Gastroenterology & Endoscopy News - Special Edition - Annual Supplement 2023

gastroendonews.com Annual Supplement to Gastroenterology & Endoscopy News • 2023

REVIEW ARTICLES A Gastroenterologist’s Guide To Bowel Prep Challenges in the Diagnosis Of Barrett’s Esophagus And Related Neoplasia Health Maintenance For Patients With IBD A New Era for Managing Clostridioides difficile Infection A Practical Guide to the Microbiome for Gastroenterologists Improving the Safety Of Endoscopy Procedures In Pregnant Patients

SPOTLIGHT SECTIONS Liver Cancer DDW Expert Picks: Crohn’s Disease Motility Lower GI Bleeding

REACH

BEYOND with IMFINZI + IMJUDO

FOR THE FIRST-LINE TREATMENT OF ADULTS WITH UNRESECTABLE HCC1-3

NCCN CATEGORY 1, PREFERRED

National Comprehensive Cancer Network® (NCCN®) Category 1, Preferred Durvalumab (IMFINZI®) + tremelimumab-actl (IMJUDO®) is an NCCN Category 1, preferred first-line systemic treatment option for unresectable HCC4*†‡

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatocellular Carcinoma V.1.2023. ©National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 13, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. *In patients who are not transplant candidates.4 † NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. ‡ See the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for detailed recommendations, including other preferred treatment options.4 Study design: HIMALAYA was a large, Phase III, randomized, open-label, global study of patients with previously untreated unresectable HCC. 1171§ patients were randomized to 1 of 3 arms: IMFINZI + IMJUDO, 1 dose of IMJUDO (300 mg) + IMFINZI (1500 mg Q4W) (n=393), IMFINZI monotherapy, an unapproved regimen for unresectable HCC (1500 mg Q4W) (n=389), or sorafenib (400 mg PO BID) (n=389). All treatments were given until disease progression or unacceptable toxicity.

Patients in all arms could continue to receive treatment after evidence of disease progression if, in the investigator's opinion, they were still benefiting from treatment and continued to meet inclusion and exclusion criteria. The primary endpoint of the study was overall survival for IMFINZI + IMJUDO vs sorafenib. At the 4-year exploratory analysis, overall survival rates at 18, 24, 36, and 48 months were exploratory endpoints and not formally tested for statistical significance.1-3,5 § The HIMALAYA study included an additional arm of therapy: The IMJUDO 75-mg + IMFINZI arm (n=153) was closed following a preplanned analysis of a Phase II study. Results from this arm are not reported in this material, and this dosing regimen is not approved for use. 3

Indication: IMFINZI in combination with IMJUDO is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).

IMPORTANT SAFETY INFORMATION There are no contraindications for IMFINZI® (durvalumab) or IMJUDO® (tremelimumab-actl).

Severe and Fatal Immune-Mediated Adverse Reactions Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI and IMJUDO depending on severity. See USPI Dosing and Administration for specific details. In general, if combination of IMFINZI and IMJUDO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/ day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis IMFINZI in combination with IMJUDO can cause immune-mediated pneumonitis, which may be fatal. Immunemediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMFINZI and IMJUDO, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions.

NEW

A first in uHCC: The ONLY approved 1L IO regimen with 4-year OS data from a Phase III study1-3,5-9

4-YEAR

DATA

PRIMARY ANALYSIS: STATISTICALLY SUPERIOR OS1,2

22% REDUCTION IN RISK of death with IMFINZI + IMJUDO vs sorafenib HR=0.78 (95% CI, 0.66-0.92); P=0.0035|| 16.4 months mOS with IMFINZI + IMJUDO

13.8 months mOS with sorafenib

VS

(95% CI, 14.2-19.6)

(95% CI, 12.3-16.1)

||

The HR is based on the stratified Cox proportional hazard model. The P value is based on a stratified log-rank test and a Lan-DeMets alpha spending function with O'Brien-Fleming–type boundary and the actual number of events observed. The boundary for declaring statistical significance for IMFINZI + IMJUDO vs sorafenib was 0.0398. Median duration of follow-up was 33.2 months (range, 31.7-34.5) for IMFINZI + IMJUDO and 32.2 months (range, 30.4-33.7) for sorafenib. Data cutoff: August 27, 2021.1-3

NEW

4-YEAR EXPLORATORY ANALYSIS: OS RATES 5¶

1 IN 4

1.0

ALIVE AT 4 YEARS

1.5 years

Probability of OS

0.8

48.7%

0.6

2 years 3 years

40.5%

4 years

30.7%

25.2%

0.4

0.2

Events (n/N, %) IMFINZI + IMJUDO (291/393, 74.0%) Sorafenib (316/389, 81.2%)

0.0 0 Number of patients at risk IMFINZI + IMJUDO 393 Sorafenib 389

6

12

18

24

30

36

42

48

54

60

88 50

54 28

19 9

0 1

Time from randomization (months) 308 283

235 211

190 155

158 121

131 83

103 64

¶

At the time of the 4-year analysis, mOS was 16.4 months (95% CI, 14.2-19.6) with IMFINZI + IMJUDO and 13.8 months (95% CI, 12.3-16.1) with sorafenib (HR=0.78 [95% CI, 0.67-0.92]); not formally tested for statistical significance. OS data maturity across the IMFINZI + IMJUDO and sorafenib arms was 78%.

Data cutoff: January 23, 2023.

Estimates of OS rates calculated using Kaplan-Meier technique. OS rates at 18, 24, 36, and 48 months were exploratory endpoints and were not formally tested for statistical significance3,5 In the exploratory analysis, median duration of follow-up was 49.1 months (range, 47.0-50.2) for IMFINZI + IMJUDO and 47.3 months (range, 45.1-49.2) for sorafenib5

Safety and tolerability for IMFINZI + IMJUDO • At the primary analysis, serious adverse reactions occurred in 41% of patients who received IMFINZI + IMJUDO. Serious adverse reactions occurring in >1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). At the 4-year exploratory analysis, serious adverse reactions occurred in 41% of patients who received IMFINZI + IMJUDO, and no new serious treatment-related safety events were reported1,2,5 • Fatal adverse reactions occurred in 8% of patients who received IMFINZI + IMJUDO, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%)1,2

Explore the updated analysis at IMFINZIhcp.com/HCCEfficacy 1L=first line; BID=twice a day; CI=confidence interval; HCC=hepatocellular carcinoma; HR=hazard ratio; IO=immuno-oncology; mOS=median overall survival; NCCN=National Comprehensive Cancer Network® (NCCN®); OS=overall survival; PO=by mouth; Q4W=every 4 weeks; uHCC=unresectable hepatocellular carcinoma.

Please see additional Important Safety Information throughout and Brief Summary of Full Prescribing Information for IMFINZI and IMJUDO on adjacent pages.

IMPORTANT SAFETY INFORMATION (continued) Immune-Mediated Colitis IMFINZI in combination with IMJUDO can cause immune-mediated colitis that is frequently associated with diarrhea.

Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immunemediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (3.6%) adverse reactions. Intestinal perforation has been observed in other studies of IMFINZI and IMJUDO. Immune-Mediated Hepatitis IMFINZI in combination with IMJUDO can cause immune-mediated hepatitis, which may be fatal. Immune-mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMFINZI and IMJUDO, including fatal (0.8%), Grade 4 (0.3%) and Grade 3 (4.1%) adverse reactions.

Immune-Mediated Endocrinopathies • Adrenal Insufficiency: IMFINZI in combination with IMJUDO can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated.

Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%) adverse reactions.

• Hypophysitis: IMFINZI in combination with IMJUDO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Immune-mediated hypophysitis/hypopituitarism occurred in 1% (4/388) of patients receiving IMFINZI and IMJUDO. • Thyroid Disorders (Thyroiditis, Hyperthyroidism, and Hypothyroidism): IMFINZI in combination with IMJUDO can cause immunemediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism.

Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated.

– Immune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving IMFINZI and IMJUDO. – Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%) adverse reactions.

– Immune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMFINZI and IMJUDO. • Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Two patients 0.5% (2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up.

Immune-Mediated Nephritis with Renal Dysfunction IMFINZI in combination with IMJUDO can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 1% (4/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.5%) adverse reactions.

Immune-Mediated Dermatology Reactions IMFINZI in combination with IMJUDO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including StevensJohnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 and CTLA-4 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 4.9% (19/388) of patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions.

Immune-Mediated Pancreatitis IMFINZI in combination with IMJUDO can cause immune-mediated pancreatitis. Immune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions.

Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI in combination with IMJUDO or were reported with the use of other immune-checkpoint inhibitors.

• Cardiac/vascular: Myocarditis, pericarditis, vasculitis.

• Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

• Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

• Gastrointestinal: Gastritis, duodenitis.

• Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.

Other Immune-Mediated Adverse Reactions (continued) • Endocrine: Hypoparathyroidism.

• Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection.

Infusion-Related Reactions IMFINZI and IMJUDO can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI and IMJUDO based on the severity. See USPI Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.

Infusion-related reactions occurred in 10 (2.6%) patients receiving IMFINZI and IMJUDO. Complications of Allogeneic HSCT after IMFINZI Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT. Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, IMFINZI and IMJUDO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and IMJUDO and advise them to use effective contraception during treatment with IMFINZI and IMJUDO and for 3 months after the last dose of IMFINZI and IMJUDO. Lactation There is no information regarding the presence of either IMFINZI or IMJUDO in human milk; however, because of the potential for serious adverse reactions in breastfed infants from IMFINZI and IMJUDO, advise women not to breastfeed during treatment and for 3 months after the last dose.

Adverse Reactions • In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO (n=388), the most common adverse reactions (occurring in 20% of patients) were rash (32%), diarrhea (27%), fatigue (26%), pruritus (23%), musculoskeletal pain (22%), and abdominal pain (20%).

• In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO (n=388), serious adverse reactions occurred in 41% of patients. Serious adverse reactions in >1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMJUDO in combination with durvalumab, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). Permanent discontinuation of treatment regimen due to an adverse reaction occurred in 14% of patients.

The safety and effectiveness of IMFINZI and IMJUDO have not been established in pediatric patients.

Please see additional Important Safety Information throughout and Brief Summary of Full Prescribing Information for IMFINZI and IMJUDO on adjacent pages.

You are encouraged to report the negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

IMFINZI® (durvalumab) injection, for intravenous use Initial U.S. Approval: 2017 Brief Summary of Prescribing Information For complete prescribing information consult official package insert.

INDICATIONS AND USAGE Hepatocellular Carcinoma IMFINZI, in combination with tremelimumab-actl, is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).

DOSAGE AND ADMINISTRATION Recommended Dosage The recommended dosages for IMFINZI as a single agent and IMFINZI in combination with other therapeutic agents are presented in Table 1.

Administer IMFINZI as an intravenous infusion after dilution as recommended [see Dosage and Administration (2.3) in the full Prescribing Information].

Table 1. Recommended Dosages of IMFINZI Indication Recommended IMFINZI Dosage Duration of Therapy Combination with Other Therapeutic Agents uHCC Patients with a body weight After of ≥ 30 kg: Cycle 1 of combination • IMFINZI 1,500 mg following a $ therapy, single dose of tremelimumab-actl administer 300 mg at Day 1 of Cycle 1; IMFINZI as a • Continue IMFINZI 1,500 mg as single agent a single agent every 4 weeks every Patients with a body weight 4 weeks of < 30 kg: until disease • IMFINZI 20 mg/kg following a progression or $ single dose of tremelimumab-actl unacceptable 4 mg/kg at Day 1 of Cycle 1; toxicity • Continue IMFINZI 20 mg/kg as a single agent every 4 weeks $

Administer tremelimumab-actl prior to IMFINZI on the same day. When tremelimumab-actl is administered in combination with IMFINZI, refer to the Prescribing Information for tremelimumab-actl dosing information.

Dosage Modifications for Adverse Reactions No dose reduction for IMFINZI is recommended. In general, withhold IMFINZI for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue IMFINZI for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.

Dosage modifications for IMFINZI or IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy for adverse reactions that require management different from these general guidelines are summarized in Table 4.

Table 4. Recommended Dosage Modifications for Adverse Reactions Adverse Dosage Severity* Reaction Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) in the full Prescribing Information] Grade 2 Withhold† Pneumonitis Permanently Grade 3 or 4 discontinue Grade 2 Withhold† Withhold† or Grade 3 permanently Colitis discontinue‡ Permanently Grade 4 discontinue Intestinal Permanently Any grade perforation discontinue ALT or AST increases to more than 3 and up to 8 times the ULN or Withhold† Hepatitis with total bilirubin increases to more than 1.5 and up to no tumor 3 times ULN involvement of the liver ALT or AST increases to more than 8 times ULN Permanently or discontinue total bilirubin increases to more than 3 times the ULN

Table 4. Recommended Dosage Modifications for Adverse Reactions (cont’d) Adverse Dosage Severity* Reaction Modification AST or ALT is more than 1 and up to 3 times ULN at baseline and increases to more than 5 and up to 10 times ULN or Withhold† AST or ALT is more than Hepatitis 3 and up to 5 times ULN at with tumor involvement of baseline and increases to more § than 8 and up to 10 times ULN the liver AST or ALT increases to more than 10 times ULN Permanently or discontinue total bilirubin increases to more than 3 times ULN Withhold until clinically stable or permanently Endocrinopathies Grade 3 or 4 discontinue depending on severity Grade 2 or 3 increased Nephritis with blood creatinine Withhold† Renal Grade 4 increased Permanently Dysfunction blood creatinine discontinue Suspected SJS, TEN, Exfoliative Withhold† or DRESS Dermatologic Confirmed SJS, TEN, Permanently Conditions or DRESS discontinue Permanently Myocarditis Grade 2, 3, or 4 discontinue Grade 2 Withhold† Neurological Permanently Toxicities Grade 3 or 4 discontinue Other Adverse Reactions Infusion-related Interrupt or reactions [see Grade 1 or 2 slow the rate Warnings and of infusion Precautions (5.2) in the full Permanently Grade 3 or 4 Prescribing discontinue Information] ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal. * Based on National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. † Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating corticosteroids or an inability to reduce corticosteroid dose to 10 mg of prednisone or less per day (or equivalent) within 12 weeks of initiating corticosteroids. ‡ Permanently discontinue IMFINZI for Grade 3 colitis when administered as part of a tremelimumab-actl containing regimen. § If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue IMFINZI based on recommendations for hepatitis with no liver involvement.

Preparation and Administration Preparation • Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.

• Do not shake the vial.

• Withdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL. • Discard partially used or empty vials of IMFINZI. Storage of Infusion Solution • IMFINZI does not contain a preservative.

• Administer infusion solution immediately once prepared. If the infusion solution is not administered immediately and needs to be stored, the time from preparation until the completion of the infusion should not exceed: o 28 days in a refrigerator at 2°C to 8°C (36°F to 46°F) o 8 hours at room temperature up to 25°C (77°F) • Do not freeze.

• Do not shake.

Administration • Administer infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.

• Use separate infusion bags and filters for each drug product.

IMFINZI in Combination with Other Products • Administer all drug products as separate intravenous infusions.

• Do not co-administer other drugs through the same infusion line.

• For platinum-based chemotherapy, refer to Prescribing Information for administration information.

• For pemetrexed therapy, refer to Prescribing Information for administration information.

Combination Regimens: Order of Infusions IMFINZI in Combination with Tremelimumab-actl • Infuse tremelimumab-actl first, followed by IMFINZI on the same day of dosing.

IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy • Infuse tremelimumab-actl first, followed by IMFINZI and then platinum-based chemotherapy on the day of dosing.

IMFINZI in Combination with Tremelimumab-actl and Pemetrexed Therapy • Infuse tremelimumab-actl first, followed by IMFINZI and then pemetrexed therapy on the day of dosing.

Combination Regimens: Infusion Instructions IMFINZI in Combination with Tremelimumab-actl • Administer tremelimumab-actl over 60 minutes followed by a 60 minute observation period. Then administer IMFINZI as a separate intravenous infusion over 60 minutes.

IMFINZI in Combination with Tremelimumab-actl and PlatinumBased Chemotherapy/ Pemetrexed Therapy Cycle 1 • Infuse tremelimumab-actl over 1 hour. One to two hours after completion of tremelimumab-actl infusion, infuse IMFINZI over 1 hour. One to two hours after completion of IMFINZI infusion, administer platinum-based chemotherapy.

Subsequent Cycles • If there are no infusion reactions during cycle 1, subsequent cycles of IMFINZI can be given immediately after tremelimumabactl. The time between the end of the IMFINZI infusion and the start of chemotherapy can be reduced to 30 minutes.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Immune-Mediated Adverse Reactions IMFINZI is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.

The incidence and severity of immune-mediated adverse reactions were similar when IMFINZI was administered as a single agent or in combination with chemotherapy or in combination with tremelimumab-actl and platinum-based chemotherapy, unless otherwise noted.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/ PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.2) in the full Prescribing Information]. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.

Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

IMFINZI® (durvalumab) injection, for intravenous use Immune-Mediated Pneumonitis IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

IMFINZI as a Single Agent In Patients Who Did Not Receive Recent Prior Radiation In patients who received IMFINZI on clinical trials in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (< 0.1%), and Grade 3-4 (0.4%) adverse reactions. Events resolved in 19 of the 34 patients and resulted in permanent discontinuation in 5 patients. Systemic corticosteroids were required in 19 patients (19/34) with pneumonitis who did not receive chemoradiation prior to initiation of IMFINZI. In Patients Who Received Recent Prior Radiation The incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475) 1.1% were fatal and 2.7% were Grade 3 adverse reactions. Events resolved in 50 of the 87 patients and resulted in permanent discontinuation in 27 patients.

Systemic corticosteroids were required in 64 patients (64/87) with pneumonitis who had received chemoradiation prior to initiation of IMFINZI, while 2 patients required use of infliximab with high-dose steroids.

The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar whether IMFINZI was given as a single agent in patients with various cancers in a pooled data set or in patients with ES-SCLC or BTC when given in combination with chemotherapy.

IMFINZI with Tremelimumab-actl Immune-mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions. Events resolved in 3 of the 5 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in all patients; of these, 4 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient (1/5) required other immunosuppressants.

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated pneumonitis occurred in 3.5% (21/596) of patients receiving IMFINZI in combination with tremelimumabactl and platinum-based chemotherapy, including fatal (0.5%), and Grade 3 (1%) adverse reactions. Events resolved in 11 of the 21 patients and resulted in permanent discontinuation in 7 patients. Systemic corticosteroids were required in all patients with immune-mediated pneumonitis, while 1 patient (1/21) required other immunosuppressants.

Immune-Mediated Colitis IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

IMFINZI as a Single Agent Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (< 0.1%) and Grade 3 (0.4%) adverse reactions. Events resolved in 27 of the 37 patients and resulted in permanent discontinuation in 8 patients. Systemic corticosteroids were required in all patients with immune-mediated colitis, while 2 patients (2/37) required other immunosuppressants (e.g., infliximab, mycophenolate).

IMFINZI with Tremelimumab-actl Immune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (3.6%) adverse reactions. Events resolved in 22 of the 23 patients and resulted in permanent discontinuation in 5 patients. All patients received systemic corticosteroids, and 20 of the 23 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received other immunosuppressants.

Intestinal perforation has been observed in other studies of IMFINZI in combination with tremelimumab-actl.

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated colitis occurred in 6.5% (39/596) of patients receiving IMFINZI in combination with tremelimumab-actl including fatal (0.2%) and Grade 3 (2.5%) adverse reactions. Events resolved in 33 of 39 patients and resulted in permanent discontinuation in 11 patients. Systemic corticosteroids were required in all patients with immune-mediated colitis, while 4 patients (4/39) required other corticosteroids.

Intestinal perforation and large intestine perforation were reported in 0.1% of patients receiving IMFINZI in combination with tremelimumab-actl.

Immune-Mediated Hepatitis IMFINZI can cause immune-mediated hepatitis.

IMFINZI as a Single Agent Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions. Events resolved in 21 of the 52 patients and resulted in permanent discontinuation of IMFINZI in 6 patients. Systemic corticosteroids were required in all patients with immune-mediated hepatitis, while 2 patients (2/52) required use of mycophenolate with high-dose steroids.

IMFINZI with Tremelimumab-actl Immune-mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.8%), Grade 4 (0.3%), and Grade 3 (4.1%) adverse reactions.

Events resolved in 12 of the 29 patients and resulted in permanent discontinuation in 9 patients. Systemic corticosteroids were required in all 29 patients and all 29 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients (8/29) required other immunosuppressants.

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated hepatitis occurred in 3.9% (23/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.3%), Grade 4 (0.5%), and Grade 3 (2.0%) adverse reactions.

Events resolved in 12 of the 23 patients and resulted in permanent discontinuation in 10 patients. Systemic corticosteroids were required in all patients with immune-mediated hepatitis, while 2 patients (2/23) required use of other immunosuppressants.

Immune-Mediated Endocrinopathies Adrenal Insufficiency IMFINZI can cause primary or secondary adrenal insufficiency.

For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated.

Withhold or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMFINZI as a Single Agent Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions. Events resolved in 1 of the 9 patients and did not lead to permanent discontinuation of IMFINZI in any patients.

Systemic corticosteroids were required in all patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids.

IMFINZI with Tremelimumab-actl Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMFINZI in combination with tremelimumabactl, including Grade 3 (0.3%) adverse reactions. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in all 6 patients, and of these, 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated adrenal insufficiency occurred in 2.2% (13/596) of patients receiving IMFINZI in combination with tremelimumabactl, including Grade 3 (0.8%) adverse reactions. Events resolved in 2 of the 13 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in all patients with adrenal insufficiency. One patient also required endocrine therapy.

Hypophysitis IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMFINZI as a Single Agent Grade 3 hypophysitis/hypopituitarism occurred in < 0.1% (1/1889) of patients who received IMFINZI. Treatment with systemic corticosteroids was administered in this patient. The event did not lead to permanent discontinuation of IMFINZI. IMFINZI with Tremelimumab-actl Immune-mediated hypophysitis/hypopituitarism occurred in 1% (4/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 2 of the 4 patients.

Systemic corticosteroids were required in 3 patients, and of these, 1 patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Two patients also required endocrine therapy.

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated hypophysitis occurred in 1.3% (8/596) of

2 patients receiving IMFINZI in combination with tremelimumabactl, including Grade 3 (0.5%) adverse reactions. Events resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in 6 patients with immune-mediated hypophysitis; of these, 2 of the 8 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also required endocrine therapy.

Thyroid Disorders IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or discontinue IMFINZI based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information].

Thyroiditis IMFINZI as a Single Agent Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions.

Events resolved in 4 of the 9 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in 3 patients (3/9) with immune-mediated thyroiditis, while 8 patients (8/9) required endocrine therapy.

IMFINZI with Tremelimumab-actl Immune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in 2 patients (2/6) with immune-mediated thyroiditis; of these, 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker.

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated thyroiditis occurred in 1.2% (7/596) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 2 of the 7 patients and one resulted in permanent discontinuation. Systemic corticosteroids were required in 2 patients (2/7) with immune-mediated thyroiditis, while all patients required endocrine therapy.

Hyperthyroidism IMFINZI as a Single Agent Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. Events resolved in 30 of the 39 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in 9 patients (9/39) with immune-mediated hyperthyroidism, while 35 patients (35/39) required endocrine therapy.

IMFINZI with Tremelimumab-actl Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. Events resolved in 15 of the 18 patients. Two patients (2/18) required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seventeen patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated hyperthyroidism occurred in 5% (30/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.2%) adverse reactions. Events resolved in 21 of the 30 patients. Systemic corticosteroids were required in 5 patients (5/30) with immune-mediated hyperthyroidism, while 28 patients (28/30) required endocrine therapy.

Hypothyroidism IMFINZI as a Single Agent Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Events resolved in 31 of the 156 patients and did not lead to permanent discontinuation of IMFINZI in any patients.

Systemic corticosteroids were required in 11 patients (11/156) and the majority of patients (152/156) required long-term thyroid hormone replacement.

IMFINZI with Tremelimumab-actl Immune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMFINZI in combination with tremelimumab-actl.

Events resolved in 5 of the 42 patients. One patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated hypothyroidism occurred in 8.6% (51/596) of patients receiving IMFINZI in combination with tremelimumab-actl,

IMFINZI® (durvalumab) injection, for intravenous use including Grade 3 (0.5%) adverse reactions. Systemic corticosteroids were required in 2 patients (2/51) and all patients required endocrine therapy.

Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMFINZI as a Single Agent Grade 3 immune-mediated type 1 diabetes mellitus occurred in < 0.1% (1/1889) of patients receiving IMFINZI. This patient required long-term insulin therapy and IMFINZI was permanently discontinued. Two additional patients (0.1%, 2/1889) had events of hyperglycemia requiring insulin therapy that did not resolve at the time of reporting.

IMFINZI with Tremelimumab-actl Two patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up.

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated Type 1 diabetes mellitus occurred in 0.5% (3/596) of patients receiving IMFINZI in combination with tremelimumabactl, including Grade 3 (0.3%) adverse reactions. All patients required endocrine therapy.

Immune-Mediated Nephritis with Renal Dysfunction IMFINZI can cause immune-mediated nephritis.

IMFINZI as a Single Agent Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions.

Events resolved in 5 of the 10 patients and resulted in permanent discontinuation in 3 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis.

IMFINZI with Tremelimumab-actl Immune-mediated nephritis occurred in 1% (4/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.5%) adverse reactions. Events resolved in 3 of the 4 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis; of these, 3 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated nephritis occurred in 0.7% (4/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.2%) adverse reactions. Events resolved in 1 of the 4 patients and resulted in permanent discontinuation in 3 patients.

Systemic corticosteroids were required in all patients with immune-mediated nephritis.

