the durability of these treatments. “Understanding the multiple factors associated with primary nonresponse as well as loss of response is critical to our care of patients with IBD,” Dr. Rubin said. “This real-world study provides insights that can translate to our conversations with patients regarding the durability of therapies and inform additional work that we as physician-scientists must do to optimize therapies.” —Adam Leitenberger Dr. Barnes served as a consultant to AbbVie, Gilead, Pfizer and Takeda. Dr. Rubin disclosed financial relationships with AbbVie, Arena, Biomica, Bristol Myers Squibb, Ferring, Genentech/Roche, Janssen, Lilly, Merck and Takeda. The findings were reported at the 2020 AIBD meeting (abstract P27).

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

It’s Just a Phase: Filgotinib for Moderately to Severely Active Ulcerative Colitis astroenterology & Endoscopy News generally avoids coverage of phase 2 trials. After all, preliminary results frequently fail to meet early expectations, and even promising phase 3 data often fail to bring a drug to market. But that’s not to say that phase 2 findings are irrelevant. They may be the harbinger of exciting developments in the drug pipeline that clinicians should be aware of, or a preview of the future management of a given condition. With that in mind, we’re launching a new feature called “It’s Just a Phase,” in which we will look at recent phase 2 data in gastroenterology. For our first installment, we’ve chosen studies of the preferential Janus kinase 1 (JAK1) inhibitor filgotinib (Galapagos/Gilead), which is in trials as a potential therapy for the treatment of patients with moderate to severe ulcerative colitis. The findings, from the phase 2b/3 SELECTION Trials, were reported in the Journal of the Canadian Association of Gastroenterology (2021;4[suppl 1]:18-23).

Filgotinib, an oral agent, was tested as induction therapy for patients with moderately to severely active ulcerative colitis who were biologic-naive but failed conventional therapy (Induction Study A) or failed prior biologics (Induction Study B). Patients were randomized 2:2:1 to 200 mg of filgotinib, 100 mg of filgotinib or placebo taken once daily. At week 10, researchers assessed the primary end point (clinical remission), key secondary end points (Mayo score remission, endoscopic remission and histologic remission) and exploratory end points (Mayo score response and endoscopic improvement). In Study A, which randomized 659 patients, the baseline mean Mayo score was 8.6, and 56% of participants had a Mayo endoscopic subscore of 3. A significantly higher proportion of biologic-naive patients on the 200-mg dose of filgotinib achieved clinical remission compared with placebo and all key secondary end points (Table 1). In Study B, which included 689 patients, the baseline mean Mayo score was 9.3, and 78% of participants had an endoscopic subscore of 3. Prior treatment failures were anti–tumor necrosis factor agents (86%), vedolizumab (Entyvio, Takeda; 52%) and both therapies (dual refractory; 43%). A significantly higher proportion of biologic-experienced patients on the 200-mg dose of filgotinib achieved clinical remission compared with placebo. In Studies A and B, patients receiving the higher dose of filgotinib were more likely to achieve a Mayo score response and endoscopic improvement compared with those receiving placebo, according to the researchers. Patients receiving filgotinib and placebo had similar rates of adverse events (AEs), serious AEs and discontinuations due to AEs. In Studies A and B, serious infections were less common with the higher dose of filgotinib (Study A, 0.4% vs. 0.7% vs. 0.7%; Study B, 0.8% vs. 1.4% vs. 1.4%). Herpes zoster occurred in less than 1% in both groups receiving filgotinib. In the maintenance part of the trial, patients who achieved clinical remission or a Mayo score response after 10 weeks of therapy were rerandomized 2:1 to their induction dose of filgotinib or placebo. Patients randomized to placebo induction continued placebo maintenance, and steroid tapering was mandatory. The

primary end point, clinical remission, as well as secondary and exploratory end points were assessed at week 58. The trial treated 664 patients (93, 270 and 301 from induction with placebo, 100 mg of filgotinib and 200 mg of filgotinib, respectively), and 40% were biologicexperienced. The researchers found that patients receiving either dose of filgotinib were more likely to achieve clinical remission than those receiving placebo (Table 2). Compared with placebo, patients receiving 200 mg of filgotinib were more likely to achieve key secondary end points, including six-month corticosteroidfree clinical remission, sustained clinical remission, Mayo score remission, endoscopic remission, histologic remission, Mayo score response and endoscopic improvement, the researchers reported. Compared with placebo, patients on either dose of filgotinib were more likely to experience a Mayo score response and endoscopic improvement. The incidences of all AEs, serious AEs and

discontinuations due to AEs were similar across arms. Serious infection (<2%) and herpes zoster (<1%) were infrequent among patients treated with filgotinib. No venous thromboses, including pulmonary embolism, occurred among patients who received the drug.

Experts Weigh In Brian Feagan, MD, the senior scientific director at Alimentiv Inc. (formerly Robarts Clinical Trials Inc.), and a professor of medicine at Western University, in

Table 1. Outcomes of SELECTION Induction Studies Cohort A Induction Study (Biologic-Naive)

Clinical remission, n (%)

Cohort B Induction Study (Biologic-Experienced)

PBO (n=137)

FIL 100 mg (n=277)

FIL 200 mg (n=245)

Δ% FIL 200 mg vs. PBO

21 (15.3)

53 (19.1)

64 (26.1)

10.8 6 (4.2) P=0.0157

PBO (n=142)

FIL 100 mg (n=285)

FIL 200 mg (n=262)

Δ% FIL 200 mg vs. PBO

27 (9.5)

30 (11.5)

7.2 P=0.0103

FIL, filgotinib; PBO, placebo

Table 2. Outcomes of SELECTION Maintenance Trial Induction Treatment

Clinical remission, n/N (%) a

Filgotinib 200 mg

Filgotinib 100 mg

Placebo

Filgotinib 200 mg

Placebo

Filgotinib 100 mg

11/98 (11.2)

74/199 (37.2)a

12/89 (13.5)

41/172 (23.8)b

P<0.025. b P<0.05 FIL dose arm versus placebo.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

therapies. Moreover, a substantial percentage of patients who respond to a therapy will lose this response over time. “There is an unmet need for effective therapies with different mechanisms of action. An effective oral drug with a good safety profile is a very attractive option for patients in terms of acceptance, convenience and adherence,” said Dr. Charabaty, who was not involved in the SELECTION trials. “JAK inhibition [with tofacitinib] was shown to be effective in controlling inflammation in ulcerative colitis, and with a preferential

London, Ontario, said there is a need for more oral agents in ulcerative colitis. Although the oral agent tofacitinib (Xeljanz, Pfizer) was the first JAK inhibitor to be approved for the condition, the drug’s association with flares of herpes zoster is concerning. This side effect appears to be less frequent with filgotinib. “Filgotinib is safe, especially with regards to infection,” Dr. Feagan said. Currently, no other ulcerative colitis trials are underway for the drug because of reproductive safety concerns that have arisen in animal studies. “The drug has run into issues at the FDA with regard to concern about reproductive toxicology in animals, notwithstanding that it has been on the market in Europe for rheumatoid arthritis,” Dr. Feagan said. “The company is undergoing trials and steps to assure the FDA that it is of a species-specific concern and not a human concern, but that has held up the development of the drug in the United States.” Aline Charabaty, MD, the assistant clinical director of the Division of Gastroenterology at the Johns Hopkins University School of Medicine, in Baltimore, and clinical director of the IBD Center at Johns Hopkins Sibley Memorial Hospital, in Washington, D.C., said more than 40% of patients with moderate to severe ulcerative colitis do not reach remission with current available

JAK1 inhibitor we are expecting to combine the JAK inhibition mechanism efficacy with an improved safety. In this study, we see a low rate of serious infection with filgotinib and a low rate of zoster in contrast to the rate of zoster seen with nonselective JAK inhibitors such as tofacitinib, which inhibits JAK1 and JAK3, and where the rate of zoster is 1.5% to 5% depending on the dose used. These studies show that filgotinib is not only an effective option in bio-naive patients, but also effective in the more difficult to treat ulcerative

colitis patients with severe endoscopic activity and prior failure of one or two biologics. What is even more exciting is the rate of histological remission in bio-naive [35%] and bio-experienced [20%] patients as early as 10 weeks of therapy.” —Kate O’Rourke Dr. Charabaty reported serving as a consultant to/an advisory board member of AbbVie, Janssen, Pfizer and Takeda. She is a member of the editorial board of . Dr. Feagan reported financial relationships with Galapagos and Gilead.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

A #MondayNightIBD Conversation: Fatigue, a Frustrating, Multifactorial Manifestation of IBD Aline Charabaty, MD, AGAF, FACG

Waseem Ahmed, MD

Sabina Ali, MD

Assistant Clinical Director, Division of Gastroenterology Johns Hopkins School of Medicine Clinical Director, IBD Center Johns Hopkins–Sibley Memorial Hospital Washington, DC

Advanced Fellow in Inflammatory Bowel Disease Jill Roberts Center for Inflammatory Bowel Disease Division of Gastroenterology & Hepatology Weill Cornell Medicine New York, New York

Associate Clinical Professor Department of Pediatrics Inflammatory Disease Program UCSF Benioff Children’s Hospital Oakland, California

@DCharabaty

@Waseem_AhmedMD

@sabpeds

atigue is a common symptom experienced by patients with inflammatory bowel disease. Although fatigue can be expected when a patient has a flare or nutrient deficiencies, it also is persistent in a significant proportion of patients despite adequate disease control and normal laboratory values.1

In the absence of formal guidelines on the evaluation and management of fatigue in IBD, clinicians routinely need to address this frustrating symptom that affects patients’ quality of life (QOL). In this article, we review the case of a young patient with ileal Crohn’s disease (CD) presenting with fatigue and numerous associated symptoms. This case was discussed on @MondayNightIBD, with informed opinions from health care professionals (HCPs) who have a focus in IBD, including gastroenterologists, psychologists, and dieticians, as well as from patients with IBD. We review the literature on fatigue and IBD, referring to the opinions of participants in our conversation and the answers to the poll questions. We also propose an #IBDAlgorithm for the evaluation of fatigue in patients with IBD (Figure).

Clinical Case Scenario Presented to HCPs A 19-year-old male patient with CD ileitis on infliximab, in clinical and endoscopic remission (colonoscopy 1 year ago), presents for follow-up. He complains of fatigue over the past 3 months and reports that he has poor sleep, wakes up feeling tired, and does not routinely exercise. In addition, he mentions breaking up with his girlfriend this past year. He has 1 to 2 loose, nonbloody bowel movements daily, with mild abdominal cramping, and has lost 3 lb coinciding with the fatigue. Our poll asked participants which of several tests have the highest diagnostic yield in this setting. The results are shown in Table 1.