Immune-Mediated Dermatology Reactions IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMFINZI as a Single Agent Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions. Events resolved in 19 of the 34 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis.

IMFINZI with Tremelimumab-actl Immune-mediated rash or dermatitis occurred in 4.9% (19/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions.

Events resolved in 13 of the 19 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis; of these, 12 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient received other immunosuppressants.

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated rash or dermatitis occurred in 7.2% (43/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. Events resolved in 32 of the 43 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis.

Immune-Mediated Pancreatitis IMFINZI in combination with tremelimumab-actl can cause immune-mediated pancreatitis.

IMFINZI with Tremelimumab-actl Immune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Events resolved in 6 of the 9 patients. Systemic corticosteroids were required in all 9 patients and of these 7 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or IMFINZI in combination with tremelimumab-actl, or were reported with the use of other PD-1/ PD-L1 blocking antibodies.

Cardiac/vascular: Myocarditis, pericarditis, vasculitis.

Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment.

Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.

Musculoskeletal and connective tissue disorders: Myositis/ polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.

Endocrine: Hypoparathyroidism.

Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection.

Infusion-Related Reactions IMFINZI can cause severe or life-threatening infusion-related reactions.

Monitor for signs and symptoms of infusion-related reactions.

Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information]. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.

IMFINZI as a Single Agent Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.

IMFINZI in Combination with Tremelimumab-actl Infusion-related reactions occurred in 10 (2.6%) patients receiving IMFINZI in combination with tremelimumab-actl.

IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Infusion-related reactions occurred in 2.9% (17/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions.

Complications of Allogeneic HSCT after IMFINZI Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody.

Transplant-related complications include hyperacute graft-versushost-disease (GVHD), acute GVHD, chronic GVHD, hepatic venoocclusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT. Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of durvalumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased premature delivery, fetal loss and premature neonatal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for 3 months after the last dose of IMFINZI [see Use in Specific Populations (8.1, 8.3) in the full Prescribing Information].

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling.

3 • Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) in the full Prescribing Information].

• Infusion-Related Reactions [see Warnings and Precautions (5.2) in the full Prescribing Information].

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.

The data described in the Warnings and Precautions section reflect exposure to IMFINZI as a single agent in a total of 1889 patients enrolled in the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with Stage III NSCLC), Study 1108 (an open-label, single-arm, multicohort study that enrolled 970 patients with advanced solid tumors), and an additional open-label, single-arm trial (ATLANTIC Study) that enrolled 444 patients with advanced solid tumors, including NSCLC. In these trials, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks. Among the 1889 patients, 38% were exposed for 6 months or more and 18% were exposed for 12 months or more. The data also reflect exposure to IMFINZI in combination with chemotherapy in 265 patients from the CASPIAN study (a randomized, open-label study in patients with ES-SCLC), in 338 patients from the TOPAZ-1 study (a randomized, doubleblind study in patients with BTC). In the CASPIAN and TOPAZ-1 studies, IMFINZI was administered at a dose of 1,500 mg every 3 or 4 weeks.

The data described in the Warnings and Precautions also reflect exposure to IMFINZI 1,500 mg in combination with tremelimumabactl 300 mg in 388 patients in HIMALAYA. In the HIMALAYA study patients received IMFINZI 1,500 mg in combination with tremelimumab-actl as a single intravenous infusion of 300 mg, followed by IMFINZI 1,500 mg every 4 weeks. The pooled safety population (N = 596) described in the Warnings and Precautions section reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab-actl 75 mg and histology-based platinum chemotherapy regimens in 330 patients in POSEIDON [see Clinical Studies (14.1) in the full Prescribing Information] and 266 patients with ES-SCLC in CASPIAN who received up to four cycles of platinum-etoposide plus IMFINZI 1,500 mg with tremelimumab-actl 75 mg every 3 weeks followed by IMFINZI 1,500 mg every 4 weeks (an unapproved regimen for extensive stage small cell lung cancer). Among the 596 patients, 55% were exposed to IMFINZI for 6 months or more and 24% were exposed for 12 months or more.

The data described in this section reflect exposure to IMFINZI in patients with Stage III NSCLC enrolled in the PACIFIC study, in patients with metastatic NSCLC enrolled in the POSEIDON study, in patients with ES-SCLC enrolled in the CASPIAN study, in patients with BTC enrolled in the TOPAZ-1 study and in patients with uHCC included in the HIMALAYA study.

Hepatocellular Carcinoma Unresectable HCC - HIMALAYA The safety of IMFINZI in combination with tremelimumab-actl was evaluated in a total of 388 patients with uHCC in HIMALAYA, a randomized, open-label, multicenter study [see Clinical Studies (14.1) in the full Prescribing Information]. Patients received IMFINZI 1,500 mg administered as a single intravenous infusion in combination with tremelimumab-actl 300 mg on the same day, followed by IMFINZI every 4 weeks or sorafenib 400 mg given orally twice daily.

Serious adverse reactions occurred in 41% of patients who received IMFINZI in combination with tremelimumab-actl. Serious adverse reactions in > 1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMFINZI in combination with tremelimumab-actl, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). The most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritis, musculoskeletal pain, and abdominal pain.

Permanent discontinuation of treatment regimen due to an adverse reaction occurred in 14% of patients; the most common adverse reactions leading to treatment discontinuation (≥ 1%) were hemorrhage (1.8%), diarrhea (1.5%), AST increased (1%), and hepatitis (1%).

Dosage interruptions or delay of the treatment regimen due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption or delay in ≥ 1% of patients included ALT increased (3.6%), diarrhea (3.6%), rash (3.6%), amylase increased (3.4%), AST increased (3.1%), lipase increased (2.8%), pneumonia (1.5%), hepatitis (1.5%), pyrexia (1.5%), anemia (1.3%), thrombocytopenia (1%), hyperthyroidism (1%), pneumonitis (1%), and blood creatinine increased (1%).

IMFINZI® (durvalumab) injection, for intravenous use Table 13 summarizes the adverse reactions that occurred in patients treated with IMFINZI in combination with tremelimumab-actl in the HIMALAYA study.

Table 13. Adverse Reactions Occurring in ≥ 10% of Patients in the HIMALAYA study Sorafenib IMFINZI and (N = 374) Tremelimumab-actl (N = 388) Adverse All Grades Grade 3-4 All Grades Grade 3-4 Reaction (%) (%) (%) (%) Gastrointestinal disorders Diarrhea* 27 6 45 4.3 Abdominal pain* 20 1.8 24 4 Nausea 12 0 14 0 Skin and subcutaneous tissue disorders Rash* 32 2.8 57 12 Pruritus 23 0 6 0.3 Metabolism and nutrition disorders Decreased 17 1.3 18 0.8 appetite General disorders and administration site conditions Fatigue* 26 3.9 30 6 Pyrexia* 13 0.3 9 0.3 Psychiatric disorders Insomnia 10 0.3 4.3 0 Endocrine disorders Hypothyroidism* 14 0 6 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal 22 2.6 17 0.8 pain* * Represents a composite of multiple related terms.

Table 14 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI in combination with tremelimumabactl in the HIMALAYA study.

Table 14. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the HIMALAYA study

Laboratory Abnormality Chemistry Aspartate Aminotransferase increased Alanine Aminotransferase increased Sodium decreased Bilirubin increased Alkaline Phosphatase increased Glucose increased Calcium decreased Albumin decreased Potassium increased Creatinine increased Hematology Hemoglobin decreased Lymphocytes decreased Platelets decreased Leukocytes decreased †

IMFINZI and Tremelimumab-actl Any Grade 3† grade† or 4 (%)‡ (%)‡

Sorafenib Any grade† (%)‡

Grade 3† or 4 (%)‡

63

27

55

21

56

18

53

12

46

15

40

11

41

8

47

11

41

8

44

5

39 34

14 0

29 43

4 0.3

31

0.5

37

1.7

28

3.8

21

2.6

21

1.3

15

0.9

52

4.8

40

6

41

11

39

10

29

1.6

35

3.1

20

0.8

30

1.1

Graded according to NCI CTCAE version 4.03.

‡

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with tremelimumab-actl (range: 367-378) and sorafenib (range: 344-352).

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, IMFINZI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in the full Prescribing Information]. There are no available data on the use of IMFINZI in pregnant women.

In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg based on area under the curve (AUC), resulted in an increase in premature delivery, fetal loss, and premature neonatal death (see Data). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal Data As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at a clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice.

Lactation Risk Summary There are no data on the presence of durvalumab in human milk, its effects on the breastfed child, or the effects on milk production.

Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to IMFINZI are unknown. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death (see Data).

Because of the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IMFINZI and for 3 months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended duration to not breastfeed, as appropriate.

Data In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature neonatal death.

Females and Males of Reproductive Potential Pregnancy testing Verify pregnancy status of females of reproductive potential prior to initiating treatment with IMFINZI. Contraception Females IMFINZI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for 3 months following the last dose of IMFINZI. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended contraception duration, as appropriate.

Pediatric Use The safety and effectiveness of IMFINZI have not been established in pediatric patients.

4 Geriatric Use Of the 476 patients treated with IMFINZI in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older.

No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients.

Of the 393 patients with uHCC treated with IMFINZI in combination with tremelimumab-actl, 50% of patients were 65 years of age or older and 13% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide in the full Prescribing Information).

Immune-Mediated Adverse Reactions Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMFINZI [see Warnings and Precautions (5.1) in the full Prescribing Information], including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.

• Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.

• Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.

• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis.

• Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.

• Dermatological Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of severe dermatological reactions.

• Pancreatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis.

• Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis, aseptic meningitis, encephalitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, and myasthenia gravis.

Infusion-Related Reactions: • Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2) in the full Prescribing Information].

Complications of Allogeneic HSCT: • Advise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.3) in the full Prescribing Information].

Embryo-Fetal Toxicity: • Advise females of reproductive potential that IMFINZI can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3) in the full Prescribing Information].

• Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of IMFINZI [see Use in Specific Populations (8.3) in the full Prescribing Information].

Lactation: • Advise female patients not to breastfeed while taking IMFINZI and for 3 months after the last dose [see Warnings and Precautions (5.4) and Use in Specific Populations (8.2) in the full Prescribing Information].

Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 By: AstraZeneca UK Limited 1 Francis Crick Ave., Cambridge, England CB2 0AA US License No. 2043 IMFINZI is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2022 6/23 US-77669 7/23

IMJUDO® (tremelimumab-actl) injection, for intravenous use Initial U.S. Approval: 2022 Brief Summary of Prescribing Information For complete prescribing information consult official package insert.

INDICATIONS AND USAGE Hepatocellular Carcinoma IMJUDO, in combination with durvalumab, is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).

DOSAGE AND ADMINISTRATION Recommended Dosage The recommended dosages of IMJUDO are presented in Table 1.

Administer IMJUDO as an intravenous infusion after dilution as recommended [see Dosage and Administration (2.3) in the full Prescribing Information].

IMJUDO in Combination with Durvalumab Table 1. Recommended dosage of IMJUDO Indication Recommended IMJUDO Dosage Patients with a body weight uHCC of 30 kg and more: • A single dose of IMJUDO1 300 mg followed by durvalumab2 1,500 mg at Day 1 of Cycle 1; • Continue durvalumab 1,500 mg as a single agent every 4 weeks Patients with a body weight of less than 30 kg: • A single dose of IMJUDO1 4 mg/kg followed by durvalumab2 20 mg/kg at Day 1 of Cycle 1; • Continue durvalumab 20 mg/kg as a single agent every 4 weeks 1 2

Table 4. Recommended Dosage Modifications for Adverse Reactions (cont’d) Adverse Reaction

Hepatitis with tumor involvement of the liver3

Severity1 AST or ALT is more than 1 and up to 3 times ULN at baseline and increases to more than 5 and up to 10 times ULN or AST or ALT is more than 3 and up to 5 times ULN at baseline and increases to more than 8 and up to 10 times ULN AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN

Duration of Therapy After Cycle 1 of combination therapy, administer durvalumab as a single agent every 4 weeks until disease progression or unacceptable toxicity

Administer IMJUDO prior to durvalumab on the same day.

Refer to the Prescribing Information for durvalumab dosing information.

Dosage Modifications for Adverse Reactions No dose reduction for treatment is recommended. In general, withhold treatment regimen for severe (Grade 3) immunemediated adverse reactions. Permanently discontinue treatment regimen for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.

Recommended treatment modifications are presented in Table 4.

Table 4. Recommended Dosage Modifications for Adverse Reactions Adverse Dosage Reaction Severity1 Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) in the full Prescribing Information] Grade 2 Withhold2 Pneumonitis Permanently Grade 3 or 4 discontinue Grade 2 Withhold2 Colitis Permanently Grade 3 or 4 discontinue Intestinal Permanently Any grade perforation discontinue ALT or AST increases to more than 3 and up to 8 times the ULN or Withhold2 total bilirubin increases to Hepatitis with more than 1.5 and up to no tumor 3 times ULN involvement of the liver ALT or AST increases to more than 8 times ULN Permanently or discontinue total bilirubin increases to more than 3 times the ULN

Endocrinopathies

Nephritis with Renal Dysfunction Exfoliative Dermatologic Conditions Myocarditis Neurological Toxicities

Grade 3 or 4

Grade 2 or 3 increased blood creatinine Grade 4 increased blood creatinine Suspected SJS, TEN, or DRESS Confirmed SJS, TEN, or DRESS Grade 2, 3, or 4 Grade 2 Grade 3 or 4

Other Adverse Reactions Infusion-related reactions [see Grade 1 or 2 Warnings and Precautions (5.2) in the full Prescribing Grade 3 or 4 Information]

Dosage Modification

Withhold2

Permanently discontinue Withhold until clinically stable or permanently discontinue depending on severity Withhold2 Permanently discontinue Withhold2 Permanently discontinue Permanently discontinue Withhold2 Permanently discontinue Interrupt or slow the rate of infusion Permanently discontinue

ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal 1 Based on National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.

2 Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or an inability to reduce corticosteroid dose to 10 mg of prednisone or less per day (or equivalent) within 12 weeks of initiating corticosteroids.

3 If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue durvalumab based on recommendations for hepatitis with no liver involvement.

Preparation and Administration Preparation • Visually inspect drug product for particulate matter and discoloration. Discard if the solution is cloudy, discolored, or visible particles are observed.

• Do not shake the vial.

• Withdraw the required volume from the vial(s) of IMJUDO and discard the vial with any unused portion.

• Transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and dilute to a concentration between 0.1 mg/mL and 10 mg/mL. Mix diluted solution by gentle inversion. Do not shake the solution.

Storage of Diluted IMJUDO Infusion Solution • IMJUDO does not contain a preservative. Administer infusion solution immediately once prepared. If infusion solution is not administered immediately and needs to be stored, the total time from preparation to the start of administration should not exceed: o 24 hours in a refrigerator at 2°C to 8°C (36°F to 46°F) o 24 hours at room temperature up to 30°C (86°F) • Do not freeze.

• Do not shake.

Administration • Administer IMJUDO infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron filter.

• Use separate infusion bags and filters for each drug product.

IMJUDO In Combination with Other Products • Administer all drug products as separate intravenous infusions.

• Do not co-administer other drugs through the same infusion line.

Combination Regimens: Order of Infusions IMJUDO in Combination with Durvalumab • Infuse IMJUDO, followed by durvalumab on the same day of dosing.

Combination Regimens: Infusion Instructions IMJUDO in Combination with Durvalumab • Observe patient for 60 minutes following completion of IMJUDO infusion [see Warnings and Precautions (5.2) in the full Prescribing Information]. Then administer durvalumab as a separate intravenous infusion over 60 minutes.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Severe and Fatal Immune-Mediated Adverse Reactions IMJUDO is a monoclonal antibody that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, thereby removing inhibition of the immune response. In combination with durvalumab, a PD-L1 inhibitor, these drugs have the potential for induction of immune-mediated adverse reactions. Immune-mediated adverse reactions listed herein may not be inclusive of all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting IMJUDO in combination with durvalumab. While immune-mediated adverse reactions usually manifest during treatment, immune-mediated adverse reactions can also manifest after discontinuation of IMJUDO and/or durvalumab.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of IMJUDO in combination with durvalumab. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue IMJUDO and durvalumab depending on severity [see Dosage and Administration (2.2) in the full Prescribing Information]. In general, if combination of IMJUDO and durvalumab requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis IMJUDO in combination with durvalumab can cause immunemediated pneumonitis, which may be fatal.

IMJUDO with Durvalumab Immune-mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMJUDO in combination with durvalumab, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions. Events resolved in 3 of the 5 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in all patients; of these, 4 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient (1/5) required other immunosuppressants.

Immune-Mediated Colitis IMJUDO in combination with durvalumab and platinum-based chemotherapy can cause immune-mediated colitis, which may be fatal.

IMJUDO in combination with durvalumab can cause immunemediated colitis that is frequently associated with diarrhea.

Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis.

In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

IMJUDO with Durvalumab Immune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 3 (3.6%) adverse reactions. Events resolved in

IMJUDO® (tremelimumab-actl) injection, for intravenous use 22 of the 23 patients and resulted in permanent discontinuation in 5 patients. All patients received systemic corticosteroids, and 20 of the 23 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received other immunosuppressants.

Intestinal perforation has been observed in other studies of IMJUDO in combination with durvalumab.

Immune-Mediated Hepatitis IMJUDO in combination with durvalumab can cause immunemediated hepatitis, which may be fatal.

IMJUDO with Durvalumab Immune-mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMJUDO in combination with durvalumab, including fatal (0.8%), Grade 4 (0.3%), and Grade 3 (4.1%) adverse reactions. Events resolved in 12 of the 29 patients and resulted in permanent discontinuation in 9 patients. Systemic corticosteroids were required in all 29 patients and all 29 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients (8/29) required other immunosuppressants.

Immune-Mediated Endocrinopathies Adrenal Insufficiency: IMJUDO in combination with durvalumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue IMJUDO in combination with durvalumab based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMJUDO with Durvalumab Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 3 (0.3%) adverse reactions. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in all 6 patients, and of these, 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

Hypophysitis: IMJUDO in combination with durvalumab can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Withhold or permanently discontinue IMJUDO in combination with durvalumab depending on severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMJUDO with Durvalumab Immune-mediated hypophysitis/hypopituitarism occurred in 1% (4/388) of patients receiving IMJUDO in combination with durvalumab. Events resolved in 2 of the 4 patients. Systemic corticosteroids were required in 3 patients, and of these, 1 patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Two patients also required endocrine therapy.

Thyroid Disorders: IMJUDO in combination with durvalumab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or discontinue IMJUDO in combination with durvalumab based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information].

Thyroiditis: IMJUDO with Durvalumab Immune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving IMJUDO in combination with durvalumab. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in 2 patients (2/6) with immune-mediated thyroiditis; of these, 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker.

Hyperthyroidism: IMJUDO with Durvalumab Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 3 (0.3%) adverse reactions. Events resolved in 15 of the 18 patients. Two patients (2/18) required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seventeen patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).

Hypothyroidism: IMJUDO with Durvalumab Immune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMJUDO in combination with durvalumab.

Events resolved in 5 of the 42 patients. One patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).

Type 1 Diabetes Mellitus, Which Can Present with Diabetic Ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue IMJUDO in combination with durvalumab based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMJUDO with Durvalumab Two patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up.

Immune-Mediated Nephritis with Renal Dysfunction IMJUDO in combination with durvalumab can cause immunemediated nephritis.

IMJUDO with Durvalumab Immune-mediated nephritis occurred in 1% (4/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 3 (0.5%) adverse reactions. Events resolved in 3 of the 4 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis; of these, 3 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

Immune-Mediated Dermatology Reactions IMJUDO in combination with durvalumab can cause immunemediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with CTLA-4 and PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue IMJUDO in combination with durvalumab depending on severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMJUDO with Durvalumab Immune-mediated rash or dermatitis occurred in 4.9% (19/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions.

Events resolved in 13 of the 19 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis; of these, 12 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient received other immunosuppressants.

Immune-Mediated Pancreatitis IMJUDO in combination with durvalumab can cause immunemediated pancreatitis.

IMJUDO with Durvalumab Immune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Events resolved in 6 of the 9 patients. Systemic corticosteroids were required in all 9 patients and of these, 7 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMJUDO in combination with durvalumab or were reported with the use of other immune-checkpoint inhibitors.

Cardiac/vascular: Myocarditis, pericarditis, vasculitis.

Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment.

Various grades of visual impairment to include blindness can occur.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Gastritis, duodenitis.

Musculoskeletal and connective tissue disorders: Myositis/ polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica.

Endocrine: Hypoparathyroidism.

Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, and immune thrombocytopenia.

2

Infusion-Related Reactions IMJUDO in combination with durvalumab can cause severe or life-threatening infusion-related reactions.

Monitor for signs and symptoms of infusion-related reactions.

Interrupt, slow the rate of, or permanently discontinue IMJUDO and durvalumab based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information]. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.

IMJUDO with Durvalumab Infusion-related reactions occurred in 10 (2.6%) patients receiving IMJUDO in combination with durvalumab.

IMJUDO with Durvalumab and Platinum-Based Chemotherapy Infusion-related reactions occurred in 2.9% (17/596) of patients receiving IMJUDO in combination with durvalumab and platinumbased chemotherapy, including Grade 3 (0.3%) adverse reactions.

Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, IMJUDO can cause fetal harm when administered to a pregnant woman. In animal studies, CTLA-4 blockade is associated with higher incidence of pregnancy loss.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMJUDO and for 3 months after the last dose of IMJUDO [see Use in Specific Populations (8.1, 8.3) in the full Prescribing Information].

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) in the full Prescribing Information].

• Infusion-Related Reactions [see Warnings and Precautions (5.2) in the full Prescribing Information].

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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.

The data described in the Warnings and Precautions reflect exposure to IMJUDO 300 mg in combination with durvalumab 1,500 mg in 388 patients in HIMALAYA. In the HIMALAYA study patients received IMJUDO 300 mg administered as a single intravenous infusion in combination with durvalumab 1,500 mg on the same day, followed by durvalumab every 4 weeks.

The data also reflects exposure to IMJUDO 75 mg in combination with durvalumab 1,500 mg and histology-based platinum chemotherapy regimens in the pooled safety population (N=596) of 330 patients in POSEIDON [see Clinical Studies (14.1) in the full Prescribing Information], and 266 patients in CASPIAN who received up to four cycles of platinum-etoposide plus durvalumab 1,500 mg with tremelimumab-actl 75 mg every 3 weeks, followed by durvalumab 1,500 mg every 4 weeks (an unapproved regimen for extensive-stage small cell lung cancer). Of these patients, 64% received the maximum of 5 doses of IMJUDO and 79% received at least 4 doses.

In this pooled safety population, the most common (> 20%) adverse reactions were nausea (37%), decreased appetite (25%), and fatigue (22%). In this pooled safety population, the most common Grade 3 or 4 (> 10%) laboratory abnormalities were neutropenia (39%), leukopenia (21%), lymphocytopenia (20%), anemia (20%), hyponatremia (14%), lipase increased (12%), and thrombocytopenia (11%).

The data described in this section reflect exposure to IMJUDO in patients with uHCC included in the HIMALAYA study and in patients with metastatic NSCLC enrolled in the POSEIDON study.

Hepatocellular Carcinoma Unresectable HCC - HIMALAYA The safety of IMJUDO administered in combination with durvalumab was evaluated in a total of 388 patients with uHCC in HIMALAYA, a randomized, open-label, multicenter study [see Clinical Studies (14.1) in the full Prescribing Information]. Patients received IMJUDO 300 mg administered as a single intravenous infusion in combination with durvalumab 1,500 mg on the same day, followed by durvalumab every 4 weeks or sorafenib 400 mg given orally twice daily.

Serious adverse reactions occurred in 41% of patients who received IMJUDO in combination with durvalumab. Serious adverse reactions in > 1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMJUDO in combination with durvalumab, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%),

IMJUDO® (tremelimumab-actl) injection, for intravenous use hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). The most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.

Permanent discontinuation of the treatment regimen due to an adverse reaction occurred in 14% of patients; the most common adverse reactions leading to treatment discontinuation (≥ 1%) were hemorrhage (1.8%), diarrhea (1.5%), AST increased (1%), and hepatitis (1%).

Dosage interruptions or delay of the treatment regimen due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption or delay in ≥ 1% of patients included ALT increased (3.6%), diarrhea (3.6%), rash (3.6%), amylase increased (3.4%), AST increased (3.1%), lipase increased (2.8%), pneumonia (1.5%), hepatitis (1.5%), pyrexia (1.5%), anemia (1.3%), thrombocytopenia (1%), hyperthyroidism (1%), pneumonitis (1%), and blood creatinine increased (1%).

Table 5 summarizes the adverse reactions that occurred in patients treated with IMJUDO in combination with durvalumab in the HIMALAYA study.

Table 5. Adverse Reactions Occurring in ≥ 10% Patients in the HIMALAYA study IMJUDO and Sorafenib Durvalumab (N=374) (N=388) Grade 3-4 All Grades Grade 3-4 Adverse Reaction All Grades (%) (%) (%) (%) Gastrointestinal disorders Diarrhea1 27 6 45 4.3 Abdominal pain1 20 1.8 24 4 Nausea 12 0 14 0 Skin and subcutaneous tissue disorders 32 2.8 57 12 Rash1 Pruritus 23 0 6 0.3 Metabolism and nutrition disorders Decreased appetite 17 1.3 18 0.8 General disorders and administration site conditions Fatigue1 26 3.9 30 6 13 0.3 9 0.3 Pyrexia1 Psychiatric disorders Insomnia 10 0.3 4.3 0 Endocrine disorders Hypothyroidism1 14 0 6 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal 22 2.6 17 0.8 pain1 1

Represents a composite of multiple related terms.