Discussion Fatigue refers to a subjectively overwhelming sense of tiredness, lack of energy, and feeling of exhaustion that decreases one’s capacity for physical and mental activity. It affects physical, emotional, cognitive, and social functioning, negatively affecting one’s QOL.1 Fatigue is one of the most common symptoms reported by patients, affecting 80% of patients during an IBD flare. Despite the advent of therapies that effectively

induce and maintain clinical and endoscopic remission, the prevalence of fatigue remains as high as 50% in patients during clinical remission.2 In our #MondayNightIBD patient polls, 66% of patients reported fatigue “most of the time,” including in times of disease control, and 47% expressed that “nothing helped,” including correcting labs and treating associated conditions, mental health therapy in any form (medications, psychotherapy, meditation, etc), and change in diet and physical activity (Tables 2 and 3). Many patients expressed frustration living with fatigue that is different from the “usual fatigue that others experience,” can be unpredictable in intensity from day to day, is exacerbated by stress and illness, and is not improved by rest or sleep. Gastroenterologists routinely face the challenge of assessing and managing ongoing fatigue in patients with IBD in remission. It is increasingly recognized that multiple factors contribute to this debilitating symptom, including anemia and nutrient deficiencies, sleep disorders, psychiatric disease and substance abuse, medication side effects, and associated conditions and comorbidities.3 However, it is also important to recognize that sometimes fatigue persists despite thorough evaluation and treatment, leading to the emerging concept that fatigue should be considered to be an extraintestinal manifestation of IBD that may or may not parallel luminal disease activity.

Active IBD Disease In our #MondayNightIBD case discussion, the majority of clinicians noted the high prevalence of fatigue during active disease and agreed that an objective assessment of disease activity, by serum C-reactive protein, fecal calprotectin, and/or a colonoscopy with ileal intubation, was necessary to evaluate the patient’s fatigue. A Dutch study of 425 patients with IBD showed that the prevalence of fatigue was significantly higher in patients referred to a tertiary care center (with more severe and complicated disease) than in patients who present to a general hospital (65.7% vs 52.5%,

WHAT IS @MondayNIGHTIBD? @MondayNightIBD is an educational Twitter handle created by Aline Charabaty, MD, (@DCharabaty) to bring together health care professionals to discuss complex IBD clinical case scenarios. On Monday afternoons, an IBD clinician posts a clinical vignette, with a management question linked to a poll listing several reasonable options. A special focus is placed on “gray areas” of IBD management, in which guidelines or randomized controlled trials and solid data are lacking, and on “reallife situations,” in which comorbidities, life events, social history, and other details need to be taken into account in decision making. Clinicians—from gastroenterologists to colorectal surgeons, nutritionists, and psychologists—tweet to discuss their approach to the clinical case, citing peer-reviewed articles and sharing their medical expertise. This open forum allows for solid scientific discussions and medical education among peers from different areas of the country and the world, at different stages of their careers (trainees, seasoned clinicians, scientists, and academic and private practice clinicians) in a social media setting without the constraints of time and space. Free 1 AMA CME credit is offered with each #MondayNightIBD conversation. The opinions shared do not reflect medical advice. On Wednesday, a poll is offered to patients who wish to share their experience on the topic discussed by clinicians earlier in the week. The goal of these polls is to highlight patients’ experiences with IBD and help bring to light their unmet needs.

respectively; P=0.01).4 A similar pattern of results was found in patients in remission in the referral center compared with those in the general hospital (53.3% vs 40.5%; P=0.061). In a single-center, cross-sectional study of 187 patients with IBD, 49% reported high levels of fatigue. On multivariable analysis, clinical remission (odds ratio [OR], 0.42; 95% CI, 0.23-0.76) and endoscopic remission (OR, 0.44; 95% CI, 0.22-0.88), but not histologic remission, were inversely associated with fatigue.5 Although a significant proportion of patients note persistence of fatigue despite clinical remission, it is important to remember that clinical remission is not a reliable marker of endoscopic healing in many IBD patients, particularly in patients with CD.6 Hence, a disease activity assessment and treatment of active subclinical inflammation remain paramount in the management of fatigue. see #MondayNightIBD, page 34

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

Pouch continued from page 26

pouch survival was 100% in the 1990s and 2000s, estimated cumulative pouch survival dropped to 72% for colectomies done in the 2010s (P<0.001). “It’s a lifesaving surgery, but over time the outcomes aren’t as good,” Dr. Runde said. “The issue isn’t the surgery, but there’s something about patients that is different from 20 and 30 years ago.” Perhaps the most tantalizing finding, according to Joseph Picoraro, MD, the associate director of the Pediatric IBD Center at Columbia University Irving Medical Center, in New York City, is that children who had received antiTNF agents before their surgery had significantly worse outcomes than their adult counterparts.

‘Before anti-TNF therapy, there weren’t as many options. Now if you get to surgery, it might be that the disease has gone through a gauntlet of medicines, which may reflect very severe disease.’ —Joseph Picoraro, MD, Columbia University Irving Medical Center

of IBD, Dr. Runde said. “The definition of medically resistant is different now compared to two or three decades ago,” he said. Although experts may have suspected that pediatric outcomes were not on par with those in adults, “this important study demonstrates the need for prospective multicenter studies,” Dr. Picoraro said. The study was limited by its retrospective design and relatively small sample size, although Dr. Runde said 53 patients is substantial for a study of

children with IBD. Furthermore, with a single-center design, “the limitation is that there could be something unique to the center,” Dr. Picoraro said. A substantial number of children diagnosed with ulcerative colitis ultimately turn out to have Crohn’s colitis, which Dr. Picoraro said could prove to be an important underlying condition in the new study. If their preoperative diagnosis of ulcerative colitis should have been Crohn’s colitis, the misdiagnosis might be the cause of pouch failure, Dr. Picoraro added.

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Lawrence R. Schiller, MD Compared with previous studies of similar design, “we have a pretty high number of patients that have received anti-TNF therapy,” Dr. Runde said. “A lot of papers predate that kind of medicine and they don’t stratify based on decades of procedure.” “Before anti-TNF therapy, there weren’t as many options,” Dr. Picoraro said. “Now if you get to surgery, it might be that the disease has gone through a gauntlet of medicines, which may reflect very severe disease.” Since anti-TNF exposure does not appear to cause worse outcomes in adults, something specific—and potentially more aggressive—may characterize the pediatric phenotype

•

The researchers excluded cases of familial adenomatous polyposis (FAP), since outcomes tend to be weighted more favorably for FAP because there are no inflammatory complications since it’s not an autoimmune disorder, Dr. Runde said. They also ruled out surgical approach as a confounding factor, as they observed no significant difference in stages or repair (two vs. three) or anastomosis technique between adults and children.

Baylor University Medical Center University of Texas Southwestern Medical Center Dallas, Texas

Release Date: December 31, 2020 Expiration Date: March 31, 2022 Learning Objectives At the completion of this activity, participants should be better able to: 1. Review the importance of patient compliance with colonoscopy prep instructions in the IǺIGXMZI HIXIGXMSR ERH VIQSZEP SJ GERGIVSYW ERH precancerous colon polyps 2. )IWGVMFI XLI FIRIǻXW ERH HVE[FEGOW SJ currently available colonoscopy prep agents, MRGPYHMRK IǽGEG] WEJIX] XSPIVEFMPMX] ERH TEXMIRX preferences 3. )MWGYWW IǽGEG] WEJIX] ERH XSPIVEFMPMX] HEXE JSV E new tablet-based bowel prep agent

Mark vB. Cleveland, PhD Pharmaceutical and Regulatory Consultant Norwell, Massachusetts

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#MondayNightIBD continued from page 32

Active disease causes fatigue likely through proinflammatory cytokine–mediated mechanisms. Inflammatory cytokines acting on the bidirectional brain‒gut axis are thought to mediate fatigue via the hypothalamic‒pituitary axis.7 A study of 84 patients with IBD in clinical remission stratified patients as having fatigue via the checklist individual strength-fatigue score. 8 The authors then conducted flow cytometry analysis and whole-blood stimulation to investigate differences in leukocyte subsets and expression of various cytokines. They noted significant differences in immune profiles between fatigued and nonfatigued patients, with higher levels of tumor necrosis factor‒ alpha (TNF-alpha), interferon-gamma, interleukin (IL)-12, and IL-10 in the fatigue group.

Anemia in IBD HCPs uniformly recommended further evaluation of the patient for anemia, with measurement of iron stores and screening for vitamin B12 and folate deficiency. Iron deficiency anemia (IDA) and anemia of chronic disease or inflammation (ACD) are the most common causes of anemia in patients with IBD, with IDA affecting 36% to 76% of patients. The Crohn’s & Colitis Foundation’s IBD anemia care pathway defines IDA as hemoglobin less than 12 g/dL in women and less than 13 g/dL in men, with a ferritin value less than 100 ng/mL or more than 100 ng/ mL and a transferrin saturation less than 20%.9 It is important for clinicians to be able to distinguish between IDA and ACD, noting the different thresholds for serum ferritin, given its role as an acutephase reactant (ferritin is normal to increased in ACD, generally >100 mcg/L), and for transferrin saturation (low in ACD, <20%).9 When routine testing of these parameters does not distinguish IDA from ACD, measurement of soluble transferrin receptor (sTfR) and sTfR-ferritin index can help clarify the diagnosis. Prompt referral to a hematologist is necessary if the diagnosis remains unclear. In addition to treating the underlying active disease, clinicians should correct iron deficiency in the context of active inflammation—with IV iron rather than an oral iron supplement. Hepcidin is upregulated by inflammatory cytokines, reducing intestinal absorption of oral iron supplements. Particular attention should be paid to vitamin B12 and/or folic acid deficiencies in patients with ileal CD, a history of small bowel resection or short bowel syndrome, chronic dietary restrictions, risk factors for small intestinal bacterial overgrowth, or use of methotrexate or sulfasalazine.7,10 Clinicians contributing to the #MondayNightIBD discussion noted the wide range of what is considered a normal vitamin B12 level, advocating for a low threshold for reflex testing of methyl-malonic acid and homocysteine levels or empiric repletion for B12 values on the lower end of

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

normal (<450 pg/mL). Finally, IBD patients are at increased risk for other macro- and micronutrient deficiencies related to malabsorption, dietary restrictions, and diarrhea.7 Patients with fatigue should be referred for a formal evaluation by a dietician when it is deemed appropriate.

Medication Side Effects Because fatigue is a common potential side effect of several pharmacologic agents, it is especially important to review current medications and recent changes in medications in the assessment of IBD-related fatigue. Fatigue can be a direct drug-related adverse effect, from azathioprine, 6-mercaptopurine, or methotrexate, rather than a secondary mechanism of bone marrow suppression.3 Systemic corticosteroids can cause insomnia, mood changes, myopathy, and fatigue. In addition, rapid steroid tapering and steroid tapering after long-term use can lead to adrenal insufficiency and severe fatigue; early morning cortisol levels and adrenocorticotrophic hormone stimulation testing should be done in patients who have taken steroids, including budesonide, in the past.11,12 Antidepressants and narcotics, commonly prescribed for patients with IBD, can be associated with lethargy and somnolence.13 In contrast, patients randomly assigned to receive adalimumab in the CHARM trial and realworld experience of patients with IBD show that antiTNF induction and maintenance therapy is associated with decreases in fatigue and depression symptoms, and improved QOL.4,14 Some studies investigating the use of cannabis in IBD showed that patients—especially young patients—can experience side effects such as sleepiness and dizziness,15,16 as well as depression symptoms.17

Mental Health Noting the patient’s recent personal relationship difficulties, poor sleep, and decreased physical activity during our #MondayNightIBD discussion, HCPs also advocated for screening for mood and substance use disorders and lifestyle modifications. Per American College of Gastroenterology guidelines, screening for depression and anxiety is recommended for all patients with IBD, given that this population has an increased prevalence of anxiety and depression compared with the general population.18 Several studies show a bidirectional relationship between mood disorders and active symptoms,19 and psychological stress has been shown to increase mucosal TNF-alpha release and reactive oxygen metabolites and reduce rectal mucosal blood flow.20 Patients with a positive screening for mood disorders should be referred for formal evaluation, with consideration of psychotherapy and pharmacotherapy. Although HCPs recognize the importance of mental health care and emotional well-being in patients with IBD, they also recognize that patients have limited access

Table 1. HCP Poll: Which of the following diagnostic tests has the highest yield? Test

Vote, % (N=269)

to dedicated gastrointestinal psychologists.