Table 6 summarizes the laboratory abnormalities that occurred in patients treated with IMJUDO in combination with durvalumab in the HIMALAYA study.

Table 6. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the HIMALAYA study

Laboratory Abnormality Chemistry Aspartate Aminotransferase increased Alanine Aminotransferase increased Sodium decreased Bilirubin increased Alkaline Phosphatase increased Glucose increased Calcium decreased Albumin decreased Potassium increased Creatinine increased

IMJUDO and Sorafenib Durvalumab Any grade1 Grade 31 Any grade1 Grade 31 (%)2 or 4 (%)2 or 4 (%)2 (%)2 63

27

55

21

56

18

53

12

46 41 41

15 8 8

40 47 44

11 11 5

39 34 31 28

14 0 0.5 3.8

29 43 37 21

4 0.3 1.7 2.6

21

1.3

15

0.9

Table 6. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the HIMALAYA study (cont’d)

Laboratory Abnormality Hematology Hemoglobin decreased Lymphocytes decreased Platelets decreased Leukocytes decreased

IMJUDO and Sorafenib Durvalumab 1 1 Any grade Grade 3 Any grade1 Grade 31 (%)2 or 4 (%)2 or 4 (%)2 (%)2 52

4.8

40

6

41

11

39

10

29 20

1.6 0.8

35 30

3.1 1.1

1

Graded according to NCI CTCAE version 4.03.

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMJUDO with durvalumab (range: 367-378) and sorafenib (range: 344-352).

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USE IN SPECIFIC POPULATIONS Pregnancy Risk summary Based on findings from animal studies and its mechanism of action, IMJUDO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in the full Prescribing Information]. There are no available data on the use of IMJUDO in pregnant women. In animal studies, CTLA-4 blockade is associated with increased risk of immune-mediated rejection of the developing fetus and fetal death (see Data).

Human immunoglobulin G2 (IgG2) is known to cross the placental barrier; therefore, IMJUDO has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Animal Data In a reproduction study, administration of tremelimumab-actl to pregnant cynomolgus monkeys during the period of organogenesis was not associated with maternal toxicity or effects on embryo-fetal development at exposure levels approximately 4 to 31-times higher than those observed at a recommended dose range of 75 mg to 300 mg based on area under the curve (AUC).

CTLA-4 plays a role in maintaining maternal immune tolerance to the fetus to preserve pregnancy and in immune regulation of the newborn. In a murine model of pregnancy, CTLA-4 blockade resulted in increased resorptions and reduced live fetuses. Mated genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-) gave birth to CTLA-4+/- offspring and offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-) that appeared healthy at birth.

The CTLA-4-/- homozygous negative offspring developed signs of a lymphoproliferative disorder and died by 3 to 4 weeks of age with multiorgan tissue destruction. Based on its mechanism of action, fetal exposure to tremelimumab-actl may increase the risk of developing immune-mediated disorders or altering the normal immune response.

Lactation Risk Summary There are no data on the presence of tremelimumab-actl in human milk, its effects on a breastfed child, or on milk production.

Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to IMJUDO are unknown. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IMJUDO and for 3 months after the last dose. Refer to the Prescribing Information for agents administered in combination with IMJUDO for breastfeeding recommendations, as appropriate.

Females and Males of Reproductive Potential IMJUDO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information].

Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating treatment with IMJUDO. Contraception Advise females of reproductive potential to use effective contraception during treatment with IMJUDO and for 3 months after the last dose. Refer to the Prescribing Information for

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the agents administered in combination with IMJUDO for recommended contraception duration, as appropriate.

Pediatric Use The safety and effectiveness of tremelimumab-actl have not been established in pediatric patients.

Geriatric Use Of the 393 patients with uHCC treated with IMJUDO in combination with durvalumab, 50% of patients were 65 years or older and 13% of patients were 75 years or older. No overall differences in safety or efficacy of IMJUDO have been observed between patients 65 years or older and younger adult patients.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (see Medication Guide in the full Prescribing Information).

Immune-Mediated Adverse Reactions Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMJUDO in combination with durvalumab, including [see Warnings and Precautions (5.1) in the full Prescribing Information]: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.

• Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.

• Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.

• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis.

• Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.

• Dermatological Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of severe dermatological reactions.

• Pancreatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis.

• Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of aseptic meningitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, and myasthenia gravis.

Infusion-Related Reactions: • Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2) in the full Prescribing Information].

Embryo-Fetal Toxicity: • Advise females of reproductive potential that IMJUDO can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3) in the full Prescribing Information].

• Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of IMJUDO [see Use in Specific Populations (8.3) in the full Prescribing Information].

Lactation: • Advise female patients not to breastfeed while taking IMJUDO and for 3 months after the last dose [see Warnings and Precautions (5.3) and Use in Specific Populations (8.2) in the full Prescribing Information].

Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 Manufactured By: AstraZeneca AB, Södertälje, Sweden SE-15185 US License No. 2059 IMJUDO® is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2022 06/23 US-77951 7/23

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DISCLAIMER—The reviews in this issue are designed to be a summary of information, and they represent the opinions of the authors. Although detailed, the reviews are not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of these reviews, and the absence of typographical errors is not guaranteed.

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gastroendonews.com Annual Supplement to Gastroenterology & Endoscopy News • 2023

REVIEW ARTICLES

SPOTLIGHT SECTIONS

21 A Gastroenterologist’s Guide To Bowel Prep

16 Liver Cancer

Jonathan Beard, MD, and Audrey H. Calderwood, MD

31 Challenges in the Diagnosis of Barrett’s Esophagus and Related Neoplasia Abhilash Perisetti, MD, and Prateek Sharma, MD

35 Health Maintenance for Patients With Inflammatory Bowel Disease Oscar Ramirez Ramirez, MD, and Freddy Caldera, DO, MS

59 A New Era for Managing Clostridioides difficile Infection Mark H. Wilcox, MD

62 A Practical Guide to the Microbiome For Gastroenterologists Elena Ivanina, DO, MPH

68 Improving the Safety of Endoscopy Procedures in Pregnant Patients Waqar Qureshi, MD

46 DDW Expert Picks: Crohn’s Disease 51 Motility 74 Lower GI Bleeding

GASTROENTEROLOGIST† RECOMMENDED Brands for Digestive Health

DAILY FIBER SUPPLEMENT Recommend METAMUCIL® To Help With Occasional Constipation*. ®

PSYLLIUM FIBER SUPPLEMENT

FREQUENT HEARTBURN Recommend PRILOSEC OTC® For 24 Hour Relief With 1 Pill Each Morning^

DAILY PROBIOTIC SUPPLEMENT Recommend ALIGN® to help with occasional:* · Abdominal discomfort · Gas · Bloating

† Based on ProVoiceTM Surveys 2022. Prilosec OTC®: Frequent Heartburn Medicine / OTC Acid Reducer Category.

Metamucil®: OTC Therapeutic Fiber category. Align®: Probiotic Category. ^ It’s possible while taking Prilosec OTC. Use as directed for 14 days to treat frequent heartburn. May take 1-4 days for full effect. * THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE, TREAT, CURE, OR PREVENT ANY DISEASE.

Albumin-Bilirubin Grade Proposed as Prognostic Tool In Hepatocellular Carcinoma

T

he Child-Pugh classification commonly is used for classifying patients with hepatocellular carcinoma and considering their eligibility for a clinical trial, but results of a retrospective study suggest that the albuminbilirubin grade might be more useful.

“Our data suggests that the ALBI grade may improve the prognostic power for risk stratification,” reported investigator Munaf Alkadimi, MD, an oncologist and a hospitalist at the University of Texas Health Science Center, in San Antonio.

In this retrospective cohort study, 322 patients receiving atezolizumab (Tecentriq, Genentech) plus bevacizumab (A/B) for first-line treatment of advanced HCC were identified in the VA Health Care system. Stratified by ALBI grade, all patients had to have at least six months of follow-up to be included. Response to treatment was evaluated through death, loss to follow-up or the end of the study, which was terminated at the end of 2021.

More than half (56%) of participants had HCC associated with viral hepatitis. Most patients were in ALBI grade 1 (29.2%) or 2 (62.3%). The remainder were in grade 3.

The objective response rate was higher for grades 1 (30.8%) and 2 (30.7%) relative to grade 3 (20.9%). In addition, there was a stepwise association between grade and overall survival (OS). At six months, OS was 31% for grade 3, 75.2% for grade 2 and 86.6% for grade 1; at one year, OS was 16.0%, 48.2% and 70.9%, respectively. The differences between grades 3 and 1 were significant (P<0.001 for both).

Progression-free survival followed the same pattern. At one year, PFS was 14.3% in participants with ALBI grade 3, 33.2% in patients with grade 2 and 48.8% in those with grade 1.

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The Child-Pugh classification system initially was developed to assess liver function in cirrhosis, so it is not considered accurate in noncirrhotic disease, according to Dr. Alkadimi, who presented this analysis at the 2023 annual meeting of the American Society of Clinical Oncology (abstract 4107).

The ALBI score was developed by Philip J. Johnson, MD, a professor in translational oncology at the University of Liverpool, in England. Of numerous studies he conducted in the nearly 10 years since it was introduced, one involved a comparison of ALBI and Child-Pugh in multiple international cohorts involving more than 6,000 patients (J Clin Oncol 2015;33:550-558). ALBI, which eliminates subjective variables considered in Child-Pugh, such as ascites and encephalopathy, was more discriminatory for liver function.

Relative to Child-Pugh, ALBI also provided greater discrimination for prognosis.

Pointing out the weaknesses of the Child-Pugh score, Dr. Johnson concurred that ALBI is a better discriminator for documenting liver function relevant to outcomes. Similar to Dr. Alkadimi, he called for larger trials with sufficient power to establish ALBI as a more accurate tool for determining liver function status across pathologies.

—Ted Bosworth Drs. Alkadimi and Johnson reported no relevant financial disclosures.

Novel First-Line Therapy’s OS Benefit for Liver Cancer Persists

L

ong-term overall survival in hepatocellular carcinoma with the anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) tremelimumab plus the anti-programmed death ligand-1 (PD-L1) durvalumab treatment is durable, according to an update of the HIMALAYA trial.

In the multinational trial, which evaluated the combination of checkpoint inhibitors as first-line therapy in HCC, 1,171 patients with unresectable and previously untreated HCC were randomly assigned to receive the combination of durvalumab (Imfinzi, AstraZeneca) plus tremelimumab (Imjudo, AstraZeneca), durvalumab alone or the tyrosine kinase inhibitor sorafenib. In the combination arm durvalumab and tremelimumab were administered on an every-four-week schedule (STRIDE regimen).

The overall survival (OS) advantage of STRIDE over sorafenib, first reported in 2022 (NEJM Evid 2022;1[8]. doi:10.1056/EVIDoa2100070), was only slightly stronger than the new findings. Median OS was 16.43 months with STRIDE (95% CI, 14.16-19.58) compared with 12.77 months with sorafenib (95% CI, 12.25-16.13). The OS survival rate was 30.7% for STRIDE and 19.8% for sorafenib. In addition, the investigators found durvalumab monotherapy to be noninferior to sorafenib (hazard ratio, 0.86; 95.67% CI, 0.73-1.03; noninferiority margin, 1.08).

The new data, presented at the 2023 European Society for Medical Oncology World Congress on Gastrointestinal Cancer (abstract SO-15), show durability of response, reported principal investigator Bruno Sangro, MD, PhD, the director of the Liver Unit at the Clínica Universidad de Navarra, in Pamplona, Spain. At 48 months, the proportion of patients surviving was 67% higher with the combination than

with sorafenib (25.2% vs. 15.1%) (hazard ratio [HR], 0.78; 95% confidence interval [CI] 0.67-0.92; 78% data maturity).

The contribution of an anti–CTLA-4 drug to an anti–PD-L1 therapy is early inhibition of lymphocyte activation that favors the anti-tumor effect of the checkpoint inhibitor durvalumab.

Citing previous studies in other cancers, particularly melanoma, for which an additive benefit has also been seen with anti-CTLA-4 priming followed by a PD-L1 inhibitor, Dr. Sangro said the new data support this principle. He also said the HIMALAYA trial establishes the STRIDE regimen as a new standard of care in previously untreated advanced HCC. Grade 3 and higher adverse events were more common in participants randomized to the STRIDE regimen than in those given sorafenib (17.5% vs. 9.6%), but there were no safety issues in long-term follow-up that were unexpected based on previous studies with tremelimumab or durvalumab alone.

In a separate analysis of safety signals in the HIMALAYA trial presented at the 2023 annual meeting of the American Society for Clinical Oncology (abstract 4073), HIMALAYA coinvestigator George Lau, MD, the chair of gastroenterology and hepatology at the Humanity & Health Medical Group, in Hong Kong, called the immune-mediated adverse events of the STRIDE regimen “manageable and low-grade.”

He said that the OS advantage in the phase 3 trial establishes this therapy as a new standard of care.

—Ted Bosworth

Dr. Lau reported a financial relationship with AstraZeneca. Dr. Sangro reported financial relationships with Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Incyte, Ipsen, Roche/Genentech, Sirtex Medical and Terumo.

GASTROENTEROLOGY & ENDOSCOPY NEWS SPECIAL EDITION • OCTOBER 2023

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Tislelizumab Vies for First-Line Designation in Treatment Of Advanced HCC

T

he checkpoint inhibitor tislelizumab might reasonably be considered a better choice for hepatocellular carcinoma than sorafenib based on new analyses from a pivotal phase 3 trial presented at the 2023 American Society of Clinical Oncology Breakthrough Meeting.

Although the overall survival advantage was not significant, the quality of life on this therapy is better, according to the newly released data.

inferior for tislelizumab.

In more detailed analyses of the RATIONALE-301 trial— In new analyses presented at the ASCO meeting (abstract which was first presented in 2022 and found tislelizumab 43), the investigators compared QOL outcomes for the to be noninferior to sorafenib for overall survival (OS)— two therapies using three questionnaires: EORTC QLQtislelizumab improved numerous domains of quality of life C30, which measures health sta(QOL) relative to the kinase inhibtus; QLQ-HCC18, which measures itor sorafenib, according to inves‘It’s not just improving their HCC-specific effects on QOL; and tigator Masatoshi Kudo, MD, PhD, survival but [also] their quality EQ5D-5L, which evaluates change a professor and the chair of the in activities of daily living, mood, Department of Gastroenterology of life that is important.’ self-care and pain. and Hepatology at Kindai University, —Richard S. Finn, MD With the exception in Osaka, Japan.

UCLA of pain, which was simIn this analysis, the greater ilar in the two groups, activity, greater safety and delayed tislelizumab was supedecline in health status associated with tislelizumab rior for preserving QOL relative to sorafenib support it’s use “as a potential over time, with up to 50% first-line treatment option for unresectable HCC,” reductions in risks for Dr. Kudo said. fatigue, HCC-related sympIn the trial, tislelizumab—an anti-protoms, impaired physical funcgrammed death receptor 1 monoclonal immutioning and deterioration in QOL. noglobulin G 4 antibody—was compared with Tislelizumab also showed a lower sorafenib in patients with unresectable HCC rate of grade 3 or higher adverse events at Barcelona Clinic Liver Cancer stage B/C, who (48.2% vs. 65.4%). had not been previously treated or had progressed In the context of this favorable safety profile, Dr. after receiving locoregional treatment.

Kudo concluded that tislelizumab should be regarded Dr. Kudo and his co-investigators presented findas a potential first-line treatment. ings related to the OS primary end point as well as objecinvestigator Richard S. Finn, MD, a professor of medicine in tive response rate (ORR), progression-free survival (PFS) the Division of Hematology/Oncology at the University of Caliand duration of response (DOR) at the 2022 European fornia, Los Angeles Geffen School of Medicine, also considers Society for Medical Oncology (abstract LBA36). Tislelizumab the QOL advantages of tislelizumab over sorafenib to be relshowed a two-month median OS advantage over sorafenib evant. “Especially now that we have level 1 evidence” of at (15.9 vs. 14.1 months), but it did not reach statistical signifileast similar efficacy but a better QOL profile, he said, “it’s cance (hazard ratio, 0.85; 95% CI, 0.712-1.019). In addition, the not just improving their survival but [also] their quality of life ORR with tiselizumab was more than twice as high as with that is important.” sorafenib (14.3% vs. 5.4%) and the DOR also was longer —Ted Bosworth (4.1 vs. 2.7 months). However, PFS (2.2 vs. 3.6 months) was Dr. Finn reported financial relationships with AstraZeneca (AZ), Bayer, Bristol Myers Squibb, CStone, Eisai, Exelixis, Genentech/Roche, Hengrui, Lilly, Merck and Pfizer. Dr. Kudo reported financial relationships with AZ, Bayer, Chugai/Roche, Eisai, Lilly Japan and Takeda.

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BRIEF SUMMARY: Before prescribing, please see Full Prescribing Information and Medication Guide for SUFLAVE™ (polyethylene glycol 3350, sodium sulfate, potassium chloride, magnesium sulfate, and sodium chloride for oral solution).

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) Recommended Dosage: The Day Prior to Colonoscopy: A low residue breakfast may be consumed. After breakfast, only consume clear liquids until after the colonoscopy.

Day 1, Dose 1 - Early in the Evening Prior to Colonoscopy: Open 1 flavor enhancing packet and pour the contents into one bottle. Fill the provided container (bottle) with lukewarm water up to the fill line. After capping the bottle, gently shake the bottle until all the powder has dissolved. For best taste, refrigerate the solution for an hour before drinking.

Do not freeze. Use within 24 hours. Drink 8 ounces of solution every 15 minutes until the bottle is empty. Drink an additional 16 ounces of water during the evening. If nausea, bloating, or abdominal cramping occurs, pause or slow the rate of drinking the solution and additional water until symptoms diminish. Day 2, Dose 2 – The Morning of the Colonoscopy (5 to 8 hours prior to the colonoscopy and no sooner than 4 hours from starting Dose 1): Continue to consume only clear liquids until after the colonoscopy. Repeat Step 1 to Step 3 from Day 1, Dose 1. Drink an additional 16 ounces of water during the morning. Stop drinking liquids at least 2 hours prior to colonoscopy. If nausea, bloating, or abdominal cramping occurs, pause or slow the rate of drinking the solution and additional water until symptoms diminish. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention, hypersensitivity to any ingredient in SUFLAVE. WARNINGS AND PRECAUTIONS: Serious Fluid and Electrolyte Abnormalities: Advise all patients to hydrate adequately before, during, and after the use of SUFLAVE. If a patient develops significant vomiting or signs of dehydration after taking SUFLAVE, 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 fluid and electrolyte abnormalities before treatment with SUFLAVE. Use SUFLAVE with caution in patients with conditions, or who are using medications, that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and renal impairment; Cardiac arrhythmias: Use caution when prescribing SUFLAVE 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 SUFLAVE 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 SUFLAVE with caution in patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal anti-inflammatory drugs). These patients may be at risk for renal injury. Advise these patients of the importance of adequate hydration with SUFLAVE 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 SUFLAVE may increase these risks.

Consider the potential for mucosal ulcerations resulting from the bowel preparation when interpreting colonoscopy findings in patients with known or suspect inflammatory bowel disease; Use in Patients with Significant Gastrointestinal Disease: If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering SUFLAVE. Use with caution in patients with severe active ulcerative colitis.

Aspiration: Patients with impaired gag reflex or other swallowing abnormalities are at risk for regurgitation or aspiration of SUFLAVE. Do not combine SUFLAVE with starch-based thickeners. Observe these patients during administration of SUFLAVE. Hypersensitivity reactions, including anaphylaxis: SUFLAVE contains polyethylene glycol (PEG) and other ingredients that may cause serious hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, and pruritus. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. ADVERSE REACTIONS: Most common adverse reactions are: nausea, abdominal distension, vomiting, abdominal pain, and headache. POTENTIAL FOR DRUG ABSORPTION: SUFLAVE can reduce the absorption of other co-administered drugs. Administer oral medications at least one hour before starting each dose of SUFLAVE. Administer tetracycline and fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, and penicillamine at least 2 hours before and not less than 6 hours after administration of each dose of SUFLAVE to avoid chelation with magnesium. Pregnancy: There are no available data on the use of SUFLAVE during pregnancy to evaluate for a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not conducted with polyethylene glycol 3350, sodium sulfate, potassium chloride, magnesium sulfate, and sodium chloride (SUFLAVE). Lactation: There are no available data on the presence of SUFLAVE 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 have not been established. Geriatric Use: Of the 460 patients who received SUFLAVE in pivotal clinical trials, 125 (27%) were 65 years of age or older. No differences in effectiveness of SUFLAVE were observed between geriatric patients and younger adult patients. In geriatric patients, decreases in blood pressure on the day of colonoscopy were reported more frequently in SUFLAVE patients than with the active comparator in Study 1 (6% vs 0%) and Study 2 (3% vs 0%). Geriatric patients are more likely to have decreased hepatic, renal or cardiac function and may be more susceptible to adverse reactions resulting from fluid and electrolyte abnormalities. STORAGE: Store SUFLAVE at room temperature between 20°C to 25°C (68°F to 77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F). See USP controlled room temperature. Rx only. Manufactured by Braintree Laboratories, Inc. Braintree, MA 02185 See Full Prescribing Information and Medication Guide at SUFLAVE.com.

References: 1. Bhandari R, Goldstein M, McGowan J, et al. A safety and efficacy comparison of new BLI4900 bowel preparation to oral sulfate solution. Poster Sa1024 presented at: Digestive Disease Week Annual Meeting; May 21-24, 2022; San Diego, California. https://www.emedevents.com/medical-hybrid-events-2022/digestive -disease-week-ddw-conference-2022. 2. SUFLAVE [package insert]. Braintree, MA: Braintree Laboratories, Inc. 3. Bhandari R, Goldstein M, McGowan J, et al. The new flavor enhanced bowel preparation BLI4900 provides a superior patient experience. Poster Mo1024 presented at: Digestive Disease Week Annual Meeting; May 21-24, 2022; San Diego, California. https://www.emedevents.com/medical-hybrid-events-2022/digestive-disease-week -ddw-conference-2022. 4. Data on file, Braintree, MA: Braintree Laboratories Inc.

For additional information, please call 1-800-874-6756 ©2023 Braintree Laboratories, Inc.

All rights reserved.

550-750-v1-A

August 2023

FLAVOR CHOICE IN W E BOWEL PREPARATION N

RESULTS FROM A PHASE 3 CLINICAL TRIAL

94% of patients achieved successful* bowel cleansing with SUFLAVE 87% of patients found SUFLAVE tolerable to very easy to consume 79% of patients found the taste of SUFLAVE neutral to very pleasant

1,2

3

4

THE MAJORITY OF PATIENTS SAID SUFLAVE TASTES LIKE A SPORTS DRINK3 *Success was defined as an overall cleansing assessment of excellent or good by the blinded endoscopist; scores were assigned following completion of the colonoscopy; P<0.001 in this noninferiority clinical trial.

IMPORTANT SAFETY INFORMATION SUFLAVE™ (polyethylene glycol 3350, sodium sulfate, potassium chloride, magnesium sulfate, and sodium chloride for oral solution) 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 on the day before colonoscopy, followed by clear liquids up to 2 hours prior to colonoscopy. Administration of two doses of SUFLAVE are required for a complete preparation for colonoscopy. Each bottle must be reconstituted with water before ingestion. Each bottle and one flavor enhancing packet are equivalent to one dose. An additional 16 ounces of water must be consumed after each dose. Stop consumption of all fluids at least 2 hours before the colonoscopy. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention, hypersensitivity to any ingredient in SUFLAVE. WARNINGS AND PRECAUTIONS: Risk of fluid and electrolyte abnormalities: 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; Colonic mucosal ulcerations: Consider potential for mucosal ulcerations when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease; 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; Patients at risk for aspiration: Observe during administration; Hypersensitivity reactions, including anaphylaxis: Inform patients to seek immediate medical care if symptoms occur. ADVERSE REACTIONS: Most common adverse reactions (* 2%) are: nausea, abdominal distension, vomiting, abdominal pain, and headache. DRUG INTERACTIONS: Drugs that increase risk of fluid and electrolyte imbalance.

Please see Brief Summary of Prescribing Information on reverse side. See Full Prescribing Information and Medication Guide at SUFLAVE.com.

Scan the QR code to learn more, or visit SUFLAVE.com

A Gastroenterologist’s Guide To Bowel Prep

JONATHAN BEARD, MD Section of Gastroenterology Department of Medicine Dartmouth Hitchcock Medical Center Lebanon, New Hampshire

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

A

s the leading gastrointestinal procedure performed in the United States, colonoscopy is an important tool for colorectal cancer screening,

post polypectomy surveillance, guidance in management of inflammatory bowel disease, and diagnosis of symptoms.1

High-quality colonoscopy depends on several factors, including cecal intubation and adequate inspection of the mucosa for adenomas and other pathology, which are dependent on adequate withdrawal time and bowel preparation quality. Current quality indicators recommend that gastroenterologists should strive for adequate bowel preparation in greater than 85% of exams.2 However, of the more than 15 million colonoscopies performed annually,3 approximately 20% to 25% involve inadequate preparation, which has consequences for both patients and the healthcare system. Patients may suffer from increased pain,4 missed adenomas,5-7 subsequent cancers,8,9 repeat colonoscopies10 with associated missed days of work and lost wages,11 and increased complications. System implications include increased intra-procedural time,4 reduced ability to perform other procedures, and increased costs.12

GASTROENTEROLOGY & ENDOSCOPY NEWS SPECIAL EDITION • OCTOBER 2023

21

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

Total volume/instructions

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

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

Average retail price without discountsa CoLyte: $48.26 Gavilyte G: $28.04 Gavilyte N: $41.68 GoLytely: $48.26

$125 3L 2 1-L bottles and 2 “flavor-enhancing” packets; patient empties 1 packet into 1 bottle and then fills bottle with lukewarm water and shakes until powder dissolves; store in refrigerator until ready to drink; solution is ingested at 240 mL every 15 min until empty; patient then consumes an additional 475 mL of water. Process is repeated with second packet the morning of the procedure. $133.44 3L MoviPrep (Salix) (PEG-3350, sodium ascorbate, 4 packets labeled A (2) and B (2) and a 1-L container; evening before sodium sulfate, sodium chloride, exam: mix contents of pouch A and pouch B (1 each) in container; potassium chloride + ascorbic ingest 240 mL every 15 min until complete, then drink additional 500 mL of clear liquid (1.5 L total); repeat process morning of exam acid [PEG-ELS + ASC])

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

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

$161.12 2L 1 pouch labeled dose 1, and 2 additional pouches (dose 2 pouch A and dose 2 pouch B) and 500-mL container; evening before exam: mix pouch labeled dose 1 in the container and drink solution over 30 min; then drink an additional 500 mL of clear fluid over 30 min; repeat process morning of exam with packets labeled dose 2

Sodium sulfate–based regimens SUPREP (Braintree) 3L (sodium sulfate, potassium 2 small (180 mL) flavored bottles; evening before exam: dilute 1 bottle sulfate, magnesium sulfate) with water to 500 mL and drink; then drink 1 L of water over the next hour; repeat process morning of exam SUTAB (Braintree) (sodium sulfate, magnesium sulfate, potassium chloride)

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

$124

$159.14

Sodium phosphate regimen OsmoPrep (Salix) (sodium phosphate)

$329.31 ~1.9 L (2 quarts) 32 tablets; evening before exam: take 4 tablets with 240 mL of water every 15 min until 20 tablets are taken (5 doses); morning of exam: take 4 tablets every 15 min with 240 mL of water until 12 tablets are taken (3 doses)

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

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

$195.94

a

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

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

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Contraindications/cautions

Palatability

Dietary considerations

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

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

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

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

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

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

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

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

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

Berry/cherry flavored

Light breakfast or clear liquids allowed the morning before starting the prep

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

No flavor; patient must be able to swallow 24 pills

Low-residue breakfast or clear liquids allowed the day before the exam

No flavor; patient must be able Contraindicated in obstruction, perforation, gastric bypass, ileus, toxic colitis/megacolon; boxed warning of rare but serious to swallow 32 pills acute phosphate nephropathy; caution in seizure disorders, hypovolemia, active colitis, CKD, and those aged >65 y or taking certain medications (diuretics, ACEIs, ARBs, NSAIDs)

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

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

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

First half of prep is mango flavored; If using split dose, light lunch to be completed 3 h before second half of prep is fruit punch starting prep; for morningflavored only dose, NPO after 8 PM

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

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

Total volume/instructions

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

Average Contraindications/ retail pricea cautions $25.00 ($8.32 per bottle)

$21.77 1.9 L (64 oz) 238 g (8.3 oz bottle), mixed into 64 oz of sports drink (do NOT use red) until dissolved; generally, bisacodyl delayed-release oral tablet to be taken before PEG-3350

Palatability

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

Bitter taste may be improved if chilled before use

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

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

Dietary considerations None given; off-label usage

a

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

Product currently under recall (fda.gov/safety/recalls-market-withdrawals-safety-alerts/vi-jon-llc-expands-voluntaryworldwide-recall-all-flavors-and-lots-within-expiry-magnesium-citrate).

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

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

b

The goal of this article is to review available bowel purgative agents for colonoscopy and other related bowel preparation issues.

Choosing an Agent An ideal bowel preparation regimen should be maximally efficacious, safe, and tolerable,2 while remaining affordable and easy to use. Tables 1 and 2 list available agents approved by the FDA as well as non–FDA-approved regimens, respectively. The US gastroenterology societies advise individualizing the regimen for each patient, taking into consideration comorbidities, medications, and patient preferences, and do not endorse any one specific regimen (Table 3). This recommendation may be due, in part, to the limited number of comparative effectiveness studies that include multiple laxatives.2,13-18 In one large prospective comparative effectiveness study of more than 4,000 patients at a single center, investigators compared various bowel preparation regimens with respect to efficacy and tolerability.19 Adequate cleansing (defined as Boston Bowel Preparation Scale [BBPS] score of >6, with each segment BBPS score >2) was found in 92.5% of patients using polyethylene glycol-3350 (PEG-3350) with a sports drink, 91.7% with sodium phosphate, 91.1% with MoviPrep (Salix), 90.7% with Prepopik/Clenpiq (Ferring), 90.6% with SUPREP (Braintree), 90.6% with magnesium citrate, and 84% with GoLytely (Braintree). After adjusting for various preparation, procedure, endoscopist, and patient-level factors, PEG-3350 with a sports drink was the only agent that demonstrated statistically significant superior cleansing compared with GoLytely. In terms of tolerability (defined as the percentage of patients who reported finishing the entire regimen), Prepopik/Clenpiq (99.1%), magnesium citrate (98.1%), SUPREP (94.4%), OsmoPrep (Salix) (92.7%),

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PEG-3350 with a sports drink (92.6%), and MoviPrep (91.4%) were all rated as more tolerable than GoLytely (82.9%). Multivariable logistic regression analysis found that patients were less likely to complete GoLytely than any other option.

In addition to efficacy and tolerability, safety is an essential consideration when selecting a bowel purgative agent.

The safety profiles vary, partly based on their mechanism of action. They may be classified as either isotonic, hypertonic, or hypotonic.

Isotonic options, such as GoLytely, work by retaining fluid within the bowel lumen and generally cause minimal fluid shifts.20 Despite the challenges typically associated with drinking large volumes of PEG, PEG-based agents generally are considered the preferred option for patients who cannot tolerate fluid or electrolyte shifts (eg, patients with congestive heart failure or chronic kidney disease).21 In contrast, hypertonic options, such as sodium phosphate and magnesium citrate, work by causing large paracellular fluid shifts into the bowel lumen.20 Accordingly, these agents should be selected thoughtfully and avoided in patients with comorbid renal disease, cardiac disease, hepatic disease, and those who are advanced in age.22 Sodium phosphate, in particular, has been documented as a cause of acute phosphate nephropathy,23 for which it carries an FDA black box warning. Thus, sodium phosphate should not be used routinely as a preparation option.24 Although caution should be used when considering a hypertonic preparation, some of the newer agents in this class, such as Clenpiq, have not demonstrated any significant effects on cardiac conduction, magnesium levels,25 renal function, or glucose levels,26 even when used in populations with chronic kidney disease and diabetes. If further research continues to support minimal side effects with these newer hypertonic agents, their use may be

considered more widely in patients with comorbidities.

Although hypotonic PEG-3350 with a sports drink generally is considered safe, there have been documented reports of prep-induced hyponatremia occurring at higher rates than with traditional PEG,27 albeit this occurs infrequently and possibly with minimal clinical consequence. Although PEG-3350 with a sports drink lacks a significant amount of long-term safety data because it is not FDA approved, historically, it has been preferred by gastroenterologists before colonoscopy in pregnant patients, and could be considered if necessary.

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

Most bowel preparation studies exclude patients with IBD. Another factor contributing to the lack of guidance on bowel prep in IBD is that patients with a history of ulcerative colitis frequently are evaluated with flexible sigmoidoscopy and receive minimal oral preparation, and those with Crohn’s disease have additional challenges related to active inflammation, bowel resections, and stricturing disease.28 A Spanish study of 92 patients with IBD evaluated sodium picosulfate, magnesium oxide, and citric acid (SPMC) versus low-volume 1-L PEG and 2-L PEG preparations.29 There were no differences in efficacy among the 3 regimens; however, patients preferred SPMC over the other regimens, and it was more likely to be taken for future colonoscopies. Another small study using low-volume Plenvu (Salix) found higher cleansing success in patients with IBD compared with healthy controls (92.9% vs 85.4%) and no significant difference in adverse events.30 The study excluded patients with active, severe IBD, previous colonic resection, recent or active GI bleeding, and several other conditions, limiting the ability to generalize the results across a heterogeneous population of patients with IBD. An important consideration is knowing which agents to avoid in patients with IBD. In trials of patients without IBD, preparation-induced mucosal lesions were increased 10-fold with sodium phosphate or SPMC regimens compared with PEG.31 This potential for strong osmotic laxatives to cause minor mucosal damage and be confused with Crohn’s disease has been well documented,32 making these agents less appealing for use in IBD; thus, they should be avoided.

Older adults have higher rates of inadequate preparation, possibly related to diet, colonic transit time,33 more comorbidities, and medications. A few studies have focused on preparation efficacy and safety in older adults.

A 2022 study found higher rates of adequate preparation in patients aged at least 65 years who received 1 L of PEG plus ascorbic acid (PEG+ASC) (93%) compared with those receiving SPMC (78%). Safety was also more favorable with 1-L PEG+ASC compared with SPMC, with fewer episodes of clinically relevant hyponatremia.34 Another study of 1,289 patients that included 575 patients older than 65 years of age compared the use of 1-, 2-, or 4-L PEG.35 Several key findings related to the older subgroup included

higher tolerability scores and higher cleansing success with 1- versus 4-L PEG (81.2% vs 69.4%), as well as higher right colon cleansing and overall cleansing success when choosing a split-dose preparation. The investigators recommended a combined approach for older adults who are at risk for inadequate preparation (eg, low-fiber diet for 3 days, split-dose regimen, completion of preparation within 5 hours of colonoscopy start), which resulted in successful cleansing in 87.4% to 91.7% of patients, versus 45.6% when these strategies were not used.

Careful consideration also is needed when selecting a bowel purgative regimen for pregnant and lactating patients, given the potential for fetal hypoxia, premature labor, trauma, and teratogenesis secondary to endoscopic evaluations.36 When feasible, postponing exams until the postpartum period is recommended, although certain clinical situations such as GI bleeding, severe abdominal pain, refractory diarrhea, or suspicion of a colon mass require urgent evaluation, as outlined by the 2012 American Society for Gastrointestinal Endoscopy guidelines.37 Few case– control studies of bowel preparation in pregnancy exist.

Even the efficacy or safety of well-established prep regimens, such as GoLytely, have not been studied extensively in animal reproduction models, and it is unknown whether these cause fetal harm or are excreted in human milk.38 Although the FDA is rolling out new categories for medication pregnancy and lactation labeling,39 according to the old nomenclature, both PEG and sodium phosphate are category C.2 Nonetheless, PEG, in particular, has long been used safely in pregnancy to improve constipation40 and could be considered, if necessary. Historical trends show the preference of gastroenterologists in recommending PEG-based solutions before colonoscopy.41 For now, recommendations from GI societies are limited to tap water enemas before flexible sigmoidoscopy,2,42 pending further large-scale studies.

Bowel Preparation Timing Although the literature does not support one best agent as of yet, there are ample data to support split-dose preparation, a process in which half to three-fourths of the purgative is ingested the night before the procedure, with the remaining half to one-fourth completed the morning of the procedure. Split-dose preparation is associated with higher rates of adequate preparation, increased patient tolerance (ie, less nausea, vomiting), improved detection of colonic lesions, and lower rates of incomplete or aborted exams.43-49 Despite its superiority in cleansing, a split-dose approach may not be acceptable for all patients, particularly those who may be worried about sleep disturbance, travel interruption, and fecal incontinence en route to the procedure.50 Another option is same-day preparation, a process in which the entire purgative is ingested in the morning before an afternoon colonoscopy. Multiple large studies have demonstrated comparable cleanliness, cecal intubation rates, and adenoma detection with sameday prep compared with split-dose regimens.51,52 Ultimately, the biggest timing consideration with either split-dose or same-day preparation is the “runway time,”

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

US Multi-Society Task Force (2014)

Agent selection

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

Timing/dosing

-Use of a split-dose regimen is strongly recommended; second dose of split regimen should begin 4-6 h before exam with completion 2 h before start -Same-day regimens are acceptable alternatives for patients undergoing afternoon exams -Regardless of OTC selected, efficacy and tolerability are enhanced with split-dose regimen

Diet

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

Tolerability

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

Education

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

High risk for prep failure/special populations

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

Safety

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

Adjunctive agents

-Routine use of adjunctive agents is not recommended

CKD, chronic kidney disease; IBD, inflammatory bowel disease; OTC, over the counter; PEG-ELS, polyethylene glycol electrolyte solution.

Based on references 2, 13, and 42.

defined as the interval between the last dose of laxative and the initiation of the exam. A large meta-analysis that included 20 studies and 10,341 individuals found higher rates of adequate cleanliness with shorter runway times: less than 5 hours before the exam (94%), 6 to 10 hours before (92%), and more than 11 hours before (85%). Shorter runway times also were associated with higher polyp detection rates compared with longer runway times (47% vs 30%).53 Practices should instruct patients to complete their preparation with “5 golden hours” of runway time48 and no later than 2 hours before the start of procedures to minimize aspiration risk, according to guidelines by the American Society of Anesthesiologists (ASA).54

Diet Considerations Dietary recommendations related to bowel preparation typically revolve around using a clear liquid diet (CLD) versus a low-residue diet (LRD) in the days leading up to the exam. LRD is not defined clearly55 or consistently applied in clinical studies,56,57 but is loosely defined as a “lowfiber diet” that restricts dietary fiber to less than 10 g per day.58 A large meta-analysis including 13 randomized controlled trials and 2,587 patients reported no difference between the adequacy of bowel prep with CLD versus

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LRD.59 Of note, patients reported fewer adverse effects and improved tolerability with LRD. LRD should be considered by endoscopy units.

Patient Education In addition to patient-friendly educational handouts that are written at no more than a sixth-grade level,60 visual presentations and reminder calls have been shown to significantly affect the adequacy of bowel prep and cecal intubation.61 Technology-based tools also appear to have a role in enhancing bowel preparation education, with computer-based education demonstrating noninferiority compared with nursing education.62 One pragmatic benefit of using computer or internet-based strategies63 is lower time and cost burdens on clinical staff, with similar outcomes. Another approach already in the palm of patients’ hands includes a smartphone app, which according to a recent meta-analysis, improves bowel prep from 76.7% to 86.6% and adenoma detection rate (ADR) from 19.3% to 26.2%.64 Any form of enhanced patient education (eg, cartoons, phone calls, mobile apps, etc) results in improved rates of detection of polyps, adenomas, and sessile serrated polyps.65 Although ideally all patients could benefit from receiving enhanced education,

American Society for Gastrointestinal Endoscopy (2015)

European Society of Gastrointestinal Endoscopy (2019)

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

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

-Split-dose regimen for all patients -Same-day preps are acceptable for afternoon exams if taken within 3-8 h of exam

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

-Low-residue diet

-Low-fiber diet day before exam

-Split dosing or same day prep may enhance patient tolerance

-Tolerance not addressed directly

-Verbal counseling should be provided along with simple -Enhanced instructions for bowel prep and easy-to-follow written instructions -Specific verbal or written instructions to patients and clinic staff caring for hospitalized patients to improve prep -Consider intensive education and more aggressive than standard prep for patients with predictors for inadequate prep

-No specific prep recommendations in patients with constipation -PEG-based regimen in IBD -PEG-based regimen safety in pregnancy unknown

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

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

-No adjunctive agents routinely recommended

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

tailoring resources to patients with lower levels of educational attainment should be prioritized.66

Putting the Odds in Your Favor Recognizing which patients are at risk for inadequate preparation and tailoring strategies accordingly will help increase rates of adequate bowel preparation above the target of greater than 85%. Older age, male sex, inpatient status, type 2 diabetes, hypertension, cirrhosis, narcotic use, chronic constipation, history of stroke, and tricyclic agent use were associated with inadequate prep in a meta-analysis of 50,000 patients.67 Several other welldocumented risk factors include lower socioeconomic class, afternoon colonoscopy, ASA class greater than III, pre-procedure nausea and vomiting,68 and obesity.15 Several prediction tools accounting for many of these factors have been developed.69-71 Although these models had strong internal validity metrics, external validation72 revealed disappointing performance (receiver operating characteristic curve, 65), suggesting that these tools are not yet ready for widespread clinical adoption.

A prospective, multicenter study of 1,000 patients in 10 Italian hospitals evaluated factors associated with negative symptoms during the bowel preparation process.

Being female (odds ratio [OR], 3.64), heavier working hours (OR, 1.13), previous GI symptoms (OR, 7.81), somatic symptoms (OR, 2.19), and a day-before regimen (OR, 2.71) were associated with negative symptoms, whereas age older than 60 years and a baseline good mood (defined by a 36-question survey) were protective factors against negative symptoms.73 Recognizing these potential risk factors may help in the selection of the purgative agent and allow for extra education about what to expect during the preparation process.

Conclusion Achieving high-quality bowel preparation can be done!

When choosing an agent, discuss the various available options with patients and engage in a shared decision-making process, allowing them to help select a preparation that best aligns with their goals (ie, taste vs volume vs cost). Use a split-dose regimen when possible, reserving same-day preparation for afternoon exams only. Don’t forget the 5 golden hours or the low-fiber diet when counseling patients.

Finally, be sure to leverage the endoscopy units’ staff and technology to enhance patient education, particularly in patients at high risk for inadequate preparation or a negative preparation experience based on known risk factors.

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38. FDA. GoLytely prescribing information. Accessed January 5, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2013/019011s025lbl.pdf

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

72. Yuan X, et al. Int J Colorectal Dis. 2022;37(6):1223-1229.

Dr Beard reported no relevant financial disclosures. Dr. Calderwood reported a financial relationship with Dark Canyon Laboratories.

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Complete archives Web-only content Multimedia And more …

Which Barrett’s esophagus patient is likely to progress to high grade dysplasia or esophageal cancer?

Two non-dysplastic patients nearly identical by pathology and clinical risk factors

TissueCypher Score / Risk Class 3.6 / Low Risk

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Progressed to HGD in 2.7 years following baseline

Know your patient’s individual risk of progression to esophageal cancer

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TC-015v3 – 042122

Challenges in the Diagnosis Of Barrett’s Esophagus and Related Neoplasia: Top 10 FAQs ABHILASH PERISETTI, MD

Department of Gastroenterology Kansas City VA Medical Center Kansas City, Missouri

PRATEEK SHARMA, MD Department of Gastroenterology Kansas City VA Medical Center Kansas City, Missouri Division of Gastroenterology and Hepatology Department of Internal Medicine University of Kansas School of Medicine Kansas City, Kansas

B

arrett’s esophagus is the premalignant condition for esophageal

adenocarcinoma, characterized by transformation of the normal squamous lining of the esophagus to columnar epithelium.

Risk factors for BE include older age, male sex, white race, long-standing gastroesophageal reflux disease, positive family history, and tobacco smoking. Given the risk for malignant transformation, early identification of BE-related neoplasia is essential because these lesions can harbor cancer, which may be curable if identified early. With advances in endoscopic visualization and interventions, detection and characterization of both BE and BERN have improved significantly.

Despite these advances, there is a BERN miss rate of up to 25%.1 Gastroenterologists can encounter challenges in the diagnosis of BE, evaluation of BE segments, identification of BERN lesions, intricacies of histologic interpretation, appropriate use of scoring systems, and optimal time frame for BE surveillance. In this article, we aim to highlight some of the most common challenging clinical scenarios in the diagnosis of BE and offer practical solutions.

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Question 1. In the case of a 60-year-old man with possible short-segment BE and intestinal metaplasia noted in the distal esophagus, how do you assess for a diagnosis of true BE and handle future surveillance?

A diagnosis of BE needs careful documentation of the landmarks (gastroesophageal junction [GEJ] and squamocolumnar junction) and the presence of a columnarlined esophagus. 2 It is critical to document the Prague extent of BE: circumferential (C) and maximal (M) extent of the esophagus’ columnar lining, along with identification of the GEJ at the top of the gastric mucosal fold and evaluation of hiatal hernia (if any, not to be mistaken for GEJ).2 A columnar-lined esophagus area of less than 1 cm or an irregular Z-line should not be biopsied due to high interobserver variability in measuring this extent and the extremely low (if any) risk for progression to esophageal adenocarcinoma (EAC). 3 In such a scenario, no further surveillance is needed. In contrast, if the columnar lining is 1 cm or larger, biopsies will be required to confirm the presence of intestinal metaplasia and any associated neoplasia.3

Question 2. During surveillance endoscopy, a patient’s assessed length of BE segment is different from that found during previous endoscopy. Is this a change in the extent of BE? There could be variation in the length of the BE segment assessed by endoscopists due to interobserver variability.

Discrepancies can occur because of differing time spent in assessment, diaphragmatic movements, tortuosity of the esophagus, excessive tension on the endoscope or lack of a straight endoscope during the exam, and food and debris in the distal esophagus.

In a prospective study to assess the length of BE in 96 patients, 2 endoscopists performed examinations 16 to 19 months apart; segment length varied 1.4 to 1.6 cm between the exams. 4 To minimize this variation, the Prague criteria were developed, incorporating methodological inspection of the diaphragm, upper end of gastric folds, and circumferential and maximum extent of the columnar esophagus (using minimal air sufflation during measurement).5

Question 3. How much time should you spend examining and inspecting the BE segment?

The evaluation of BE during upper endoscopy requires extensive cleaning of the entire segment along with a slow withdrawal during the inspection portion of the exam. Endoscopists with a mean inspection time longer than 1 minute per centimeter of BE detected more lesions than those with inspection time less than 1 minute (54.2% vs 13.3%; P=0.04).6 If there are extensive neoplastic mucosal changes in a patient with long-segment BE, some experts recommend referral to a BE center of excellence with a multidisciplinary approach to diagnosis and management.

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Question 4. If columnar islands are noted proximally along with contiguous columnar mucosa in the distal esophagus, do they count toward the Prague classification?

Isolated islands of columnar epithelium, unconnected to the columnar-lined esophagus, should not be counted toward the Prague C and M classification and should be noted separately in the endoscopy report.7 Counting the isolated islands could artificially increase the extent of the BE segment, which could have implications for treatment and surveillance. Furthermore, the validation studies with reliability coefficients performed for endoscopic Prague C and M grading of BE above the GEJ were 0.95 and 0.94, respectively, and isolated islands were excluded.2 In the setting of neoplastic BE and visible lesions in BE, these islands potentially could harbor neoplasia,8 and hence need attention during endoscopic therapy.9

Question 5. A patient with suspected BE undergoes biopsies. Histologic interpretation states the presence of cardiac-type mucosa but no intestinal metaplasia. What is the next step?

The definition of BE varies based on the geographic region.10 In the United States, BE is defined as replacement of normal squamous mucosa with columnar (intestinal type) mucosa with goblet cells. These goblet cells are considered a hallmark of columnar epithelium. They can be detected readily by hematoxylin-and-eosin staining and, if required, the addition of Alcian blue stain. However, in the United Kingdom, the presence of endoscopic features defines BE and documentation of goblet cells is not mandatory. In Japan, the diagnosis of BE is based on the presence of endoscopic features such as palisading vessels that indicate the GEJ and any columnar mucosa above these vessels (without goblet cells). The presence of inflammation (such as Los Angeles grade B-D) in the segment can confound the results of underlying BE and potentially lead to underdiagnosis. So, efforts should be made to provide effective antisecretory therapy to eliminate these confounders (visual and histologic) before making a diagnosis of BE. In this patient, the absence of intestinal metaplasia may be related to inadequate sampling (biopsy errors) or in the setting of a very short area of BE (<2 cm) due to nongoblet columnar cells (eg, cardiac type). The patient probably should undergo a repeat procedure, and the endoscopist should obtain biopsies based on the Seattle protocol to document intestinal metaplasia.

Question 6. During surveillance of a patient with BE, an area of mucosa was biopsied due to abnormal appearance. The pathologist interpreted the area as “indeterminate dysplasia.” What is the next step?

Visible lesions in patients with BE can harbor high-grade neoplasia (high-grade dysplasia or cancer).1 Any abnormal mucosa observed during endoscopy should be categorized on the basis of Paris classification as slightly elevated (0-IIa),

flat (0-IIb), slightly depressed (0-IIc), excavated (0-III), or a mixed pattern.2 Characterization of these areas requires close inspection with high-definition white light endoscopy along with chromoendoscopy (electronic or dye-based).

If there is evidence of an irregular or disrupted mucosal pattern, an irregular vascular pattern, or abnormal blood vessels, the area should be resected using endoscopic mucosal dissection for diagnosis and staging and to serve as initial endoscopic therapy.11 The patient should undergo a repeat endoscopy, and the provider should inspect the abnormal-appearing mucosa carefully and interpret it based on the Paris classification.11 The provider should perform repeat biopsies and resection from the area involved.

changes within the BE segment (Figure 1). Endoscopists should perform targeted biopsies of any visible abnormalities first, followed by 4-quadrant biopsies every 2 cm (Figure 2). Based on the grading of the biopsies, they can determine future surveillance intervals. Patients with nondysplastic BE will need surveillance every 5 years (<3 cm in extent) or every 3 years (≥3 cm in extent).15 The presence of any neoplasia in biopsies requires reexamination, repeat biopsy, and review of the slides by another experienced gastrointestinal pathologist. Patients with confirmed

Question 7. What are BERN lesions, and how can you improve detection of BERN? Early neoplasia in patients with BE usually presents as subtle mucosal abnormalities that are flat or slightly raised.

Performing a high-quality BE endoscopy after CLEAN (cleaning, learning, endoscopic [virtual], acquiring, and neoplasia detection) quality metric assessment could improve BERN detection rates. Referring cases to expert centers for multidisciplinary team care could assist in further management of these lesions. Given the high miss rate for BERN lesions, in the near future, artificial intelligence could be a promising tool to help endoscopists identify these subtle lesions with improved sensitivity (>90%) and specificity (>80%).12 In addition, machine learning with convolutional neural networks could assess lesion depth and submucosal invasion. In general, AI could improve endoscopy quality and blind spot assessment, as well as provide feedback and report quality metrics needed to reduce missed lesions.