Physical Inactivity Previous randomized controlled trials have demonstrated improved QOL in IBD patients undergoing a standardized low- to moderate-intensity physical activity regimen.21,22 However, IBD patients commonly are less physically active after their initial diagnosis, for many disease-related reasons (active symptoms, anemia, fatigue, poor body image, and others). A prospective multicenter, cross-sectional study assessed the level of physical activity (with the Godin score) before and after a recent diagnosis of IBD in 158 patients who were in clinical remission or on a stable medication regimen.23 There was a significant decrease in the mean Godin score of 6.94 after IBD diagnosis (P=0.002), and one-third of the patients reduced their activity level after diagnosis. Patients with IBD should be encouraged to resume physical activity at a level that they can tolerate and enjoy.

Sleep Disorders Active disease and nocturnal symptoms are associated with sleep disturbances, and poor sleep has been postulated to be a marker of subclinical disease activ ity. In addition, it is increasingly recognized that even patients with inactive IBD are at higher risk for sleep disorders. In a recent prospective study, 36 patients with inactive IBD and 27 healthy controls underwent polysomnography.24 The inactive IBD cohort had significantly less rapid-eye-movement sleep than controls (23.7% vs 27.8%; P=0.047), and longer periods of oxygen desaturation below 90%. In light of these findings, clinicians should have a low threshold for a formal evaluation of patients by a sleep specialist and screening for a primary sleep disorder, in addition to screening IBD patients with poor sleep for active disease and mood disorders.25

The Thiamine Connection As mentioned previously and highlighted in our #MondayNightIBD patient experience poll (with Table 2. Patient Poll 1: What is your experience with fatigue? When do you have fatigue, what exacerbates it? Factor

Response, % (N=143)

Fatigue mainly with active disease

Fatigue most of the time

Fatigue mainly with increased stress

I get tired “like others”

Table 3. Patient Poll 2: What measures improved your fatigue? Factor

Response, % (N=98)

Correcting lab test deficiencies or treating other organic causes

Labs including vitamin B12, iron studies, C-reactive protein (CRP), fecal calprotectin

Mental health therapy

Colonoscopy

5 36

Change in diet and/or physical activity

Screen for depression and anxiety with appropriate referral Sleep study

Nothing helped

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

46% reporting no intervention was effective in helping with fatigue), fatigue can remain a frustrating symptom despite thorough evaluation and comprehensive interventions, pointing to other still obscure factors at play. The recent randomized, double-blind, placebo-controlled TARIF crossover trial has garnered attention by looking at high-dose oral thiamine supplementation in patients with quiescent IBD and severe, chronic fatigue.26 In the trial, 40 patients were randomly assigned to receive a weight-based high dose of oral thiamine for 4 weeks followed by 4 weeks of washout and 4 weeks of placebo, or oral placebo for 4 weeks with subsequent 4 weeks of washout and 4 weeks of high-dose oral thiamine. The supplementation dose in this study ranged from 600 to 1,800 mg per day, which is much higher than the recommended daily intake of 2 mg. Fatigue was measured using the IBD-Fatigue Questionnaire. Crossover analysis showed a mean reduction of 4.5 points in fatigue after thiamine supplementation compared with a mean increase of 0.75 points after placebo (P=0.0003). The number needed to treat to improve fatigue was 3. Despite the limitations of a small study, thiamine offers a potential effective option because it is an inexpensive and well-tolerated intervention that improved fatigue independent of age, sex, IBD therapy, anxiety or depression, and thiamine levels at enrollment. Thiamine deficiency is uncommon in the Western world, and it is unlikely that fatigue in IBD is due to thiamine deficiency, but rather it could be due to a dysfunction

#MondayNightIBD #GITwitter #MedTwitter Teaching Points • Fatigue is a common symptom in patients with active and inactive IBD. • A complaint of fatigue by a patient should prompt an objective assessment of disease activity by the clinician.

in thiamine transport from blood to mitochondria and low intracellular thiamine levels.

Conclusion Fatigue in IBD is often a manifestation of active disease and/or its associated comorbidities. The mnemonic AAAMMENS can remind clinicians to assess for correctable factors: active IBD, anemia (iron, vitamin B12, folate), associated disorders (not covered here, but consider hepatobiliary disease, testing for thyroid and celiac disease, and testosterone level), medication side effects, mental health and exercise, nutrition, and sleep. Management of fatigue often requires a multidisciplinary approach that includes gastroenterologists, registered dietitians, and psychologists, as well as multidimensional interventions aimed at optimizing the basics of healthy living (physical activity, healthy

• Comprehensive screening for anemia, associated conditions, medication side effects, malnutrition, and mood and sleep disorders is recommended.

eating, and restorative sleep). However, fatigue often becomes a chronic and frustrating symptom refractory to interventions in many patients with IBD in remission, which lead some experts to consider fatigue as an extraintestinal manifestation of IBD. There is a clear immeasurable effect of IBD itself on the persistence of fatigue, and uncovered contributing factors likely exist, as suggested by the TARIF study.26 As a highly relevant patient-reported outcome, fatigue should be included in disease activity measurement scoring systems and assessment as well as in the end points of clinical trials in IBD. As a summary of the #MondayNightIBD conversation and review of the literature, we point to our #IBDAlgorithm for the evaluation of fatigue in IBD. see #MondayNightIBD, page 36

Fatigue and IBD Fatigue and IBD 40%-50% of patients have fatigue despite clinical remission Prevalence: CD > UC Risk factors: • Anemia • Depression, sleep disturbance • Female sex • Thiopurine, MTX

Positive Screen

(GI) Psych Referral (Polysomnography, evaluate sleep hygiene and medical treatment)

Fatigue

Screen for Mood, Sleep, and Substance Use Disorders (ethyl alcohol, THC)

Assess IBD Activity (CRP, FCP, CT/MRE, TDM, colonoscopy)

Assess for Anemia (Check B12, folate, iron, drug toxicity, etc)

Nutritional Status (Screen for vitamin and micronutrient deficiencies)

Optimize Therapy

Treat Anemia

IBD Dietician Evaluation

Mucosal Healing

Anemia Resolved

Optimize Nutrition

Persistent Fatigue

Lifestyle Modifications Consider high-dose thiamine

If active disease Anemia and IBD Pearls • IDA and active IBD: IV iron more effective than oral iron • Ferric carboxymaltose, ferric dextran, and ferric sucrose: fewer infusion reactions than other IV ferrous formulations • Check sTfR to differentiate IDA from ACD • Supplement folate (1 mg per day) in patients taking MTX or SSZ • Monitor and correct vitamin B12 for ileal CD/resection/restricted diet/ deficiency symptoms, even if B12 in low normal range • If macrocytosis persists after correction of B12 and discontinuation of IMM, consider hematology evaluation

Assess for Medical Comorbidities • • • • •

Hepatobiliary Endocrine Celiac disease Autoimmune Occult infection

Drug Adverse Effect

Figure 1. #IBDAlgorithm for the management of fatigue in inflammatory bowel disease. ACD, anemia of chronic disease or inflammation; CD, Crohn’s disease; IDA, iron deficiency anemia; IMM, immunomodulators (azathioprine, mercaptopurine, MTX); MMA, methylmalonic acid; MTX, methotrexate; SSZ, sulfasalazine; sTfR, soluble transferrin receptor; UC, ulcerative colitis

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2021

#MondayNightIBD continued from page 35

References 1. Borren NZ, van der Woude CJ, Anantakrishnan AN. Fatigue in IBD: epidemiology, pathophysiology and management. Nat Rev Gastroenterol Hepatol. 2019;16(4):247-259. 2. Villoria A, Garcia V, Dosal A, et al. Fatigue in out-patients with inflammatory bowel disease: prevalence and predictive factors. PLoS One. 2017;12(7):e0181435. 3. Kreijne JE, Lie MR, Vogelaar L, et al. Practical guideline for fatigue management in inflammatory bowel disease. J Crohns Colitis. 2016;10(1):105-111. 4. Vogelaar L, van’t Spijker A, van Tilburg AJ, et al. Determinants of fatigue in Crohn’s disease patients. Eur J Gastroenterol Hepatol. 2013;25(2):246-251. 5. Lakhani O, Durbin L, Agrawal M, et al. Fatigue is inversely associated with endoscopic but not histologic remission in IBD patients. Am J Gastroenterol. 2019;114(suppl):s413. 6. Pineton de Chambrun G, Blanc P, Peyrin-Biroulet L. Current evidence supporting mucosal healing and deep remission as important treatment goals for inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2016;10(8):915-927. 7. Nocerino A, Nguyen A, Agrawal M, et al.

Fatigue in inflammatory bowel diseases: etiologies and management. Adv Ther. 2020;37(1):97-112. 8. Vogelaar L, de Haar C, Aerts BR, et al. Fatigue in patients with inflammatory bowel disease is associated with distinct differences in immune parameters. Clin Exp Gastroenterol. 2017;10:83-90. 9. Crohn’s & Colitis Foundation. Crohn’s & Colitis Foundation’s IBD anemia care pathway. Accessed June 25, 2021. https://www. crohnscolitisfoundation.org/sites/default/ files/legacy/assets/pdfs/anemiafactsheet.pdf 10. Murawska N, Fabisiak A, Fichna J. Anemia of chronic disease and iron deficiency anemia in inflammatory bowel diseases: pathophysiology, diagnosis, and treatment. Inflamm Bowel Dis. 2016;22(5):1198-1208. 11. Ibrahim A, Dahlqvist P, Olsson T, et al. The clinical course after glucocorticoid treatment in patients with inflammatory bowel disease is linked to suppression of the hypothalamicpituitary-adrenal axis: a retrospective observational study. Therap Adv Gastroenterol. 2017;10(11):829-836. 12. Berkelhammer C, Trabolsi M, Andrejic J, et al. Severe adrenal insufficiency complicating budesonide therapy for Crohn’s disease. Inflamm Bowel Dis. 2011;17(4):1053-1054. 13. Hashash JG, Ramos-Rivers C, Youk A, et al. Quality of sleep and coexistent psychopathology have significant Impact on fatigue burden in patients with