Question 8. Are there any nonendoscopic modalities for diagnosing BE?

Figure 1. Islands of columnar epithelium (yellow arrows) in the distal third of the esophagus.

Using high-definition upper endoscopy with systematic biopsies remains the gold standard for an accurate diagnosis of BE.13 However, for patients who cannot tolerate sedation, office-based procedures, such as unsedated transnasal endoscopy or esophageal capsule endoscopy, have been proposed.14 In the former technique, an ultrathin endoscope is passed through the nose and advanced to the esophagus to evaluate for mucosal abnormalities. More recently, other nonendoscopic cell collection devices have been developed. One such device is a capsule sponge (Cytosponge, Medtronic). After being swallowed, the capsule dissolves and a compressed sponge emerges. The sponge is pulled out with a string for laboratory biomarker assessment. When combined with biomarkers, such as trefoil factor 3 and methylated DNA markers, the capsule sponge can be considered for people who have chronic GERD.14

Question 9. What surveillance intervals are appropriate for patients with BE, and how should surveillance be performed?

The most important steps for BE surveillance include an appropriate diagnosis, assessment of extent of disease (by the Prague criteria), and evaluation for any mucosal

Figure 2. Prague classification requires accurate identification of diaphragmatic pinch (green arrow), upper end of gastric folds (red arrow), and extent of BE with circumferential (extent of 2 cm) and maximum (extent of 4 cm) classification (yellow arrows).

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low-grade dysplasia can undergo either surveillance every year or endoscopic therapy, whereas all patients with highgrade dysplasia and early EAC will need definitive endoscopic therapy.3

Question 10. When can you consider discontinuing screening and surveillance for patients with nondysplastic BE? There is a lack of data on when to stop surveillance for patients with nondysplastic BE. Although screening can lead to an increase in the number of patients with BE and need for further surveillance, an important consideration should be given to overall life expectancy.16 If the patient’s overall life expectancy is less than 10 years, the value of screening or surveillance decreases significantly.17 In this scenario, shared decision making with the patient should be done, with discussion about the risk for progression to EAC, the utility of surveillance with endoscopy, and sedation-related risks.

References 1.

Perisetti A, Sharma P. Tips for improving the identification of neoplastic visible lesions in Barrett’s esophagus.

Gastrointest Endosc. 2022;97(2):248-250.

2.

Sharma P, Dent J, Armstrong D, et al. The development and validation of an endoscopic grading system for Barrett’s esophagus: the Prague C & M criteria. Gastroenterology.

2006;131(5):1392-1399.

3.

Sharma P. Barrett esophagus: a review. JAMA. 2022;328(7):663-671.

4.

Dekel R, Wakelin DE, Wendel C, et al. Progression or regression of Barrett’s esophagus—is it all in the eye of the beholder? Am J Gastroenterol. 2003;98(12):2612-2615.

5.

6.

Sharma P, Katzka DA, Gupta N, et al. Quality indicators for the management of Barrett’s esophagus, dysplasia, and esophageal adenocarcinoma: international consensus recommendations from the American Gastroenterological Association Symposium. Gastroenterology.

2015;149(6):1599-1606.

Gupta N, Gaddam S, Wani SB, et al. Longer inspection time is associated with increased detection of high-grade

dysplasia and esophageal adenocarcinoma in Barrett’s esophagus. Gastrointest Endosc. 2012;76(3):531-538.

7.

Sharma P, Morales TG, Bhattacharyya A, et al. Squamous islands in Barrett’s esophagus: what lies underneath? Am J Gastroenterol. 1998;93(3):332-335.

8.

Epstein JA, Cosby H, Falk GW, et al. Columnar islands in Barrett’s esophagus: do they impact Prague C&M criteria and dysplasia grade? J Gastroenterol Hepatol.

2017;32(9):1598-1603.

9.

Choe JW, Kim YC, Joo MK, et al. Application of the Prague C and M criteria for endoscopic description of columnar-lined esophagus in South Korea. World J Gastrointest Endosc.

2016;8(8):357-361.

10. Hagen CE, Lauwers GY, Mino-Kenudson M. Barrett esophagus: diagnostic challenges. Semin Diagn Pathol.

2014;31(2):100-113.

11.

Kara MA, Ennahachi M, Fockens P, et al. Detection and classification of the mucosal and vascular patterns (mucosal morphology) in Barrett’s esophagus by using narrow band imaging. Gastrointest Endosc. 2006;64(2):155-166.

12. Hamade N, Bhavsar-Burke I, Jansson-Knodell C, et al.

Virtual gastroenterology fellowship recruitment during COVID-19 and its implications for the future. Dig Dis Sci. 2022;67(6):2019-2028.

13. Sharma P, Shaheen NJ, Katzka D, et al. AGA clinical practice update on endoscopic treatment of Barrett’s Esophagus with dysplasia and/or early cancer: expert review.

Gastroenterology. 2020;158(3):760-769.

14. Spechler SJ, Sharma P, Souza RF, et al. American Gastroenterological Association technical review on the management of Barrett’s esophagus. Gastroenterology. 2011;140(3):e18-52; quiz e13.

15. Shaheen NJ, Falk GW, Iyer PG, et al. ACG clinical guideline: diagnosis and management of Barrett’s esophagus. Am J Gastroenterol. 2016;111(1):30-50; quiz 1.

16. Omidvari AH, Hazelton WD, Lauren BN, et al. The optimal age to stop endoscopic surveillance of patients with Barrett’s esophagus based on sex and comorbidity: a comparative cost-effectiveness analysis. Gastroenterology. 2021;161(2):487494.e4.

17.

Srinivasan S, Sharma P. Real-world data for endoscopic therapy in LGD: not looking so good. Gut. 2022;71(8):1457-1458.

Dr Sharma reported financial relationships with Bausch, Boston Scientific, CDx Labs, Cosmo, Covidien LP, Docbot, ERBE, Exact Sciences, Fujifilm, Ironwood, Lucid, Lumendi, Medtronic, Phathom, Olympus, Samsung Bioepis, and Takeda. Dr Perisetti reported a financial relationship with Intercept.

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Health Maintenance for Patients With Inflammatory Bowel Disease OSCAR RAMIREZ RAMIREZ, MD Division of Internal Medicine

FREDDY CALDERA, DO, MS Division of Gastroenterology and Hepatology Department of Medicine School of Medicine and Public Health University of Wisconsin–Madison Madison, Wisconsin

C

haracterized by chronic inflammation of the gastrointestinal tract

resulting in abdominal pain, diarrhea, and other chronic symptoms, inflammatory bowel disease is estimated to affect at least 3.1 million people in the United States.1 Patients with IBD are at increased risk for vaccine-preventable diseases, malignancies, and bone mineral disease, making preventive care paramount in this population.

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Table 1. Recommended Vaccinations for Patients With IBD Vaccines

Patient group

COVID-19 (Moderna, Pfizer, Novavax)

• All adults

Influenza (Fluzone High Dose, Sanofi Pasteur; Flublok recombinant, Sanofi Pasteur; Fluad adjuvanted, CSL Sequirus)

• All adults, unless otherwise noted: standard dose • Adults on anti-TNF monotherapy: high-dose vaccine • Adults ≥65 y of age: high-dose, recombinant, or adjuvanted influenza vaccine • Those on systemic immunosuppresion should avoid live influenza vaccine (nasal)

15-valent or 20-valent pneumococcal conjugate vaccine (PCV15 or PCV20) or pneumococcal polysaccharide vaccine (PPSV23)

• All patients ≥19 y of age receiving systemic immunosuppressiona

RZV (adjuvanted non-live) (Shingrix, GlaxoSmithKline)

• All patients with IBD ≥19 y of age

HPV (9-valent) (Gardasil 9, Merck)

• All adults ≥18-26 y of age • Adults 26-45 y of age: shared decision between patient and provider

Hepatitis A (Havrix, GSK; Vaqta, Merck)b

• All adults not previously vaccinated

Hepatitis B (Heplisav-B, Dynavax; Engerix-B, GSK; Recombivax HB, Merck)b

• All adults with IBD. • Universal vaccination is recommended for adults 19-59 y of age

Meningococcal A, C, W, Y (MenACWY); Men B

• Adults who live in college residence halls and missed routine immunizations • Military recruits • Adults with asplenia, complement deficiency, or HIV

Tetanus, diphtheria, pertussis (Tdap or Td)

• All adults • Pregnant patients

MMR 2-dose live vaccine

• Patients not immune to MMR (if immune status is uncertain, obtain immunization historyc)

Varicella 2-dose live vaccine

• Check for documentation of 2 doses of varicella vaccined

ACIP, Advisory Committee on Immunization Practices; IgG, immunoglobulin G; MMR, measles, mumps, and rubella; RZV, recombinant zoster vaccine; TNF, tumor necrosis factor. a Current treatment with prednisone (>20 mg/d for more than 14 d), azathioprine (>2.5 mg/kg/d), mercaptopurine (>1.5 mg/kg/d), methotrexate (>0.4 mg/kg/wk), cyclosporine, tacrolimus, infliximab, adalimumab, golimumab, certolizumab, ustekinumab, risankizumab, ozanimod, upadacitinib, or tofacitinib. b Patients who require vaccination for both hepatitis A and B may benefit from one combination vaccine, Twinrix (GSK), which is given as a 3-dose series at 0, 1, and 6 mo. c

IgG antibody titer can be checked but not recommended by the ACIP.

d

Serology not recommended by ACIP for evaluation of vaccine-induced immunity in those with appropriate documentation.

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Frequency • Follow CDC recommendation for the general population • Annually

• Vaccine-naive patients: PCV20 or PCV15, followed by PPSV23 8 wk later • Those previously vaccinated with PCV13 and PPSV23: 1 PCV20 dose at least 1 year after last dose of pneumococcal vaccine • Those ≥65 y of age: a dose of PCV20 • If on systemic immunosuppresion: 2 doses of RHZ vaccine 1-2 mo apart • If not on systemic immunosuppresion: 2 doses of RHZ vaccine 2-6 mo apart • 3-dose series at 0, 1-2, and 6 mo

• 2-dose series 6-12 mo apart • Heplisav-B: 2-dose series at 0 and 1 mo • Engerix or Recombivax: 3-dose series at 0, 1, and 6 mo

• MenACWY every 5 y • Men B 1 y after completing series and then every 2-3 y

• If previously immunized: single dose of Tdap then Td or Tdap every 10 y • 1 dose of Tdap during third trimester of each pregnancy • 2-dose series, at least 4 wk apart • Contraindicated in those on systemic immunosuppresion • All patients who are not immune: 2-dose series, 4-8 wk apart, ≥4 wk before immunosuppression, if therapy cannot be postponed • Contraindicated in those on systemic immunosuppression

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Table 2. Timing for CRC Screening After a Negative Colonoscopy for Dysplasia Schedule

Every year

Patient • Ongoing moderate or severe characteristics inflammation

1-3 years

Every 5 years

• Mild inflammation

Continuous disease remission since last colonoscopy and one of the following:

• Primary sclerosing cholangitis

• Family history of CRC, but not in first-degree members <50 y of age

• Family history of CRC in firstdegree relative diagnosed <50 y of age

• Prior evidence of severe colitis by endoscopy (moderate pseudopolyps and/or extensive scarring)

• Dense pseudopolyps

• History of invisible dysplasia of high-risk visible dysplasia <5 y ago

• History of invisible dysplasia of high-risk visible dysplasia <5 y ago

• History of invisible dysplasia of low-risk visible dysplasia <5 y ago

There are 2 main causes of this increased risk for vaccine-preventable diseases (VPDs) in patients with IBD, the disease state itself and treatment-related complications associated with corticosteroids or immune-modifying therapies. These novel therapies are associated with higher rates of clinical and endoscopic remission than conventional therapies, but the treatments also have an increased risk for complications such as VPDs.2 Patients with IBD receive lower rates of preventive care compared with the general population.3 The causes are multifactorial but can include gaps in primary care provider (PCP) knowledge of preventive care recommendations for this population and low levels of PCP comfort in vaccinating patients who are taking novel biologic medications.4 Alongside these causes, there is discordance on whether the PCP or gastroenterologist should provide preventive care recommendations. Preventive care guidelines for IBD recommend that gastroenterologists should provide vaccine recommendations and share the responsibility of ensuring that vaccines are administered.5 Implementing this strategy can increase the uptake of preventive care among patients with IBD. In this review, we discuss various areas of health maintenance in patients with IBD, including vaccination, cancer screening, osteoporosis screening, mental health screening, and tobacco use cessation recommendations.

Vaccines Patients with IBD commonly are treated with immunemodifying therapy that may increase their risk for infections, some of which are VPDs.2 Thus, it is of utmost importance that patients are up to date with appropriate age-related vaccines. They can follow the adult immunization schedule from the Advisory Committee on Immunization Practices (ACIP),

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• ≥2 consecutive exams without dysplasia • Minimal historical colonic extent (<1/3 of the total colon in CD or ulcerative proctitis)

with some considerations that are discussed in this review.

The recommended vaccines for adults with IBD are summarized in Table 1.

Vaccines are not associated with IBD flares and are safe to administer if no contraindications are present. 6 Liveattenuated vaccines are contraindicated in immunocompromised patients.2 Certain treatment regimens, particularly anti–tumor necrosis factor (TNF) therapy, may blunt the vaccine response.2 Thus, the optimal time to vaccinate patients is at diagnosis, but a lack of vaccination should not delay IBD treatment initiation. Vaccines also should be offered to patients at all clinical time points during follow-up.2

Influenza Patients with IBD are at increased risk for influenza, and complications such as hospitalization and superimposed bacterial pneumonia are more frequent in this population.7 All adults should receive an influenza vaccine annually.8 The ACIP provided new recommendation for adults 65 years of age and older, who are at increased risk for influenza complications. They should receive a vaccine that is more likely to induce higher antibodies, such as the high-dose influenza, recombinant, or adjuvanted inactive influenza vaccine.8 Patients taking anti-TNF monotherapy also should receive an high-dose influenza vaccine since it has been found to induce higher antibodies in this population.9

Streptococcus pneumoniae People living with IBD are also at risk for acquiring pneumococcal pneumonia, with a 1.5- to 2-fold increased risk compared with those without IBD.10 The ACIP recommends that patients who are 19 years of age or older and on immunosuppressive therapy should be vaccinated with

Central DEXA at diagnosis if 1 of the following risk factors: • Age ≥65 y in women and ≥70 in men • Low body mass index • More than 3 mo of cumulative steroid use at dosages greater than 7.5 mg of prednisone or the equivalent • Tobacco use • Postmenopausal status • Hypogonadism

If initial screening is positive, follow up with primary care to discuss treatment options.

If initial screening is negative, repeat in 5 y (no sooner than 2 y).

Figure. Osteoporosis screening recommendations for patients with IBD. DEXA, dual-energy x-ray absorptiometry.

a single dose of either the 20-valent (PCV20) or 15-valent (PCV15) pneumococcal conjugate vaccine. For those who receive PCV15, this vaccination should be followed by the pneumococcal polysaccharide vaccine (PPSV23) 8 weeks later. Those previously vaccinated with PCV13 and PPSV23 should receive a single dose of PCV20 at least 1 year after the last dose of pneumococcal vaccine. Patients who are 65 years of age and older should receive a dose of PCV20 at least 5 years after their last pneumococcal vaccine.11

COVID-19 Evidence from the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease database suggests an increased risk for severe COVID-19 infection in patients with IBD who are on systemic corticosteroids, older in age, or have certain comorbidities, especially chronic obstructive pulmonary disease and chronic kidney disease.12 Immune-modifying therapies used to treat IBD have not been associated with an increased risk for severe COVID-19.12 Most patients with IBD can mount a humoral immune response after a 2-dose primary series and achieve a robust response after 3 doses.13 Non-anti–TNF biologics do not appear to affect the humoral immune response after COVID-19 vaccination, but patients on anti-TNF therapy may have a lower antibody concentration.14 Studies evaluating the cell-mediated immune response after COVID-19 vaccination have found that most patients respond to the primary series.15 Patients on anti-TNF therapy have an augmented cell-mediated immune response compared with those not on this regimen.15 The majority of patients with IBD can follow COVID-19 vaccine recommendations for the general population and receive booster doses as recommended by the ACIP. It appears that bivalent boosters will be recommended annually during the Fall season.

Cancer Screening Colorectal Cancer It is well established that IBD is a risk factor for colorectal dysplasia and cancer. The risk is higher with extensive colitis, defined as involvement of greater than one-third of the colon for at least 8 years of disease. In ulcerative colitis specifically, extension above the rectum imposes a greater risk.16 Surveillance colonoscopy recommendations after negative screening vary between 1 to 3 years. The interval depends on a patient’s risk factors, including the presence of primary sclerosing cholangitis and high-risk gastrointestinal features, such as a history of adenomatous polyps, dysplasia, family history of colon cancer, and increased inflammatory burden. The American Gastroenterological Association clinical practice update proposed a 1- to 5-year interval (Table 2).16

Cervical Cancer Persistence of high-risk HPV is the main risk factor for the development of cervical dysplasia and cancer. Impaired viral clearance is one of the mechanisms that lead to higher rates of complications in immunocompromised individuals.

There is no clear evidence to demonstrate that IBD alone increases the risk for cervical pathology, although the prevailing data show an increased risk for high-grade cervical dysplasia in patients with IBD on systemic immunosuppression.17 A recent meta-analysis of population-based studies showed no increased risk for cervical cancer among patients regardless of IBD treatment. However, patients are at increased risk for low-grade cervical lesions compared with the general population.18 Given no evidence for an increased risk for cervical cancer in patients with IBD, gastroenterologists should follow the American College of Obstetricians and Gynecologists recommendations for the

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general population.19 They also should recommend immunization with the 9-valent HPV vaccine for all patients up to 46 years of age who are likely to have a new sexual partner.

Skin Cancer The risk of melanoma and nonmelanoma skin cancer is higher in patients with IBD. Particularly, thiopurine use increases the risk for skin cancer, with the risk persisting despite discontinuation.20 Studies suggest that patients on anti-TNF therapy may be at increased risk for melanoma.21 Patients should be referred to a dermatologist or PCP for annual examinations, and providers should encourage sunscreen use.5

Bone Disease Patients with IBD have higher rates of osteopenia, osteoporosis, and bone fractures because bone diseases develop at an accelerated rate in this population. The risk for osteoporosis ranges from 15% to 40%.5 Patients with IBD have lower mineral bone density by T-score than the general population, and the risk is higher in patients with Crohn’s disease than in those with ulcerative colitis.5 The American College of Gastroenterology preventive guidelines recommend screening for osteoporosis with central (hip and spine) dual-energy x-ray absorptiometry (DEXA) at diagnosis as baseline if the patient has at least 1 risk factor.5 These factors include: age greater than 65 years in women and 70 years in men, low body mass index, more than 3 months of cumulative steroid use at doses greater than 7.5 mg of prednisone or an equivalent, tobacco use, and postmenopausal status or hypogonadism. If the initial screening is normal, DEXA should be repeated in 5 years (not sooner than 2 years) (Figure).

Lifestyle factors should be discussed, with recommendations to include at least 150 minutes weekly of moderate-to

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high-intensity aerobic and weight-bearing exercise (muscle strengthening or resistance training). Smoking cessation, avoiding excessive alcohol use, and fall prevention also should be discussed with patients during routine visits.5 In postmenopausal patients and those receiving more than 5 mg of prednisone or equivalent for at least 3 months, calcium and vitamin D supplementation should be advised.5

Mental Health People living with chronic diseases, pain, and multiple comorbidities have higher rates of depression and anxiety. IBD is not an exception, with higher rates of depression and anxiety in this population compared with healthy controls. Rates can be as high as 20%, as shown in a systematic review.22 In the study, individuals with active disease also were found to have higher rates of mood disorders compared with those in remission.22 As part of a holistic care approach, patients with IBD should be screened at baseline for anxiety and depression every year.5 If the comorbidities are identified, referral for counseling is recommended.

Tobacco Use All patients with IBD should be screened for smoking status at baseline, and current smokers should be counseled to quit smoking or even reduce the number of daily cigarettes, as the deleterious side effects are dose dependent. Referral for smoking cessation therapy is appropriate as well.5

Conclusion Preventive health is an integral component of care provided to patients with IBD. Gastroenterologists and other GI providers should play an active role in recommending and providing preventive health for patients with IBD. By sharing this responsibility with PCPs, they can improve the care of patients with IBD and prevent complications.

References 1.

Dahlhamer JM, Zammitti EP, Ward BW, et al. Prevalence of inflammatory bowel disease among adults aged ≥18 years - United States, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(42):1166-1169.

2.

Caldera F, Hayney MS, Farraye FA. Vaccination in patients with inflammatory bowel disease. Am J Gastroenterol.

2020;115(9):1356-1361.

3.

Selby L, Kane S, Wilson J, et al. Receipt of preventive health services by IBD patients is significantly lower than by primary care patients. Inflamm Bowel Dis. 2008;14(2):253-258.

4.

Selby L, Hoellein A, Wilson JF. Are primary care providers uncomfortable providing routine preventive care for inflammatory bowel disease patients? Dig Dis Sci. 2011;56(3):819-824.

5.

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.

6.

7.

8.

9.

Desalermos A, Pimienta M, Kalligeros M, et al. Safety of immunizations for the adult patient with inflammatory bowel disease-a systematic review and meta-analysis. Inflamm Bowel Dis. 2022;28(9):1430-1442.

Tinsley A, Navabi S, Williams ED, et al. Increased risk of influenza and influenza-related complications among 140,480 patients with inflammatory bowel disease. Inflamm Bowel Dis. 2019;25(2):369-376.

Grohskopf LA, Blanton LH, Ferdinands JM, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices - United States, 2022-23 influenza season. MMWR Recomm Rep. 2022;71(1):1-28.

Caldera F, Hillman L, Saha S, et al. Immunogenicity of high dose influenza vaccine for patients with inflammatory bowel disease on anti-TNF monotherapy: a randomized clinical trial. Inflamm Bowel Dis. 2020;26(4):593-602.

10. Long MD, Martin C, Sandler RS, et al. Increased risk of pneumonia among patients with inflammatory bowel disease. Am J Gastroenterol. 2013;108(2):240-248.

11.

Kobayashi M, Farrar JL, Gierke R, et al. Use of 15-valent pneumococcal conjugate vaccine and 20-valent pneumococcal conjugate vaccine among U.S. adults: updated recommendations of the Advisory Committee on Immunization Practices - United States, 2022.

MMWR Morb Mortal Wkly Rep. 2022;71(4):109-117.

12. Ungaro RC, Brenner EJ, Agrawal M, et al. Impact of medications on COVID-19 outcomes in inflammatory bowel disease: analysis of

more than 6000 patients from an international registry.

Gastroenterology. 2022;162(1):316-319.e5.

13. Schell TL, Knutson KL, Saha S, et al. Humoral immunogenicity of 3 COVID-19 messenger RNA vaccine doses in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2022;28(11):1781-1786.

14. Caldera F, Knutson KL, Saha S, et al. Humoral immunogenicity of mRNA COVID-19 vaccines among patients with inflammatory bowel disease and healthy controls. Am J Gastroenterol.

2022;117(1):176-179.

15. Caldera F, Farraye FA, Necela BM, et al. Higher cell-mediated immune responses in patients with inflammatory bowel disease on anti-TNF therapy after COVID-19 vaccination. Inflamm Bowel Dis. Published online September 14, 2022. doi:10.1093/ibd/izac193 16. Murthy SK, Feuerstein JD, Nguyen GC, et al. AGA clinical practice update on endoscopic surveillance and management of colorectal dysplasia in inflammatory bowel diseases: expert review. Gastroenterology. 2021;161(3):1043-1051.e4.

17. Allegretti JR, Barnes EL, Cameron A. Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A metaanalysis. Inflamm Bowel Dis. 2015;21(5):1089-1097.

18. Mann S, Jess T, Allin K, et al. Risk of cervical cancer in inflammatory bowel disease: a meta-analysis of population-based studies.

Clin Transl Gastroenterol. 2022;13(7):e00513.

19. American College of Obstetricians and Gynecologists. Updated guidelines for management of cervical cancer screening abnormalities. Practice Advisory. American College of Obstetricians and Gynecologists; 2020. https://www.acog.org/ clinical/clinical-guidance/practice-advisory/articles/2020/10/ updated-guidelines-for-management-of-cervical-cancer-screeningabnormalities 20. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141(5):16211628.e1-5.

21. Long MD, Martin CF, Pipkin CA, et al. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;143(2):390-399.e1.

22. Mikocka-Walus A, Knowles SR, Keefer L, et al. Controversies revisited: a systematic review of the comorbidity of depression and anxiety with inflammatory bowel diseases. Inflamm Bowel Dis. 2016;22(3):752-762.

Dr. Caldera reported financial relationships with Arena, Celgene, GlaxoSmithKline, Janssen, Novavax, and Takeda. Dr. Ramirez Ramirez reported no relevant financial disclosures.

GASTROENTEROLOGY & ENDOSCOPY NEWS SPECIAL EDITION • OCTOBER 2023

41

FOR ADULTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE (CD)

SKYRIZI provides the opportunity for endoscopic and symptom control. For your patients, that’s everything.

The FIRST and Only IL-23 Specifific Inhiibitor in Crohnn’s Diiseasse INDICATION AND IMPORTANT SAFETY INFORMATION FOR SKYRIZI® (risankizumab-rzaa)1 INDICATION1

ABBVIE SKYRIZI Page 42

SKYRIZI is indicated for the treatment of moderately to severely active Crohn’s disease in adults.