inflammatory bowel disease. J Clin Gastroenterol. 2018;52(5):423-430. 14. Loftus EV, Feagan BG, Colombel JF, et al. Effects of adalimumab maintenance therapy on health-related quality of life of patients with Crohn’s disease: patient-reported outcomes of the CHARM trial. Am J Gastroenterol. 2008;103(12):3132-3141. 15. Naftali T, Bar-Lev Schleider L, Dotan I, et al. Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol. 2013;11(10):1276-1280.e1. 16. Naftali T, Lev LB, Yablecovitch D, et al. Treatment of Crohn’s disease with cannabis: an observational study. Isr Med Assoc J. 2011;13(8):455-458. 17. Leadbeater BJ, Ames ME, LindenCarmichael AN. Age-varying effects of cannabis use frequency and disorder on symptoms of psychosis, depression and anxiety in adolescents and adults. Addiction. 2019;114(2):278-293. 18. Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline: preventive care in inflammatory bowel disease. Am J Gastroenterol. 2017;112(2):241-258. 19. Gracie DJ, Guthrie EA, Hamlin PJ, et al. Bi-directionality of brain-gut interactions in patients with inflammatory bowel disease. Gastroenterology. 2018;154(6):1635-1646. 20. Mawdsley JE, Macey MG, Feakins RM, et al. The effect of acute psychologic stress on systemic and rectal mucosal measures of

inflammation in ulcerative colitis. Gastroenterology. 2006;131(2):410-419. 21. Klare P, Nigg J, Nold J, et al. The impact of a ten-week physical exercise program on health-related quality of life in patients with inflammatory bowel disease: a prospective randomized controlled trial. Digestion. 2015;91(3):239-247. 22. Ng V, Millard W, Lebrun C, et al. Lowintensity exercise improves quality of life in patients with Crohn’s disease. Clin J Sport Med. 2007;17(5):384-388. 23. Gatt K, Schembri J, Katsanos KH, et al. Inflammatory bowel disease [IBD] and physical activity: a study on the impact of diagnosis on the level of exercise amongst patients with IBD. J Crohns Colitis. 2019;13(6):686-692. 24. Bar-Gil Shitrit A, Chen-Shuali C, Adar T, et al. Sleep disturbances can be prospectively observed in patients with an inactive inflammatory bowel disease. Dig Dis Sci. 2018;63(11):2992-2997. 25. Canakis A, Qazi T. Sleep and fatigue in IBD: an unrecognized but important extraintestinal manifestation. Curr Gastroenterol Rep. 2020;22(2):8. 26. Bager P, Hvas CL, Rud CL, et al. Randomised clinical trial: high-dose oral thiamine versus placebo for chronic fatigue in patients with quiescent inflammatory bowel disease. Aliment Pharmacol Ther. 2021;53(1):79-86.

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FDA Approves Zeposia for Treatment of Ulcerative Colitis

he FDA has approved ozanimod (Zeposia, Bristol Myers Squibb) for the treatment of adults with moderately to severely active ulcerative colitis (UC). The multicenter, randomized, double-blind phase 3 True North trial assessed the safety and efficacy of 0.92

Fibrosis continued from page 1

mg of ozanimod in patients with moderately to severely active UC who had an inadequate response or were intolerant to oral aminosalicylates, corticosteroids, immunomodulators and/or biologics. Patients were required to be receiving oral aminosalicylates and/or

corticosteroids before and during the induction period. A total of 30% of patients had previously failed or were intolerant to tumor necrosis factor (TNF) blockers. In the 10-week induction study, 645 patients were randomized in a 2:1 fashion

“look pretty promising in mice, of course there are a lot of therapies that work in mice and don’t work in people. But if we can show that it is effective in several different rodent models—which we are currently working on doing—the chances that it works in humans increases,” he said.

to the effects of MFGE8 may represent a novel approach to the management of fibrostenotic Crohn’s disease,” Dr. Rieder told Gastroenterology & Endoscopy News. Dr. Rieder and his colleagues are conducting several other projects, such as examining the effects of block- First Clinical Trial Launches Moving lab-based findings further along the ing the fibroblast surface molecules that allow these cells to bind with each other to form fibrotic tissue. They’re research and development continuum has historically also investigating the interaction between strictures and been challenging for antifibrotic strategies because of “creeping fat,” the mesenteric fat that surrounds 80% of a lack of interest from the pharmaceutical industry, Dr. Rieder said. A lack of clinical trial end points for intestinal strictures in patients with Crohn’s disease. Several other studies presented at DDW are also fibrosis treatments is one reason this has been the case. “We haven’t had good techniques to detect fibrosis encouraging, despite still being in the lab phase. Hon Wai Koon, PhD, an associate professor in the UCLA without going to surgery, which is very invasive and Vatche and Tamar Manoukian Division of Digestive can’t be done repeatedly to monitor the effects of an Diseases, in Los Angeles, and his colleagues found antifibrotic,” Dr. Rieder said. “We can’t detect fibrosis that a formulation of elafin, a human protease inhibi- on biopsies during endoscopy, and until recently, we tor and antimicrobial peptide, suppressed collagen didn’t have a universal set of symptoms to refer to.” synthesis in intestinal fibroblasts and reversed intestinal fibrosis in mouse models (abstract Su478). “An orally active elafin formulation is harmless to the body and can be a new therapeutic agent against intestinal strictures, and we are looking for partners to conduct clinical trials,” Dr. Koon said. In another study (abstract 383), Dr. Koon and his colleagues found that giving the metabolite sphingosine to mice with induced intestinal fibrosis inhibited intestinal collagen expression and again resulted in antifibrotic effects. “Sphingosine is an edible metabolite that can be readily developed into a new drug therapy with minimal safety concerns,” Dr. Koon said. Antifibrotics that target intestinal tissue specifically overcome the concern that this class of agents could systemically impair wound healing following injury or worsen inflammation by preventing ulcer healing, according to Peter Higgins, MD, PhD, the director of the IBD program at the University of Michigan, in Ann Arbor. Dr. Higgins and his colleagues developed an antifibrotic agent that is gut selective, with an ileal tissue concentration 450 times greater than the plasma concentration. The Bcl-2 inhibitor targets the characteristic resistance to apoptosis that activated myofibroblast cells demonstrate. “We tried to get apoptosis-resistant myofibroblast cells to undergo normal apoptosis, and what we found was encouraging, in that the Bcl-2 inhibitor increased apoptosis in mouse models of fibrosis and significantly reduced cecal and colon fibrosis,” said Dr. Higgins, who presented the findings at DDW 2019 (oral Figure. MR enterography of a small bowel Crohn’s disease stricture (arrow). Coronal presentation 867). Dr. Higgins acknowledged that while the findings HASTE on top and axial HASTE on bottom. The caliper delineates prestenotic dilation. Images courtesy of Dr. Florian Rieder, Cleveland Clinic.