IMPORTANT SAFETY INFORMATION1 Hypersensitivity Reactions SKYRIZI® (risankizumab-rzaa) is contraindicated in patients with a history of serious hypersensitivity reaction to risankizumab-rzaa or any of the excipients. Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of SKYRIZI. If a serious hypersensitivity reaction occurs, discontinue SKYRIZI and initiate appropriate therapy immediately.

Infection SKYRIZI may increase the risk of infection. Do not initiate treatment with SKYRIZI in patients with a clinically important active infection until it resolves or is adequately treated.

In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing SKYRIZI. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy, closely monitor and discontinue SKYRIZI until the infection resolves.

Tuberculosis (TB) Prior to initiating treatment with SKYRIZI, evaluate for TB infection and consider treatment in patients with latent or active TB for whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after SKYRIZI treatment. Do not administer SKYRIZI to patients with active TB. Hepatotoxicity in Treatment of Crohn’s Disease Drug-induced liver injury was reported in a patient with Crohn’s disease who was hospitalized for a rash during induction dosing of SKYRIZI. For the treatment of Crohn’s disease, evaluate liver enzymes and bilirubin at baseline and during induction (12 weeks); monitor thereafter according to routine patient management.

Consider an alternate treatment for patients with evidence of liver cirrhosis. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct your patient to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction.

Administration of Vaccines Avoid use of live vaccines in patients treated with SKYRIZI. Medications that interact with the immune system may increase

End doscoppicc and Sym mptom Co ontrol Ac cross Co-Prrimary Endpointts ADVANCE

MOTIVATE

FORTIFY

Mixed Population*

Biologic Failure Population†

Mixed Population*

100

INDUCTION STUDIES (at Week 12)

MAINTENANCE STUDY (at Week 52)

ENDOSCOPIC CONTROL Endoscopic Response (SES-CD)‡ Co-Primary Endpoint

PATIENTS (%)

80

50% 48%

60

40%

40

20

29%

12%

11% p<0.001

p<0.001 0

n=175

22%

n=336

n=187

n=191

n=130

p<0.05

p<0.05

n=135

n=117

100

SYMPTOM CONTROL Clinical Remission (CDAI)§ Co-Primary Endpoint

PATIENTS (%)

80

45%

60

42%

46%

61% 57%

40

25%

20%

20

p<0.001 0

n=175

p<0.001

n=336 Placebo

n=187 SKYRIZI 600 mg IV

All p-values are SKYRIZI treatment arms vs placebo.

n=191

n=130

p<0.05

p<0.05

n=135

n=117

Placebo (Induction Responders)

SKYRIZI 180 mg SC SKYRIZI 360 mg SC

Endoscopic response was defi ned as a decrease in SES-CD >50% from baseline, or a decrease of at least 2 points for subjects with a baseline score of 4 and isolated ileal disease, based on central reading. § Clinical remission was defi ned as a CDAI <150 points. ‡

ADVANCE (N=850) and MOTIVATE (N=569) Induction studies were the risk of infection following administration of live vaccines.

Prior to initiating SKYRIZI, complete all age appropriate vaccinations 12-week, randomized, double-blind, placebo-controlled studies ABBVIE SKYRIZI according to current immunization guidelines. that evaluated the efficacy and safety of SKYRIZI in patients with Page 43 moderately to severely active Crohn’s disease who demonstrated Adverse Reactions prior treatment failure to conventional and/or biologic treatment.

Most common (>3%) adverse reactions associated with SKYRIZI Patients received an IV infusion of SKYRIZI 600 mg (recommended in Crohn’s disease are upper respiratory infections, headache, dose), risankizumab-rzaa 1200 mg or placebo at Weeks 0, 4, and 8. and arthralgia in induction and arthralgia, abdominal pain, injection FORTIFY (N=382) Maintenance study was a 52-week study that site reactions, anemia, pyrexia, back pain, arthropathy, and urinary evaluated the efficacy and safety of SKYRIZI in patients who tract infection in maintenance. achieved clinical response (decrease in CDAI ≥100) from SKYRIZI Lipid Elevations: Increases from baseline and increases relative to induction in the ADVANCE and MOTIVATE studies. Patients placebo were observed at Week 4 and remained stable to Week 12 were randomized to SKYRIZI 180 mg SC, SKYRIZI 360 mg SC, or in patients treated with SKYRIZI in Crohn’s disease. placebo at Week 12 and every 8 weeks thereafter.

Dosage Forms and Strengths: SKYRIZI is available in a 600 mg/10 mL single-dose vial for intravenous infusion and a 180 mg/1.2 mL or References: 1. SKYRIZI [package insert]. North Chicago, IL: AbbVie Inc. 2. D’Haens G, Panaccione R, Baert F, et al. Risankizumab as induction therapy for Crohn’s disease: results from the phase 3 ADVANCE 360 mg/2.4 mL single-dose prefilled cartridge with on-body injector. and MOTIVATE induction trials. Lancet. 2022;399(10340):2015-2030. 3. Data on file, AbbVie Inc. ABVRRTI74186.

Please see the Brief Summary of the full Prescribing Information on the following page.

Placebo (Induction Responders): Patients who achieved CDAI clinical response (CR-100) || to SKYRIZI induction therapy and were randomized to receive placebo in the maintenance study. * The mixed population includes patients who had inadequate response, loss of response, or intolerance to one or more biologics (biologic failure), as well as patients who had never demonstrated inadequate response, loss of response, or intolerance to a biologic (bio-naive; includes 13% in ADVANCE and 8% in FORTIFY who were bio-exposed). †

For more information about treating CD with SKYRIZI, scan the QR code.

Prior biologic failure includes inadequate response, loss of response, or intolerance to one or more biologics.

||

Clinical response was defined as a reduction of CDAI ≥100 points from baseline.

CDAl=Crohn’s disease activity index; IV=intravenous; SC=subcutaneous; SES-CD=simple endoscopic score for Crohn’s disease.

© 2022 AbbVie. All rights reserved.

SKYRIZI® and its design are registered trademarks of AbbVie Biotechnology Ltd. US-SKZG-220774 December 2022

BRIEF SUMMARY SKYRIZI® (sky-RIZZ-ee) (risankizumab-rzaa) injection, for subcutaneous or intravenous use PROFESSIONAL CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

150 mg/mL single-dose pen and prefilled syringe 600 mg/10 mL single-dose vial for intravenous infusion 180 mg/1.2 mL single-dose prefilled cartridge with on-body injector 360 mg/2.4 mL single-dose prefilled cartridge with on-body injector INDICATIONS AND USAGE Plaque Psoriasis SKYRIZI® is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

Psoriatic Arthritis SKYRIZI is indicated for the treatment of active psoriatic arthritis in adults.

Crohn’s Disease SKYRIZI is indicated for the treatment of moderately to severely active Crohn’s disease in adults.

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

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported with use of SKYRIZI. If a serious hypersensitivity reaction occurs, discontinue SKYRIZI and initiate appropriate therapy immediately [see Adverse Reactions].

Infections SKYRIZI may increase the risk of infections [see Adverse Reactions].

Treatment with SKYRIZI should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.

In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing SKYRIZI. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy, monitor the patient closely and do not administer SKYRIZI until the infection resolves.

Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SKYRIZI. Across the Phase 3 psoriasis clinical studies, of the 72 subjects with latent TB who were concurrently treated with SKYRIZI and appropriate TB prophylaxis during the studies, none developed active TB during the mean follow-up of 61 weeks on SKYRIZI. Two subjects taking isoniazid for treatment of latent TB discontinued treatment due to liver injury. Of the 31 subjects from the PsO-3 study with latent TB who did not receive prophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks on SKYRIZI. Consider anti-TB therapy prior to initiating SKYRIZI in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after SKYRIZI treatment. Do not administer SKYRIZI to patients with active TB. Hepatotoxicity in Treatment of Crohn’s Disease A serious adverse reaction of drug-induced liver injury in conjunction with a rash that required hospitalization was reported in a patient with Crohn’s disease (ALT 54x ULN, AST 30x ULN, and total bilirubin 2.2x ULN) following two 600 mg intravenous doses of SKYRIZI. The liver test abnormalities resolved following administration of steroids. SKYRIZI was subsequently discontinued.

For the treatment of Crohn’s disease, evaluate liver enzymes and bilirubin at baseline, and during induction at least up to 12 weeks of treatment. Monitor thereafter according to routine patient management.

Consider other treatment options in patients with evidence of liver cirrhosis.

Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded.

Instruct patients to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction.

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

ADVERSE REACTIONS The following adverse reactions are discussed in other sections of labeling: • Hypersensitivity Reactions [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Tuberculosis [see Warnings and Precautions] • Hepatotoxicity in Treatment of Crohn’s Disease [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse drug reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Plaque Psoriasis A total of 2234 subjects were treated with SKYRIZI in clinical development trials in plaque psoriasis. Of these, 1208 subjects with psoriasis were exposed to SKYRIZI for at least one year.

Data from placebo- and active-controlled trials were pooled to evaluate the safety of SKYRIZI for up to 16 weeks. In total, 1306 subjects were evaluated in the SKYRIZI 150 mg group.

Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% and at a higher rate in the SKYRIZI group than the placebo group during the 16-week controlled period of pooled clinical trials.

Table 1. Adverse Drug Reactions Occurring in ≥ 1% of Subjects on SKYRIZI through Week 16 Adverse Drug Reactions

SKYRIZI N = 1306 n (%)

Placebo N = 300 n (%)

Upper respiratory infectionsa

170 (13.0)

29 (9.7)

Headacheb

46 (3.5)

6 (2.0)

Fatiguec

33 (2.5)

3 (1.0)

Injection site reactionsd

19 (1.5)

3 (1.0)

Tinea infectionse

15 (1.1)

1 (0.3)

a Includes: respiratory tract infection (viral, bacterial or unspecified),

sinusitis (including acute), rhinitis, nasopharyngitis, pharyngitis (including viral), tonsillitis

b Includes: headache, tension headache, sinus headache, cervicogenic

headache c Includes: fatigue, asthenia d Includes: injection site bruising, erythema, extravasation, hematoma, hemorrhage, infection, inflammation, irritation, pain, pruritus, reaction, swelling, warmth e Includes: tinea pedis, tinea cruris, body tinea, tinea versicolor, tinea manuum, tinea infection, onychomycosis Adverse drug reactions that occurred in < 1% but > 0.1% of subjects in the SKYRIZI group and at a higher rate than in the placebo group through Week 16 were folliculitis and urticaria.

Specific Adverse Drug Reactions Infections In the first 16 weeks, infections occurred in 22.1% of the SKYRIZI group (90.8 events per 100 subject-years) compared with 14.7% of the placebo group (56.5 events per 100 subject-years) and did not lead to discontinuation of SKYRIZI. The rates of serious infections for the SKYRIZI group and the placebo group were ≤0.4%. Serious infections in the SKYRIZI group included cellulitis, osteomyelitis, sepsis, and herpes zoster. In Studies PsO-1 and PsO-2, through Week 52, the rate of infections (73.9 events per 100 subject-years) was similar to the rate observed during the first 16 weeks of treatment.

Safety Through Week 52 Through Week 52, no new adverse reactions were identified, and the rates of the adverse reactions were similar to those observed during the first 16 weeks of treatment. During this period, serious infections that led to study discontinuation included pneumonia.

Psoriatic Arthritis The overall safety profile observed in subjects with psoriatic arthritis treated with SKYRIZI is generally consistent with the safety profile in subjects with plaque psoriasis. Additionally, in the Phase 3 placebo-controlled trials the incidence of hepatic events was higher in the SKYRIZI group (5.4%, 16.7 events per 100 patient years) compared to the placebo group (3.9%, 12.6 events per 100 patient years). Of these, the most common events that were reported more frequently in both the placebo group and the SKYRIZI group were ALT increased (placebo: n=12 (1.7%); SKYRIZI: n=16 (2.3%)), AST increased (placebo: n=9 (1.3%); SKYRIZI: n=13 (1.8%)), and GGT increased (placebo: n=5 (0.7%); SKYRIZI: n=8 (1.1%)). There were no serious hepatic events reported. The incidence of hypersensitivity reactions was higher in the SKYRIZI group (n=16, 2.3%) compared to the placebo group (n=9, 1.3%). In the Phase 3 placebo-controlled trials, hypersensitivity reactions reported at a higher rate in the SKYRIZI group included rash (placebo: n=4 (0.6%); SKYRIZI: n=5 (0.7%), allergic rhinitis (placebo: n=1 (0.1%); SKYRIZI: n=2 (0.3%), and facial swelling (placebo: n=0 (0.0%); SKYRIZI n=1 (0.1%). One case of anaphylaxis was reported in a subject who received SKYRIZI in the Phase 2 clinical trial.

Crohn’s Disease SKYRIZI was studied up to 12 weeks in subjects with moderately to severely active Crohn’s disease in two randomized, double-blind, placebo-controlled induction studies (CD-1, CD-2) and a randomized, double-blind, placebocontrolled, dose-finding study (CD-4; NCT02031276). Long-term safety up to 52 weeks was evaluated in subjects who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (CD-3).

In the two induction studies (CD-1, CD-2) and the dose finding study (CD-4), 620 subjects received the SKYRIZI intravenous induction regimen at Weeks 0, 4 and 8. In the maintenance study (CD-3), 297 subjects who achieved clinical response, defined as a reduction in CDAI of at least 100 points from baseline after 12 weeks of induction treatment with intravenous SKYRIZI in studies CD-1 and CD-2, received a maintenance regimen of SKYRIZI either 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.

Adverse reactions reported in > 3% of subjects in induction studies and at a higher rate than placebo are shown in Table 2.

Table 2. Adverse Drug Reactions Reported in > 3% of Subjects with Crohn’s Disease Treated with SKYRIZI in Placebo-Controlled 12-Week Induction Studies

Adverse Drug Reactions

SKYRIZI 600 mg Intravenous Infusiona N = 620 n (%)

Placebo N = 432 n (%)

Upper respiratory infectionsb

66 (10.6)

40 (9.3)

Headachec

41 (6.6)

24 (5.6)

Arthralgia

31 (5.0)

19 (4.4)

Adverse Drug Reactions

SKYRIZI 600 mg Intravenous Infusiona N = 620 n (%)

Placebo N = 432 n (%)

a SKYRIZI 600 mg as an intravenous infusion at Week 0, Week 4, and

Week 8. b Includes: influenza like illness, nasopharyngitis, influenza, pharyngitis, upper respiratory tract infection, viral upper respiratory tract infection, COVID-19, nasal congestion, respiratory tract infection viral, viral pharyngitis, tonsillitis, upper respiratory tract inflammation c Includes: headache, tension headache Adverse reactions reported in >3% of subjects in the maintenance study and at a higher rate than placebo are shown in Table 3.

Table 3. Adverse Reactions Reported in >3% of Subjects with Crohn’s Disease Treated with SKYRIZIa in Placebo-Controlled 52-Week Maintenance Study (CD-3) SKYRIZI 180 mg Subcutaneous Injection N = 155 n (%)

SKYRIZI 360 mg Subcutaneous Injection N = 142 n (%)

Placebo N = 143 n (%)

Arthralgia

13 (8.4)

13 (9.2)

12 (8.4)

Abdominal painb

9 (5.8)

12 (8.5)

6 (4.2)

Injection site reactionsc,d

7 (4.5)

8 (5.6)

4 (2.8)

Anemia

7 (4.5)

7 (4.9)

6 (4.2)

Pyrexia

4 (2.6)

7 (4.9)

4 (2.8)

Back pain

3 (1.9)

6 (4.2)

3 (2.1)

Arthropathy

1 (0.6)

5 (3.5)

2 (1.4)

Urinary tract infection

1 (0.6)

5 (3.5)

4 (2.8)

Adverse Drug Reactions

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

up to an additional 52 weeks

b Includes: abdominal pain, abdominal pain upper, abdominal pain lower c Includes: injection site rash, injection site erythema, injection site

swelling, injection site urticaria, injection site warmth, injection site pain, injection site hypersensitivity, injection site reaction d Some subjects had multiple occurrences of injection site reactions. In this table, injection site reactions are counted only once per subject for the rate calculations.

Specific Adverse Drug Reactions Infections In the maintenance study (CD-3) through Week 52, the rate of infections was 32.3% (50.2 events per 100 subject-years) in subjects who received SKYRIZI 180 mg and 36.6% (60.8 events per 100 subject-years) in subjects who received SKYRIZI 360 mg compared to 36.4% (60.3 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction.

The rate of serious infections was 2.6% (2.7 events per 100 subject-years) in subjects who received SKYRIZI 180 mg and 5.6% (7.4 events per 100 subject-years) in subjects who received SKYRIZI 360 mg compared to 2.1% (2.4 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction.

Lipid Elevations Elevations in lipid parameters (total cholesterol and low-density lipoprotein cholesterol [LDL-C]) were first assessed at 4 weeks following initiation of SKYRIZI in the induction trials (CD-1, CD-2). Increases from baseline and increases relative to placebo were observed at Week 4 and remained stable to Week 12. Following SKYRIZI induction, mean total cholesterol increased by 9.4 mg/dL from baseline to a mean absolute value of 175.1 mg/dL at Week 12. Similarly, mean LDL-C increased by 6.6 mg/dL from baseline to a mean absolute value of 92.6 mg/dL at Week 12. Mean LDL-C increased by 3.1 mg/dL from baseline to a mean absolute value of 99.0 mg/dL at Week 52 with SKYRIZI 180 mg maintenance treatment and by 2.3 mg/dL from baseline to a mean absolute value of 102.2 mg/dL at Week 52 with SKYRIZI 360 mg maintenance treatment.

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products, including other risankizumab products, may be misleading.

Plaque Psoriasis

By Week 52, approximately 24% (263/1079) of subjects treated with SKYRIZI at the recommended dose developed antibodies to risankizumabrzaa. Of the subjects who developed antibodies to risankizumab-rzaa, approximately 57% (14% of all subjects treated with SKYRIZI) had antibodies that were classified as neutralizing. Higher antibody titers in approximately 1% of subjects treated with SKYRIZI were associated with lower risankizumab-rzaa concentrations and reduced clinical response.

Psoriatic Arthritis

By Week 28, approximately 12.1% (79/652) of subjects treated with SKYRIZI at the recommended dose developed antibodies to risankizumab-rzaa.

None of the subjects who developed antibodies to risankizumab-rzaa had

antibodies that were classified as neutralizing. Antibodies to risankizumabrzaa were not associated with changes in clinical response for psoriatic arthritis. A higher proportion of subjects with anti-drug antibodies experienced hypersensitivity reactions (6.3% (5/79)) and injection site reactions (2.5% (2/79)) compared to subjects without anti-drug antibodies (3.8% (22/574) with hypersensitivity reactions and 0.7% (4/574) with injection site reactions). None of these hypersensitivity and injection site reactions led to discontinuation of risankizumab-rzaa.

Crohn’s Disease

By Week 64, antibodies to risankizumab-rzaa developed in approximately 3.4% (2/58) of subjects treated with SKYRIZI induction followed by 360 mg maintenance regimen. No subjects (0/57) treated with SKYRIZI induction followed by 180 mg maintenance regimen developed antibodies to risankizumab-rzaa. None of the subjects who developed antibodies to risankizumab-rzaa had antibodies that were classified as neutralizing.

Postmarketing Experience The following adverse reactions have been reported during post-approval of SKYRIZI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to SKYRIZI exposure: • Skin and subcutaneous tissue disorders: eczema and rash USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors outcomes in women who become pregnant while treated with SKYRIZI. Patients should be encouraged to enroll by calling 1-877-302-2161 or visiting http://glowpregnancyregistry.com.

Risk Summary Available pharmacovigilance and clinical trial data with risankizumab use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

Although there are no data on risankizumab-rzaa, monoclonal antibodies can be actively transported across the placenta, and SKYRIZI may cause immunosuppression in the in utero-exposed infant. There are adverse pregnancy outcomes in women with inflammatory bowel disease (see Clinical Considerations).

In an enhanced pre- and post-natal developmental toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of 5 or 50 mg/kg risankizumab-rzaa once weekly during the period of organogenesis up to parturition. Increased fetal/infant loss was noted in pregnant monkeys at the 50 mg/kg dose (see Data). The 50 mg/kg dose in pregnant monkeys resulted in approximately 10 times the exposure (AUC) in humans administered the 600 mg induction regimen and 39 times the exposure (AUC) to the 360 mg maintenance doses, respectively.

No risankizumab-rzaa-related effects on functional or immunological development were observed in infant monkeys from birth through 6 months of age. The clinical significance of these findings for humans is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-associated maternal and embryo/fetal risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Fetal/Neonatal adverse reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Because risankizumab may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants exposed to SKYRIZI in utero. There are insufficient data regarding infant serum levels of risankizumab at birth and the duration of persistence of risankizumab in infant serum after birth. Although a specific timeframe to delay live virus immunizations in infants exposed in utero is unknown, a minimum of 5 months after birth should be considered because of the half-life of the product.

Data Animal Data An enhanced pre- and post-natal developmental toxicity study was conducted in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered weekly subcutaneous doses of risankizumab-rzaa of 5 or 50 mg/kg from gestation day 20 to parturition, and the cynomolgus monkeys (mother and infants) were monitored for 6 months after delivery.

No maternal toxicity was noted in this study. There were no treatmentrelated effects on growth and development, malformations, developmental immunotoxicology, or neurobehavioral development. However, a dosedependent increase in fetal/infant loss was noted in the risankizumabrzaa-treated groups (32% and 43% in the 5 mg/kg and 50 mg/kg groups, respectively) compared with the vehicle control group (19%). The increased fetal/infant loss in the 50 mg/kg group was considered to be related to risankizumab-rzaa treatment. The no observed adverse effect level (NOAEL) for maternal toxicity was identified as 50 mg/kg and the NOAEL for developmental toxicity was identified as 5 mg/kg. On an exposure (AUC) basis, the 5 mg/kg dose in pregnant monkeys resulted in approximately 1.24 times the exposure in humans administered the 600 mg induction regimen and 5 times the exposure in humans administered the 360 mg maintenance doses, respectively. In the infants, mean serum concentrations increased in a dose-dependent manner and were approximately 17%-86% of the respective maternal concentrations. Following delivery, most adult female cynomolgus monkeys and all infants from the risankizumab-rzaatreated groups had measurable serum concentrations of risankizumab-rzaa up to 91 days postpartum. Serum concentrations were below detectable levels at 180 days postpartum.

Lactation Risk Summary There are no data on the presence of risankizumab-rzaa in human milk, the effects on the breastfed infant, or the effects on milk production.

Endogenous maternal IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to risankizumab-rzaa are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SKYRIZI and any potential adverse effects on the breastfed infant from SKYRIZI or from the underlying maternal condition.

Pediatric Use The safety and effectiveness of SKYRIZI have not been established in pediatric patients.

Geriatric Use Of the 2234 subjects with plaque psoriasis exposed to SKYRIZI, 243 subjects were 65 years or older and 24 subjects were 75 years or older. No overall differences in SKYRIZI exposure, safety, or effectiveness were observed between older and younger subjects who received SKYRIZI. However, the number of subjects aged 65 years and older was not sufficient to determine whether they respond differently from younger subjects.

Clinical studies of SKYRIZI for the treatment of Crohn’s disease did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

No clinically meaningful differences in the pharmacokinetics of risankizumab-rzaa were observed in geriatric subjects compared to younger adult subjects with Crohn’s disease.

PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Hypersensitivity Reactions Advise patients to discontinue SKYRIZI and seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions].

Infections Inform patients that SKYRIZI may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any symptoms of an infection [see Warnings and Precautions].

Hepatotoxicity in Treatment of Crohn’s Disease Inform patients that SKYRIZI may cause liver injury, especially during the initial 12 weeks of treatment. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of liver dysfunction. (e.g., unexplained rash, nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine) [see Warnings and Precautions].

Administration of Vaccines Advise patients that vaccination with live vaccines is not recommended during SKYRIZI treatment and immediately prior to or after SKYRIZI treatment. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Instruct patients to inform the healthcare practitioner that they are taking SKYRIZI prior to a potential vaccination [see Warnings and Precautions].

Administration Instruction Instruct patients or caregivers to perform the first self-injected dose under the supervision and guidance of a qualified healthcare professional for training in preparation and administration of SKYRIZI, including choosing anatomical sites for administration, and proper subcutaneous injection technique.

If using SKYRIZI 75 mg/0.83 mL, instruct patients or caregivers to administer two 75 mg single-dose syringes to achieve the full 150 mg dose of SKYRIZI. Instruct patients or caregivers in the technique of pen or syringe disposal.

Pregnancy Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to SKYRIZI during pregnancy [see Use in Specific Populations].

Manufactured by: AbbVie Inc. North Chicago, IL 60064, USA US License Number 1889 SKYRIZI® is a registered trademark of AbbVie Biotechnology Ltd. © 2019-2022 AbbVie Inc. Ref: 20072970 Revised: September, 2022 LAB-8089 MASTER

64 4,;(-

Expert Picks From DDW 2023: Crohn’s Disease

I EXPERT PICKS Abstract 354.

Passive monitoring device ‘This pilot study shows promise for the implementation of a new technology for patients with CD in remission or with mild activity.’

Abstract 1031.

Upadacitinib endoscopic outcomes ‘These data provide important insights in how to use upadacitinib within the bio-IR population.’

Abstract 1032.

Etrasimod induction therapy ‘This phase 2, dose-ranging study demonstrated favorable efficacy data for both doses of etrasimod in CD, with the expected adverse event signal.’

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n this installment of “Expert Picks” from DDW 2023, Dana Lukin, MD, PhD, an associate professor of clinical medicine at Weill Cornell Medical College and the clinical director of translational research for the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell, in New York City, discusses six of his favorite CD-related abstracts from the meeting.