to receive ozanimod (n=429) or placebo (n=216); 94% and 89% of these groups, respectively, completed the study. During induction at week 10, the trial met its primary end point of clinical remission (ozanimod, 18% vs. placebo, 6% ; P<0.0001).

Dr. Rieder and his colleagues in the recently formed global Stenosis Therapy and Anti-fibrosis Research Consortium have developed standardized patient-reported outcomes to define a universal set of stricture symptoms as well as an imaging index on MR enterography to measure stricture response to therapies. The measures are being used as trial end points in a new prospective phase 2, randomized controlled clinical trial looking at antistricture therapy in Crohn’s disease, starting this year. “Even if the findings are negative, the trial will have a huge impact on research in the field,” said Dr. Rieder, who declined to disclose the treatment being studied. “It will teach us about trial design for these agents and give us a clearer understanding of the direction the FDA wants us to follow when studying antifibrotics.” In another sign that the search for intestinal antifibrotics is moving into high gear, Pliant Therapeutics, which has several antifibrotics in the pipeline for nonintestinal disease states, has partnered with Cleveland Clinic to advance the discovery of therapeutic targets for gastrointestinal fibrosis. Dr. Higgins has tempered enthusiasm that his group’s research and the efforts of others will lead to a clinically applicable product in the next few years. “Fibrosis has been and continues to be a tough, tough problem,” he said. For now, he said, the best way to control fibrosis in IBD is to use biologics as soon as possible in the disease course. “The earlier we can get really effective therapy to people, the less often they’re going to develop progressive clinically significant fibrosis that requires surgery,” Dr. Higgins said. The challenge in doing this, he said, is that the current treatment pyramid and payor environment encourage use of the cheapest drugs first, such as corticosteroids and 5-aminosalicylic acid agents, and delay use of biologics, by which time many patients have already developed progressive fibrosis. But an effective antifibrotic would generate significant benefits for patients and their quality of life, Dr. Higgins said. “I think for Crohn’s disease in particular, even if we can’t reverse or prevent fibrosis altogether, if we could dramatically slow progression of fibrosis for those who repeatedly go to surgery, that could potentially double the number of years between surgeries, which would be a big deal.” —David Wild Dr. Koon reported no relevant financial disclosures. Dr. Rieder reported serving as a consultant or an advisor to 89bio, AbbVie, Adnovate, AgomAb, Allergan, Arena, Boehringer Ingelheim, Celgene/Bristol Myers Squibb (BMS), CDISC, Cowen, Galmed, Genentech, Gilead, Gossamer, Guidepoint, Index Pharma, Janssen, Koutif, Mestag, Metacrine, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Surmodics, Surrozen, Takeda, Techlab, Theravance, Thetis, UCB and Ysios. He also reported receiving research funding from AbbVie, BMS, Boehringer Ingelheim, Morphic, Pfizer, Pliant and UCB.

The trial also met several key secondary end points: • Clinical response (48% of the ozanimod group vs. 26% of the placebo group; P<0.0001). • Endoscopic improvement (27% of the ozanimod group vs. 12% of the placebo group; P<0.0001). • Endoscopic-histologic mucosal improvement (13% of the ozanimod group vs. 4% of the placebo group; P<0.001). In the maintenance study, 457 patients who received ozanimod in either UC Study 1 or in an open-label arm and achieved clinical response at week 10 were re-randomized in a 1:1 fashion and treated with 0.92 mg of ozanimod (n=230) or placebo (n=227) for 42 weeks (52 weeks of treatment total). Concomitant aminosalicylates were required through week 52. Patients on corticosteroids tapered their dose on entering the maintenance study. During maintenance at week 52, the trial met its primary end point of clinical remission (37% for ozanimod vs. 19% for placebo; P<0.0001) and key secondary end points, including clinical response (60% vs. 41%, respectively; P<0.0001), endoscopic improvement (46% vs. 26%; P<0.001), corticosteroid-free clinical remission (clinical remission at week 52 while off corticosteroids for at least 12 weeks) (32% vs. 17%; P<0.001), and endoscopic-histologic mucosal improvement (30% vs. 14%; P<0.001). Decreases in rectal bleeding and stool frequency subscores were observed as early as week 2 in patients treated with ozanimod. Eligible patients were rolled into an ongoing, open-label extension trial to assess the longer-term profile of ozanimod in this setting. The most common adverse events seen in the trial were liver function abnormalities, upper respiratory infection and headache. —GEN Staff Based on press releases from the FDA and Bristol Myers Squibb. Gastroenterology & Endoscopy News, the independent monthly newspaper for gastroenterologists, has been providing physicians with comprehensive and objective information since 1978. The newspaper is circulated to more than 19,647 gastroenterologists, colorectal surgeons, and hepatologists, and GI-specific physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of January 2020). Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Please send address changes to Gastroenterology & Endoscopy News, 545 W. 45th Street, 8th Floor, New York, NY 10036. Copyright © 2021 McMahon Publishing.