Abstract 353. Automated digital ulcer quantitation in colonoscopy is better associated with clinical remission than conventional endoscopic scoring in Crohn’s disease (Stidham et al)

Computer processing of endoscopic images may be better than simple endoscopic scores for CD (SES-CD) for assessment of both endoscopic severity and symptom experience in Crohn’s disease trials, according to a study by researchers at the University of Michigan and Janssen.

In the study, reviewers trained a program to process endoscopic videos of patients with colonic CD from the SEAVUE trial to identify, classify and quantify ulcerations. Classification was based on severity (mild versus moderate), size area sum (sum of surface area) and size class sum (observed area quartiles). Overall patient scores for each measure were calculated by summing individual ulcer values along the length of the colon.

The researchers then measured the association between the programderived burden and steroid-free clinical remission (SFCR) and Crohn’s Disease Activity Index (CDAI) scores. They also measured the associations between SES-CD scores and SFCR and CDAI scores. Finally, they compared these results from the automated program and SES-CD scoring schemes.

Of the 222 patients with colonic CD included in the study, 180 (81.1%) achieved SFCR. For all three scoring schemes—area sum and size class sum scores estimated by the automated

program, as well as the SES-CD score— scores were significantly lower in those who had achieved SFCR than those who had not. In addition, the researchers found that CDAI scores were significantly correlated with changes in ulceration (r=0.351; P<0.0001), but not SESCD score (r=0.100; P=0.239). The difference in ulcer size class scores between patients who achieved SFCR and those who did not was greater than the differences shown for the other two methods. This greater difference in scores remained for individual segments of the colon. The researchers suggested that computer processing could allow for improved clinical trial end point design that better integrates endoscopic findings and symptom experience.

Dr. Lukin: Although the SES-CD is a well-validated instrument incorporating relative size of ulcers, presence of stenosis and proportion of involved surface area of each endoscopically evaluated segment, it remains an imperfect tool. Thresholds determining active from inactive disease are based on expert opinion, and there remains debate on optimal cutoffs. Due to these inconsistencies, the use of centralized endoscopic reading within CD randomized controlled trials continues to have limitations.

Stidham el al found superior agreement with an automated ulcer characterization system when assessing for SFCR and CDAI-based remission. With further validation, this system shows the potential to revolutionize CD clinical trials

by increasing the reliability of endoscopic assessment and to complement or replace the need for central readership.

With further validalied in routine clinical practice similar to that used in polyp detection.

Abstract 354. Assessment of a passive monitoring device to track flaresin individuals with Crohn’s disease (Korzenik et al) A radio wave–based at-home sensor that passively monitors patient sleep, respiratory rate and gait speed demonstrated the ability to detect CD flares before they are clinically evident, potentially offering advantages over current flare detection methods, such as colonoscopy, imaging and biochemical marker evaluation.

Researchers from Brigham and Women’s Hospital, Massachusetts Institute of Technology, Emerald Innovations and OneStudyTeam evaluated the Emerald sensor’s ability to accurately predict CD flares, using fecal calprotectin levels (FCP) as an indicator of active disease.

They analyzed 44 adult CD patients in remission, 35 with active disease and 26 healthy controls. The participants were an average of 47 years old. CD patients had an average disease duration longer than 13 years and 83% were on biologic therapy at enrollment. Over the study period, participants were monitored via the sensor for an average of 297 days.

Thirty-seven patients experienced a change from active to inactive or inactive to active disease. Flares were associated with decreased sleep quality, increased nocturnal awakening and respiratory rate, and slower gait speed. The area under the curve for the sensor’s classification of flares was 0.80, which the study authors considered “high accuracy.” In addition, flares could be detected by the sensor up to 20 days before they became clinically evident.

Dr. Lukin: Noninvasive biomarkers, such as FCP, have become well-validated instruments to predict active disease before it is clinically evident, but availability of athome testing, cost, logistics of sample collection and adherence remain significant barriers.

The passive monitoring device described in this study allowed for remote assessment of disease activity, independent of patient adherence, achieving high accuracy for the detection of flares well before emergence of clinical symptoms. Adaptation of this technology could provide an additional means of remote disease monitoring without the need for an office visit or a blood or stool sample. The pairing of this technology with available biomarkers and endoscopic evaluation has the potential to improve treatto-target approaches to clinical care.

This pilot study shows promise for the implementation of a new technology for patients with CD in remission or with mild activity. Further proactive study of larger patient numbers and correlating with biomarkers and endoscopic disease activity can further validate the use of this system in clinical practice. The system does require in-home installation and some logistical factors, such as co-dwelling with large pets, could impact reliability, so further validation is needed.

Abstract 1027. Efficacy and safety of intravenous ustekinumab re-induction therapy in Crohn’s disease patients with secondary loss of response to ustekinumab maintenance therapy: week 16 results from the POWER trial (Lee et al) Ustekinumab reinduction among CD patients with loss of response to the drug during maintenance therapy did not result in significantly improved clinical response compared with continued maintenance therapy but did improve inflammatory biomarker levels, endoscopic outcomes and quality of life measures during the multicenter POWER study.

Sponsored by Janssen, the study included adults with CD who had an initial response to ustekinumab (Stelara, Janssen) but had loss of response. To be eligible, patients were required to have a CDAI score of 220 to 450 as well as at least one of the following: C-reactive protein above 3 mg/L, FCP above 250 mg/kg, or endoscopic evidence of at least one ulceration in the ileum or colon within three months before study initiation. Participants were randomized to receive either IV plus subcutaneous ustekinumab or IV placebo plus subcutaneous ustekinumab at baseline. Both groups subsequently received subcutaneous ustekinumab at weeks 8 and 16.

At weeks 8 and 16, the researchers compared the proportion of patients in each group who had a clinical response (CDAI score decrease of at least 100 points from

baseline or score of less than 150). The researchers also evaluated clinical remission, biomarker normalization, endoscopic findings and quality of life. The investigators analyzed data from 215 participants: 108 in the reinduction arm and 107 in the continuous subcutaneous therapy arm.

By week 16, patients in the reinduction arm (49.1%) were numerically but not significantly more likely to achieve a clinical response compared with those in the continuous subcutaneous therapy arm (37.4%) (P=0.089). However, reinduction arm patients were significantly more likely to achieve CPT normalization (28.8% vs. 8.0%; P=0.001), at least a 16-point improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) quality-of-life score (59.3% vs. 43.0%; P=0.017), at least a 25% improvement in SES-CD (40.7% vs. 15.5%; P=0.0037), endoscopic remission (18.6% vs. 5.2%; P=0.0432) and endoscopic improvement (40.7% vs. 19.0%; P=0.0149) Compared with patients in the continuous therapy arm, those in the reinduction arm also had a significantly larger average decrease in patient-reported number of stools and abdominal pain (PRO-2 score) from baseline (–19.2 vs. –12.5; P=0.017) and SES-CD (–2.3 vs. –0.8; P=0.004).

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The safety of the reinduction and continuous subcutaneous regimens were similar, with each arm having comparable proportions of patients with at least one adverse event.

Dr. Lukin: While doses of ustekinumab FDA-approved for CD are substantially higher than those used in other disease states, in clinical practice, symptom breakthrough or clinical relapse is common on standard dosing. Reinduction IV dosing or interval shortening are frequently requested by clinicians, but given the lack of prospective data, insurance authorization and widespread adoption of optimization practices have been limited.

The CDAI-based primary end point in the POWER study was not significantly different (despite numerical differences), but several key objective end points, including FCP normalization and endoscopic remission, favored reinduction. Several patient-reported outcomes and IBDrelated quality of life also were significantly improved in the

reinduction group. Therefore, although serum ustekinumab levels have been less clearly related to these outcomes, reinduction in patients with initial response to ustekinumab who experience clinical activity recurrence does appear to have significant benefits.

These data suggest that intravenous reinduction is a practical option for patients on ustekinumab maintenance therapy with symptom breakthrough or biochemical/endoscopic activity after initial therapeutic response. The secondary outcomes are highly relevant to clinical practice and should provide valuable data to payors in support of reinduction therapy.

The study only assessed the benefit of an additional intravenous dose, and patients were continued on standard dosing thereafter. Further study of dose optimization of subcutaneous ustekinumab coupled with additional intravenous dosing may aid understanding of the potential benefit of escalated dosing regimens.

Abstract 1028. Subcutaneous infliximab (CT-P13) as maintenance therapy for Crohn’s disease: a phase 3, randomized, placebo-controlled study (LIBERTY-CD) (Hanauer et al) Subcutaneous infliximab has shown promise as a maintenance therapy for CD, with clinical and endoscopic improvements seen in patients at 54 weeks post-induction.

The multicenter, phase 3 LIBERTY-CD trial enrolled CD patients with CDAI scores of 220 to 450 and SESCD scores of 6 or higher for ileocolonic CD or 4 or higher (including ulcer scores for one or more segments) for ileal or colonic CD. All enrolled patients received infliximab induction by IV, with responding patients randomized to subcutaneous infliximab (CT-P13) or placebo maintenance therapy at week 10. The primary end points evaluated in the trial were the proportion of patients who achieved clinical remission (CDAI score <150) and endoscopic response (50% decrease in SES-CD from baseline).

Of the 396 patients enrolled in the trial, 343 responded to induction therapy and were randomized to subcutaneous infliximab (n=231) or placebo (n=112). Patients who received subcutaneous infliximab were significantly more likely than those in the placebo arm to achieve both clinical remission (62.3% vs. 32.1%; P<0.0001) and endoscopic response (51.1% vs. 17.9%; P<0.0001) at week 54.

The safety of the subcutaneous infliximab and placebo arms were generally similar, but in the subcutaneous infliximab arm, participants were slightly more likely to

experience a treatment-emergent adverse event (TEAE) (72.3% vs. 61.9%), an injection site reaction (5.9% vs. 1.0%), or at least one infection (31.1% vs. 18.1%). There also was one death in the subcutaneous infliximab arm.

The researchers concluded that “these results demonstrate that maintenance therapy with CT-P13 ... could provide both a large clinical benefit and the convenience of [subcutaneous] aDministration to moderately to severely active CD patients.”

Dr. Lukin: Infliximab remains a highly effective option for the treatment of CD, with improved access to medication since the approval of several biosimilar products. One limitation of conventional infliximab therapy is the need for intravenous maintenance therapy, which may cause logistical and cost challenges for many patients.

These data are important in demonstrating the feasibility of a subcutaneous infliximab maintenance regimen as an option for patients with moderate to severe CD seeking infliximab without need for intravenous maintenance.

This induction with subcutaneous maintenance is similar to that used for vedolizumab [Entyvio, Takeda], currently approved outside of the United States and anticipated to receive regulatory approval in this country this year.

Abstract 1031. Upadacitinib improves endoscopic outcomes in patients with moderate to severely active Crohn’s disease irrespective of previous failure to respond to biologics or conventional therapies (Feagan et al) Upadacitinib’s endoscopic response and remission benefits hold for CD patients regardless of patient history of biologic failure, according to a recent subgroup analysis of the U-EXCEL, U-EXCEED and U-ENDURE phase 3 trials in CD patients.

CD patients eligible for these trials had either an average daily stool frequency of at least four, an abdominal pain score of 2 or higher, or both. In addition, they had an SES-CD of at least 6 (excluding the presence of narrowing component) or

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at least 4 for isolated ileal disease. Participants were randomized to receive 12 weeks of -upadacitinib (Rinvoq, AbbVie) or placebo. Upadacitinib patients who responded to induction were then re-randomized to 15 or 30 mg of -upadacitinib or placebo daily for a 52-week maintenance period. Endoscopic response and remission were assessed via central reading for both induction therapy (at week 12) and maintenance therapy (at week 52).

Among patients who participated in the induction phase

of treatment, 72% of those who received upadacitinib and 71.5% of those who received placebo had previously failed or had exposure to an advanced therapy. Among participants in the maintenance phase of treatment, 73.4% of those who received 15 mg of upadacitinib, 75.6% of those who received 30 mg of upadacitinib, and 76.4% of those who received placebo had previously had exposure or an inadequate response to a biologic.

At weeks 12 and 52, patients who received upadacitinib were more likely to achieve both endoscopic response and endoscopic remission than those given placebo, regardless of their history of biologic failure. In addition, a higher proportion of patients receiving either dose of maintenance upadacitinib remained in response or remission from week 0 to week 52 compared with those given placebo maintenance treatment.

Patients with a history of biologic failure were generally more likely to experience an adverse event, but the researchers noted that upadacitinib was “well-tolerated, with no new safety risks observed compared to the known safety profile.”

Dr. Lukin: Upadacitinib is an advanced therapy with labeling requiring prior receipt of a tumor necrosis factor

(TNF)-antagonist before use. The efficacy data in the overall population, including biologic-naive patients, were impressive in the phase 2 and 3 development programs. However, performance in the biologic inadequateresponse (bio-IR) subgroup is most relevant to clinical practice in the United States, where the black-box warning restricts first-line use.

These data provide important insights in how to use upadacitinib within the bio-IR population. First, we note a robust induction effect on clinical and endoscopic outcomes in the bio-IR group after they received 45 mg for 12 weeks. These data suggest that endoscopic improvement is similar regardless of treatment exposure, although remission may require more time for the bio-IR group. Second, while both bio-IR and bio-naive groups had significant endoscopic responses to maintenance therapy, the bioIR subgroup may require the 30 mg maintenance dose to achieve similar benefit. This is consistent with results for upadacitinib in ulcerative colitis (UC), as well as the clinical experience with tofacitinib in UC. These data, coupled with those from a related DDW 2023 abstract on clinical outcomes with upadacitinib therapy stratified by treatment history in CD (abstract Tu1727) will help to inform the realworld usage of this newly approved therapy for CD.

Abstract 1032. Etrasimod induction therapy in moderately to severely active Crohn’s disease: results from a phase 2, randomized, double-blind substudy (D’Haens et al) Etrasimod has shown some promise as a safe and effective induction therapy for CD patients who have failed a conventional or advanced treatment, according to results of a CULTIVATE phase 2 substudy.

Participants in the trial were randomized to receive 14 weeks of induction therapy with either 2 or 3 mg of the oral sphingosine-1-phosphate receptor modulator etrasimod (Pfizer). The researchers evaluated the proportion of patients in each arm who achieved endoscopic response (SES-CD score of ≤4 with at least a 2-point decrease from baseline and no subscore >1 or a 50% decrease in SES-CD score from baseline). The researchers also looked at endoscopic remission (SES-CD score ≤4 with a ≥2 decrease from baseline and no subscore >1) as well as clinical and qualityof-life outcomes as secondary end points.

The study enrolled 83 participants; 42 received the 2-mg dose of etrasimod and 41 received the 3-mg dose. The investigators analyzed data from the 32 participants in the 2-mg arm and 36 participants in the 3-mg arm who completed 14 weeks.

Endoscopic response was achieved by 21.4% of participants in the 2-mg arm and 9.8% of those in the 3-mg arm.

Secondary end point results for the 2- and 3-mg arms, respectively, include endoscopic remission (14.3% vs. 7.3%), clinical remission (CDAI score <150; 31.0% vs. 43.9%), IBDQ remission (≥170; 33.3% vs. 40.0%).

Most patients in both the 2-mg (69.0%) and 3-mg (85.4%) arms experienced a TEAE, but most were mild or moderate

in severity. Serious adverse events were relatively infrequent. Notably, during titration up to 3 mg, two participants experienced second-degree atrioventricular block type 1.

Dr. Lukin: Upadacitinib recently was approved as an oral CD therapy, but in the United States it is limited to secondline use after a TNF-antagonist. Currently no FDA-approved oral first-line therapy exists. So, novel agents and mechanisms of action are needed. This phase 2, dose-ranging study demonstrated favorable efficacy data for both doses of etrasimod in CD, with the expected adverse event signal.

This induction study will feed the ongoing phase 2 maintenance trial of etrasimod in CD and possibly later-stage development. If approved, etrasimod would present an attractive option as a first-line oral therapy for moderate to severe CD. We will need to see larger prospective, placebo-controlled data for both induction and maintenance. In addition, as with other S1P receptor modulators, the performance within advanced therapy–exposed (vs. bio-naive) patients will need to be assessed. Furthermore, within this small cohort, there were two instances of second-degree heart block. Understanding more about the true risk for bradyarrhythmia during induction and risk factors for this adverse effect will need to be clarified. Nevertheless, this study raises interest in etrasimod as a novel therapy for CD. —Compiled and written by Natasha Albaneze

Dr. Lukin reported financial relationships with AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Janssen, Palatin, Pfizer and Takeda. He is a member of the Gastroenterology & Endoscopy News editorial board.

GASTROENTEROLOGY & ENDOSCOPY NEWS SPECIAL EDITION • OCTOBER 2023

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AFS Classification Characterizes EGJ Integrity in GERD

A

working group from the American Foregut Society reviewed and expanded the Hill grade classification

to aid in the characterization and treatment of patients with gastroesophageal reflux disease.

“GERD is one of the most common chronic esophageal disorders, and endoscopy is one of the best ways to document the anatomic changes of the esophagogastric junction (EGJ) that are correlated with the presence of GERD. Therefore, it is important to have a user-friendly classification system that can document the anatomic findings of the EGJ during routine upper endoscopy,” said lead study author Ninh Nguyen, MD, the chief of the Division of Gastrointestinal Surgery at the University of California, Irvine.

A white paper describing the new classification was published in Foregut 2022;2[4]:339-348..

The Hill grade is an endoscopic classification developed to grade the gastroesophageal flap valve, but its use has been suboptimal, explained Ronnie Fass, MD, the director of the Division of Gastroenterology and Hepatology and medical director of the Digestive Health Center at MetroHealth Medical Center, in Cleveland.

“Surgeons feel that the Hill classification is too

Figure 1.

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Figure 2.

While the Hill classification is based on visual characterization of the gastroesophageal flap valve seen via retroflexed endoscopy view, this new classification improves on the Hill classification by not only taking into account the presence or absence of a flap valve “but also documenting the presence and degree of hiatal disruption,” Dr. Nguyen explained.

In addition to requiring New Classification ‘There’s going to be a process of adopting it. examination for the presence Includes 4 Grades or absence of a flap valve and Some will still stick to the Hill classification, measurement of the degree of A team of 13 experts in foregut disease from gastroenterbut I think as time goes by, more and more hiatal disruption, to obtain an accurate assessment of the hiaology and gastrointestinal surpeople will use the new classification and it tus, the classification system gery convened to review and requires full endoscopic insufupdate the Hill classification. will become the main classification.’ flation and rotational provocAfter their review, the working ative maneuvers in the retrogroup came to an agreement —Ronnie Fass, MD flex view to elicit potential hiatal on the anatomy of the antiMetroHealth Medical Center, Cleveland herniation. reflux barrier.

“Since this new classification “This group of experts agree takes into account both the that GERD is related to an presence or absence of a flap valve and the degree of hiaimpairment of the anti-reflux barrier, which is comprised of tus disruption, the final hiatus grade is based on the worse the flap valve, the crura of the diaphragm, and the lower finding” of the two, Dr. Nguyen said. “A patient with 1.5-cm esophageal sphincter and its gastric sling fibers,” Dr. Nguyen axial length hiatal hernia will automatically jump to a hiatus said (Figure 1). “Together, these three components contribute grade 3. In the Hill grade classification, you can observe a to the mechanical and physiologic barrier to reflux.”

Hill grade 1 flap valve while also having a 1-cm hiatal herThe new classification takes this pathophysiology into nia axial length. In this new classification, this scenario is account and stratifies EGJ integrity across four grades not possible.”

(Figure 2). Grade 1 is normal, and grades 2 to 4 describe Such “a comprehensive evaluation of the components increasing degrees of EGJ disruption. subjective, that the interrater variability is too high,” Dr. Fass told Gastroenterology & Endoscopy News. “Even though the Hill classification has been around for many, many years, they feel that the focus of the Hill classification is only on the flap valve, where this new classification describes the whole esophagogastric junction.”

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of the reflux barrier is very important to planning structural repair,” said Christy Dunst, MD, an esophageal surgical specialist at the Oregon Clinic, in Portland. “This was less important decades ago when we had a one-surgery-fits-all approach with Nissen fundoplication. But now with advancements in techniques, the choice of repair can be tailored to the individual anatomy.”

Adoption of New Classification Will Take Time Dr. Fass said he expects the new classification to become widely adopted, and he is already seeing it being incorporated into practice. “There’s going to be a process of adopting it. Some will still stick to the Hill classification, but I think as time goes by, more and more people will use the new classification and it will become the main classification on the heels of the Hill classification. If you look at the list of people that participated in the new classification’s development, it’s a combination of surgeons and gastroenterologists. The concept is that it will be used by both specialties.”

He predicted that the new classification “will be incorporated into a variety of therapeutic guidelines, for example, for gastroesophageal reflux disease. The expectation will be that before you send a patient for surgery, when you’re doing endoscopy, you will provide this information as part of the patient’s evaluation prior into reflux surgery.

And not only in surgery but also, for example, endoscopic therapy for gastroesophageal reflux disease,” Dr. Fass said.

Dr. Nguyen said next steps include performing validation studies to understand the correlation between hiatus grade and the presence and degree of GERD and grading the hiatal appearance in patients who have undergone a prior anti-reflux intervention.

“My career has been dedicated to this topic for nearly 20 years. I love seeing the enthusiasm for this complex 2 inches of the human body,” Dr. Dunst said. “With more eyes investigating the intricacies of the interplay between the flap valve, the lower esophageal sphincter and the diaphragm, the field will advance with less invasive, more effective early treatments for millions of people suffering with GERD.” —Jenna Bassett, PhD

Dr. Fass is a member of the Gastroenterology & Endoscopy News editorial board.

AFS Releases New Guidance On TIF for GERD

T

he American Foregut Society has issued new guidance on best practices

for transoral incisionless fundoplication for the management of gastroesophageal reflux disease.

TIF, which reestablishes and augments the gastroesophageal flap valve to restore its function, is a “great option to treat GERD, with an excellent safety profile and high level of patient satisfaction,” said Olaya Brewer Gutierrez, MBBS, the director of endoscopy at Sibley Memorial Hospital, in Washington, D.C., and a lead author of the white paper. TIF and concomitant TIF (cTIF), in which TIF is combined with laparoscopic hiatal hernia repair in patients with a hiatal hernia larger than 2 cm, are associated with “less bloating and dysphagia compared to the gold standard, laparoscopic Nissen fundoplication, which is appealing to patients.”

Figure 1. Device ready at the 10 o’clock position or posterior aspect of the procedure before wrap is started.

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Figure 2. Device at the 6 o’clock position.

In this position, there is no wrapping. The intention is to create the length of the valve.

Although TIF and traditional fundoplication both manipulate the gastric fundus around the distal esophagus to create a valve construct and a high-pressure zone at the distal esophagus, TIF creates a true flap valve with its wrap ability of 270 to 300 degrees. In both procedures, anatomically and physiologically similar valves are constructed.

Best-Practice Recommendations The AFS white paper summarizes published clinical data for TIF and cTIF and outlines important safety considerations and best practices related to indications, patient selection, patient evaluation, technical procedural overviews and postoperative care (Foregut 2023 May 2. doi:10.

1177/26345161231170788).

“This white paper highlights the exceptional efforts of the AFS to develop a strong collaboration between surgeons and gastroenterologists specializing in the care of patients with foregut disease, in this case, GERD,” said Philip Katz, MD, the co–editor-in-chief of Foregut, the official journal of the AFS, and director of the GI Function Labs in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine, in New York City.

Explaining the impetus for the white paper, Dr. Katz said the editors of Foregut considered the data on the TIF and cTIF procedures to be “in a place where the surgical and GI community would benefit from a comprehensive review of the procedure.”

While TIF initially was approved by the FDA to treat patients with chronic GERD who responded to proton pump inhibition, the indication for TIF has since expanded to include patients with chronic refractory GERD and partial responders to acid suppression.

“Patients with objective evidence of GERD, with primary symptoms of heartburn and especially regurgitation, [who are] incompletely responsive to medical therapy or looking

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Figure 3. Final valve, approximately 300-degree circumference and 3 cm in length.

for an option that reduces or eliminates daily medication are candidates for endoscopic and/or surgical intervention,” Dr. Katz said. He noted that TIF can be considered for patients with small hiatal hernias (<2 cm) that are Hill grade 2 or less. “In patients needing or electing a laparoscopic procedure,” he said, “a cTIF can be considered as an alternative to a traditional fundoplication (or magnetic sphincter augmentation) based on shared decision making and the expertise of the surgeon.”

“Now with the expanded indication of concomitant hernia repair and TIF and the surgery–gastroenterology collaboration, this technique can be considered a first-line therapy for almost any patient with refractory GERD, including those with some degree of esophageal dysmotility, irrespective of their anatomy,” Dr. Brewer Gutierrez said. “This white paper covers extensively all areas of the technique.”

The white paper also includes detailed descriptions of the technical aspects of TIF and cTIF, including stepby-step procedure instructions, equipment used, requirements and images of key steps.

“Our goal for publishing this white paper is to highlight the TIF procedure as part of the treatment armamentarium for GERD and expand options for clinicians to offer their patients with GERD,” Dr. Katz told Gastroenterology & Endoscopy News.

“This was a great collaboration among surgeons and gastroenterologists, which has opened the door to innovation and collegiality, bridging the gap between specialties,” Dr. Brewer Gutierrez noted. “I expect this white paper to continue to give TIF its place as an excellent option in the anti-reflux treatment armamentarium. The next steps, hopefully, will be diffusion of the technique in order to make it widely available throughout the country.”

—Jenna Bassett, PhD The sources reported no relevant financial disclosures.

Between the Guidelines

ACG Issues Updated Guidance On Gastroparesis he American College of

T

Gastroenterology recently released a new clinical guideline

on gastroparesis (Am J Gastroenterol 2022;117[8]:1197-1220). GEN’s Sarah Tilyou spoke with lead author Michael Camilleri, MD,

Michael Mi h lC Camilleri, ill i MD MD, DS DSc

DSc, a gastroenterologist and professor of medicine, physiology and pharmacology at Mayo Clinic in Rochester, Minn., about the impetus for the guideline and what it means to GI practice.

GEN: What prompted the guideline?

Dr. Camilleri: There are three really important points to make. The first is that the previous guideline from ACG was published in 2013—a decade ago (Am J Gastroenterol 2013;108[1]:18-37). The second is that there still is an unmet need in terms of diagnosis and treatment. And the third is that there’s interest in the guideline for gastroparesis, with the 2013 guideline being cited over 570 times. Although the European Society of Neurogastroenterology and Motility published a consensus document more recently (United Eur Gastroenterol J 2021;9[3]:287-306), it was based on expert opinion, in contrast to the rigor of the ACG guideline based on extensive literature search and GRADE methodology. In addition, some novel diagnostic and therapeutic approaches have come to the fore over the past decade, and they needed to be summarized for clinicians and patients.

GEN: What’s new in the guideline that clinicians need to know?

Dr. Camilleri: The first important point from a clinician standpoint is diagnosis. It’s important for clinicians to appreciate

that the diagnosis of gastroparesis requires symptoms, exclusion of obstruction and documentation of the slow emptying of solid foods from the stomach. The state of the art has been evolving. It’s clear that we have to study the emptying of solids for at least three hours with a valid test—either scintigraphy, the stable isotope–labeled spirulina breath test or the wireless motility capsule.

The second important point is reiteration of the importance of diet—both reducing the nondigestible fiber content of the diet and, based on a clinical trial from Sweden, homogenizing the diet (Am J Gastroenterol 2014;109[3]:375-385)—to facilitate the emptying of food from the stomach and provide relief of symptoms.

The third point pertains to therapy. From the pharmacologic standpoint, there have been no real novelties in the past decade, so we needed to guide clinicians regarding the evidence for various treatments—prokinetic agents, antiemetic agents, and central neuromodulators such as nortriptyline. We made specific recommendations with regard to those drugs. Also from a therapeutic standpoint, we summarize the data on gastric electrical stimulation (GES) and gastric per-oral endoscopic myotomy (G-POEM). We were able to incorporate the data from the first randomized controlled trial of active G-POEM versus sham to provide guidance to clinicians (Gut 2022;71[11]:2170-2178).

We also summarized how patients might be selected for the G-POEM procedure. For instance, data suggest that it is important to measure the distensibility and the diameter of the pylorus to help predict a good response to the G-POEM procedure. We know that in gastroparesis, sometimes there is weakness of the distal part of the stomach, so food can’t

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be broken down. But, if you just open the lower end of the stomach in a patient with weakness of the distal stomach, is it really going to help you to get the food out of the stomach and relieve the patient’s symptoms? This question is still not completely answered, but research is being done to try to uncover some of the physiologic measurements that, in the future, hopefully will help us identify the best candidates for treatment with G-POEM.

GEN: What were some of the hottest points of debate among the guideline panelists, and how did you resolve them?

Dr. Camilleri: Use of the wireless motility capsule in the setting of gastroparesis was an item of debate among the panelists. We all agree that the small bowel and colonic transit measurements with the wireless motility capsule are very accurate. But when we came to assess the diagnostic accuracy of the capsule for gastric emptying, this was an item of controversy. The reason, I think, is that a solid capsule, 8 to 10 mm in size, does not empty the same way ordinary food empties from the stomach. There has been evidence to suggest that it actually empties when the next migrating motor complex comes through the intestine and the stomach, like nondigestible vegetables (Neurogastroenterol Motil 2008;20[4]:311-309). On balance, we agreed that it would be very helpful to measure the rest of the GI tract, but we have to be very careful not to overstate the accuracy for the measurement of gastric emptying. The gold standards remain scintigraphy and the stable-isotope breath test.

A second item of controversy was the use of GES as a means to treat gastroparesis symptoms. This has been around for humanitarian use for about three decades, but the literature is mixed. GES requires surgery, and there could be the need for replacing batteries, etc. As we were going through our study of the literature, a very large multicenter study from France was published, suggesting that GES had a beneficial effect in management, particularly in patients who have very severe vomiting episodes (Clin Gastroenterol Hepatol 2022;20[8]:1857-1866).

A third point of debate centered on the role of the G-POEM procedure. Again, as we were discussing that, the first sham-controlled, randomized study was published, which makes us more optimistic that this would be a useful treatment (Gut 2022;71[11]:2170-2178). However, we have to keep in mind that it’s a relatively small study, and the procedure was most efficacious for patients with diabetic gastroparesis.

Its efficacy was not completely proven for idiopathic or postsurgical gastroparesis in the sham-controlled study.

Another thing that was a little controversial was the use of central neuromodulators, such as tricyclic agents and mirtazapine, which can reduce the symptoms in patients with gastroparesis. The problem is that tricyclic antidepressants also have anticholinergic effects that may result in delayed

gastric emptying, and a large study of nortriptyline showed no difference from placebo in patients with idiopathic gastroparesis (JAMA 2013;310[24]:2640-2649). So, you may reduce symptoms one way but induce symptoms another way.

GEN: Where are the remaining gaps |in evidence, and what can clinicians do in these cases?

Dr. Camilleri: We need to go back to first principles.

Remember to remove any medication that could be aggravating the gastric emptying delay. I often tell my students and my fellows and patients themselves: There is no such thing as an opiate that does not delay gastric emptying.

And that’s just one example.

Clinicians also need to make sure that there is a robust diagnosis using a test that’s well validated.

Then, it’s a matter of optimizing the diet and trying the available medications. The only medication actually approved in the United States is metoclopramide. Since the FDA required a black box warning to be added to the metoclopramide labeling, there have been many epidemiological studies showing that the risk for tardive dyskinesia is not 2% to 4%; it is probably closer to one in 1,000. In some cases, people think it’s one in 10,000 patient-years (Neurogastroenterol Motil 2019;31[11]:e13617; Br Med J [Clin Res Ed] 1984;288:545-547). Involuntary movements happen with metoclopramide, but if you stop the medication, it isn’t permanent. It isn’t truly tardive dyskinesia. We wanted to specify that updated information, which appeared in the literature since the last guideline, as well as clarify recommendations on the central neuromodulators, prokinetic agents and antiemetic agents, as mentioned previously.

Finally, clinicians should keep in mind the opportunity for some of those other interventions, including the G-POEM procedure, which appears to be quite safe in carefully selected patients.

The final point was to stress that patients with gastroparesis really are suffering. They often have to go to the emergency room or be admitted for hydration. The condition has a very significant negative impact on quality of life and results in significant expenses and healthcare utilization that has been very well documented in the literature. We wanted to stress, kind of indirectly, to the pharmaceutical companies and the FDA that there is still such a large unmet need for medications for gastroparesis.

Some investigational agents are being tested for the treatment of gastroparesis. For example, I am the principal investigator on a placebo-controlled clinical trial of the cannabinoid type 2 receptor agonist cannabidiol, and we’re hoping to present data in 2023 (ClinicalTrials.gov Identifier: NCT03941288). In addition, the neurokinin-1 receptor antagonist tradipitant (Vanda) is being tested in this setting (Gastroenterology 2021;160[1]:76-87).

Dr. Camilleri reported financial relationships with Allergan, Takeda and Vanda.

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A New Era for Managing Clostridioides difficile Infection MARK H. WILCOX, MD, FRCPATH Professor of Medical Microbiology Sir Edward Brotherton Chair of Bacteriology University of Leeds National Clinical Director of Antimicrobial Resistance & Infection Prevention and Control NHS England Head of Microbiology Research & Development Leeds Teaching Hospitals NHS Trust Leeds, England

I

t has long been known that disruption of the gut microbiome, usually by antibiotics, provides an environment that is conducive to the proliferation of Clostridioides difficile (either already present or acquired during or shortly after antibiotic exposure) and production of exotoxins (toxins A and B) that cause inflammation of the colonic mucosa, which typically manifests as profuse diarrhea. In the last decade, we have started to understand the critical components of the gut microbiome that prevent C. difficile expansion.1,2 With that knowledge comes the potential to block C. difficile proliferation using bacteria-based biotherapeutics.

The FDA views live microorganisms intended to have a therapeutic effect in humans to be a live biotherapeutic product. An Investigational New Drug Application is required, and the drug must be safe, pure, potent, and manufactured consistently according to good manufacturing practices. There is a general principle that all therapeutics should be administered using minimum effective doses, that is, the smallest dose that will produce a desired outcome, to limit the chance of unintended consequences of treatment (adverse events/toxicity). Of course, a margin beyond the absolute minimum effective dose may be justifiable—for example, with antimicrobials— to cover strains with reduced susceptibility. In the context of using a biotherapeutic to alter the dysbiosis that allows C. difficile to proliferate and cause C. difficile infection (CDI) or recurrent CDI (rCDI), the minimal effective dose will encompass both the numbers of microbes administered and the number of different microbes used. Of note, there has been considerable interest in the use of fecal microbiota transplantation (FMT) to treat patients with

rCDI, with variable efficacy rates reported.3 In the context of FMT, the minimal effective dose of microorganisms has not been described.

As long ago as 1989, Tvede and Rask-Madsen reported on the use of a mixture of 10 bacterial species administered rectally to achieve CDI resolution in 5 of 5 patients with rCDI.4 A more recent case series of 55 patients managed with the same nonregulated live biotherapeutic was published in 2015; 35 of 55 (64%) had no recurrence of diarrhea within 30 days of treatment.5 However, 1 patient was hospitalized 10 days after bacteriotherapy with appendicitis, fever, and Escherichia coli bacteremia. This is a cautionary example of the potential unintended consequences of bacteriotherapy, including FMT.6 Such safety concerns are partially related to the issue of defining a minimal CDI treatment, and the lack of regulated biotherapeutics for the prevention of CDI recurrence has perpetuated this situation.

Treatment options for rCDI are limited. Bezlotoxumab (Zinplava, Merck), a human monoclonal antibody directed against C. difficile toxin B, administered intravenously, has

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been the only US-licensed product indicated for the reduction in recurrence of CDI. Recent decisions by the FDA, specifically its approval of fecal microbiota, live-jslm (Rebyota, Ferring/Rebiotix)—known as RBX2660 during clinical trials, a biotherapeutic for the prevention of rCDI7—and fecal microbiota spores, live-brpk (Vowst, Seres Therapeutics), an oral microiome therapeutric for the prevention of rCDI known as SER-109 during clinical trials,8 means that we are now on the cusp of a new era for treatment options, particularly to address the challenge of rCDIs.

Live Biotherapeutic Microbiota Preparations Rebyota Rebyota aims to deliver the effectiveness of FMT using a standardized, regulated product for the treatment for rCDI. In the companies’ submission to the FDA, Ferring and Rebiotix noted that their initial pivotal phase 3 clinical trial plan was to conduct 2 independent placebo-controlled, phase 3 trials of about 300 patients each.9 However, recruitment to the first phase 3 clinical trial (2017-01) was slow and made the prospect of successfully concluding a second study very challenging. Instead, Ferring/Rebiotix proposed to use a Bayesian model, based on clinical trial results obtained to date (ie, from a randomized, double-blind, placebo-controlled, phase 3 study [2017-01] and a phase 2b study [201401]) to demonstrate a clinically meaningful treatment effect.

The FDA’s Center for Biologics Evaluation and Research (CBER) agreed that the results from these 2 similar trials could be analyzed together, and statistical success criteria were established to underpin the analyses of clinical effectiveness of Rebyota. These data formed the basis of the presentation to the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) in September 2022, and have recently been published.10 Adults who had 1 or more CDI recurrences with a positive stool assay for C. difficile (ie, either for a toxigenic strain or for toxin) and were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to a blinded, single-dose enema of Rebyota (n=180) or placebo (n=87). The primary end point was treatment success, defined as the absence of CDI diarrhea within 8 weeks of study treatment. After applying the Bayesian analysis, the treatment success rate was modeled to be 70.6% with Rebyota versus 57.5% with placebo. The majority (>90%) of successfully treated patients in both study arms at 8 weeks had a sustained response up to 6 months. The size of the improvement in treatment success for Rebyota versus placebo was 13.1% (95% CI, 2.3%-24.0%). This improvement met the posterior probability threshold equivalent to a 1-sided frequentist type 1 error rate less than 0.025, but did not meet the more stringent posterior probability threshold equivalent to a 1-sided frequentist type 1 error rate less than 0.00125.9 The pooled safety data from all patients who were exposed to at least 1 dose of Rebyota in 5 prospective studies included 749 exposed to at least 1 dose of Rebyota and 83 exposed only to placebo. A further 229 patients exposed to open-label Rebyota in Study 2019-01 brought

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the total prelicensure clinical trial safety database to 978 patients. Rebyota was generally well tolerated. The incidence of treatment-emergent adverse events was higher in Rebyota versus placebo recipients and mostly driven by a higher incidence of mild gastrointestinal events (abdominal pain and diarrhea). No serious treatment-related side effects were reported. Rebyota was evaluated in only a limited number of immunocompromised patients; CBER concluded that the available data were insufficient to determine whether the safety or effectiveness of Rebyota in immunocompromised populations differs from the general population.9 The VRBPAC voted in favor of Rebyota both in terms of its efficacy and safety. The FDA approved its indication to prevent rCDI in adults 18 years of age and older, following antibiotic treatment for rCDI on November 30, 2022.9-10

Vowst Vowst is a live biotherapeutic comprising an encapsulated mixture of purified Firmicutes spores, obtained from the feces of healthy humans. As such, this biotherapeutic contains considerably fewer different bacteria from those present in Rebyota. As the spores are so resilient, a purification process that includes ethanol treatment is used to reduce the risk that transmissible infectious agents could contaminate Vowst. The pivotal clinical trials of Vowst, which have led to the FDA approval of this oral microbiome therapeutic on April 26, 2023 for the prevention of rCDI,8 are summarized below.

ECOSPOR III (SERES-012; ClinicalTrials.gov Identifier: NCT03183128) was a phase 3, multicenter, randomized, placebo-controlled study that enrolled 182 adults with at least 3 episodes of CDI within the previous 12 months (inclusive of the study entry episode).11 All participants received standard-of-care oral antibiotic treatment (either fidaxomicin [Dificid, Merck] or vancomycin) and were stratified according to age (<65 or ≥65 years) and CDI antibiotic received before randomization to Vowst (~3×10 7 spore colonyforming units) or placebo, administered as 4 matching oral capsules once daily over 3 consecutive days. Given that fidaxomicin and vancomycin may persist in feces after cessation of oral administration, 10 ounces of magnesium citrate was administered the night before Vowst receipt to limit inactivation of the bacteria in this therapy. Of note, toxin testing was required at study entry and at suspected recurrence to ensure enrollment of patients with active CDI and accurate assessment of the end point.

Eight weeks after treatment, 88% of Vowst recipients were free from C. difficile recurrence compared with 60% in the placebo group (relative risk of rCDI in Vowst recipients, 0.32; 95% CI, 0.18-0.58; P<0.001). The primary end point, superiority of Vowst versus placebo in reducing risk for CDI recurrence after 8 weeks, was met. This reduction in risk for recurrence was durable at 24 weeks, with the respective proportions of patients without CDI recurrence being 79% versus 53%.12 Also, considering the stratified subgroups, Vowst receipt led to fewer recurrences than placebo in patients at least 65 years of age or younger, and both in those who received fidaxomicin (relative risk, 0.09;

95% CI, 0.01-0.63) or vancomycin (relative risk, 0.41; 95% CI, 0.22-0.79).

Vowst was generally well tolerated with no drug-related serious adverse events.

Stool samples obtained at baseline (within 3 days after completion of fidaxomicin or vancomycin) and at weeks 1, 2, and 8 were analyzed by whole metagenomic sequencing and targeted bile acid analyses to determine whether the spore-forming bacteria in Vowst could compete with C. difficile and/or modulate bile acid profiles leading to a reestablishment of resistance to colonization. The superiority of Vowst compared with placebo at preventing rCDI was associated with clear changes in microbiome composition and concentrations of, in particular, secondary bile acids.11 Of the 182 patients included in the efficacy analysis, 29 were excluded from the metagenomic and metabolomic analyses because of missing specimens or protocol deviations. Engraftment of Vowst bacteria was observed by week 1 and persisted through week 8. Numbers of engrafting Vowst bacterial species were higher among Vowst versus placebo recipients through week 8. Following dosing with Vowst, there were declines in pro-inflammatory Enterobacteriaceae and increases in Firmicutes.

Also, greater increases in secondary bile acids from baseline occurred in Vowst recipients at all times through week 8. Secondary bile acids are known to protect against CDI as they inhibit C. difficile spore germination and vegetative growth.13,14 These findings fit with the known key roles of colonic bacteria, including Firmicutes, to promote the synthesis of secondary bile acids.15

Conclusion With new access to these biotherapeutics for the prevention of rCDI, this will add considerable options to clinicians for the management of this challenging disease. Such regulated biotherapeutics, with clearly defined efficacy and safety parameters, will provide more certainty than is currently associated with FMT. The phase 3 clinical trials of RBX2660 and SER-109 were similar, but there were sufficient differences, including how CDI cases were defined, to add uncertainty to the question of the relative efficacy of the 2 biotherapeutics. It is too early to know the cost-effectiveness of new biotherapeutics for treating CDI, and such data will be awaited with interest, especially given the increasing costs associated with FMT, including the need to screen donors/samples for more potential pathogens.

References 1.

Berkell M, Mysara M, Xavier BB, et al; ANTICIPATE study group.

Microbiota-based markers predictive of development of Clostridioides difficile infection. Nat Commun. 2021;12(1):2241.

2. Seekatz AM, Safdar N, Khanna S. The role of the gut microbiome in colonization resistance and recurrent Clostridioides difficile infection. Therap Adv Gastroenterol. Published online 2022 November 18. doi:10.1177/17562848221134396 3. Tariq R, Pardi DS, Bartlett MG, et al. Low cure rates in controlled trials of fecal microbiota transplantation for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Clin Infect Dis. 2019;68(8):1351-1358.

4. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet.

1989;1(8648):1156-1160.

5. Tvede M, Tinggaard M, Helms M. Rectal bacteriotherapy for recurrent Clostridium difficile-associated diarrhoea: results from a case series of 55 patients in Denmark 2000-2012. Clin Microbiol Infect.

2015;21(1):48-53.

6. Wilcox MH, McGovern BH, Hecht GA. The efficacy and safety of fecal microbiota transplant for recurrent Clostridium difficile infection: current understanding and gap analysis. Open Forum Infect Dis. 2020;7(5):ofaa114.

7. FDA. Rebyota. Accessed February 1, 2023. https://bit. ly/3IXPl5D-IDSE 8. FDA. FDA approves first orally administered fecal microbiota product for the prevention of recurrence of Clostridioides difficile

infection. Accessed September 21, 2023. fda.gov/news-events/ press-announcements/fda-approves-first-orally-administered-fecalmicrobiota-product-prevention-recurrence-clostridioides.

9. FDA. Rebyota BLA clinical review memorandum. Accessed February 7, 2023. https://www.fda.gov/media/164039/download 10. Ferring receives U.S. FDA approval for REBYOTA™ (fecal microbiota, live-jslm) – a novel first-in-class microbiota-based live biotherapeutic. Accessed February 7, 2023. https://bit.ly/3JMOcPa-IDSE 11. Khanna S, Assi M, Lee C, et al. Efficacy and safety of RBX2660 in PUNCH CD3, a phase III, randomized, double-blind, placebo-controlled trial with a Bayesian primary analysis for the prevention of recurrent Clostridioides difficile infection. Drugs.

2022;82(15):1527-1538.

12. Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N Engl J Med. 2022;386(3):220-229.

13. Cohen SH, Louie TJ, Sims M, et al. Extended follow-up of microbiome therapeutic SER-109 through 24 weeks for recurrent Clostridioides difficile infection in a randomized clinical trial. JAMA. 2022;328(20):2062-2064.

14. Allegretti JR, Kearney S, Li N, et al. Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles.

Aliment Pharmacol Ther. 2016;43:1142-1153.

15. Ridlon JM, Harris SC, Bhowmik S, et al. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes.

2016;7:22-39.

Dr. Wilcox reported relationships with AiCuris, Almirall, Bayer, Crestone, Da Volterra, Deinove, EnteroBiotix, The European Tissue Symposium, Ferring, GSK, Menarini, Merck, Nestlé, Paion, Paratek, Pfizer, Phico Therapeutics, Qpex Biopharma, Seres, Surface Skins, Summit, Tillotts, Vaxxilon/Idorsia, and Vedanta.

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A Practical Guide To the Microbiome For Gastroenterologists ELENA IVANINA, DO, MPH Gastroenterologist Center for Integrative Gut Health New York, New York

H

ow many times has a patient asked you what probiotic to take? What about interpreting a direct-to-consumer microbiome test? Gastroenterologists often are assumed to be the go-to doctor to ask these questions, but due to the fast

pace of development and relative lack of educational resources, many may not feel up-to-date and confident to counsel patients in this field.

Gastroenterologists need to have a basic understanding of the current state of microbiome science and how to apply it in everyday practice. Although microbiome research is in many ways still in its infancy, there is already a substantial base of literature to help guide gastroenterologists in understanding what many call the most fascinating organ and living ecosystem in our bodies—and likely one of the cornerstones of future therapy.

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What Is the Gut Microbiome?

The gut microbiome is made up of trillions of microorganisms (bacteria, archaea, fungi, and viruses including bacteriophages) and their genomes/genes. Bacteriophages (the “virome”) outnumber bacteria and can shape the composition of gut bacterial communities. Fungi (the “mycobiome”) are the least populous, with Candida being the most prevalent genus.

When discussing the organisms that compose the microbiome, they are categorized by phyla, classes, orders, families, genera, and species (Figure). The gut microbiota varies among individuals, reflecting differences in the abundance of 4 dominant phyla: Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. Firmicutes and Bacteroidetes represent 90% of gut microbiota.1 Within the Firmicutes phylum, the Clostridium genera represent 95% of the group; Lactobacillus, Bacillus, Enterococcus, and Ruminicoccus are among the other genera in the Firmicutes phylum.

Although the focus has been mostly on the bacteria that make up the microbiome, the mycobiome and virome play very significant roles as well. The mycobiome is influenced by the environment and high-carbohydrate diets and is associated with immunodeficiency states.2 The use of antibiotics causes overgrowth of fungi, reflecting the competitive relationship of fungi and bacteria. The mycobiome has been found to be involved in altered immune responses, such as in inflammatory bowel disease (IBD), with the Crohn’s biomarker anti-Saccharomyces cerevisiae antibodies directed against a fungal cell wall epitope with cross-reactivity to Candida albicans.3 The virome is one of the most diverse biological systems and is composed mostly of bacteriophages—viruses that can infect bacterial cells. In fact, bacteriophages can affect the immune system in many direct ways, such as stimulating macrophage production of interleukin-1b and tumor necrosis factor-alpha.4 The virome also responds to dietary changes.

Gut Microbiome Components The microbiota composition varies along the gastrointestinal tract, differing in every section from the mouth to the colon. The highest bacterial density is in the colon, with increased nutrient availability and slower transit. The small intestine, on the other hand, has a lower abundance and diversity of microbiota due to shorter transit time, the influx of digestive enzymes and bile, and intermittent food substrate delivery.

The human oral cavity is home to an abundant and diverse microbial community called the oral microbiome. The oral microbiome usually exists in the form of a biofilm, and common oral bacteria include Streptococcus mutans, Porphyromonas gingivalis, Staphylococcus, and Lactobacillus.5 Streptococcus mutans is the main component of the oral microbiota and is associated with dental plaque and caries.6 Lactobacillus is a bacterium that can ferment sugar to produce lactic acid, which also can contribute to dental caries.7 In addition to oral diseases, such

as caries and periodontitis, the oral microbiome is associated systemic diseases, such as esophageal, colorectal, and pancreatic cancers, diabetes, Alzheimer’s disease, cardiovascular disease, cystic fibrosis, and rheumatoid arthritis.8 The oral microbiome also can be a target for treating disease, with probiotics such as Streptococcus A12 buffering the acidic pH within biofilms that contribute to dental caries.9 The esophagus has been found to have its own diverse microbiome, which includes Streptococcus as the most common bacterial genus, as well as Haemophilus, Neisseria, Prevotella, and Veillonella.10 Gram-negative bacteria such as Prevotella are more commonly found in the context of diseases such as gastroesophageal reflux disease and Barrett’s esophagus. Changes in the esophageal microbiome composition may be caused by acid reflux, inflammation, and exposures to proton pump inhibitors (PPIs), alcohol, and smoke.

The stomach contains 5 major phyla (Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria, and Proteobacteria); at the genera level, Prevotella, Streptococcus, Veillonella, Rothia and Haemophilus are most common.11 The gastric microbiota is affected by diets, use of medications such as PPIs and antibiotics, inflammation of gastric mucosa and atrophic gastritis, and Helicobacter pylori infection. The interaction between the preexisting gastric microbiota and H. pylori may influence the risk for developing certain conditions such as gastric cancer.12 The small intestine is the longest section of the GI tract, about 22 feet long, and contains its own microbiome. Bacterial genera commonly found in the small intestine include Lactobacillus, Clostridium, Staphylococcus, Streptococcus, and Bacteroides.13 Within the small intestine, bacterial populations increase from approximately 10 4-10 5 CFU/mL in the duodenum to 107-108 CFU/mL in the distal ileum, where transit slows.14 The proportion of gram-positive to gramnegative as well as facultative anaerobic and strict anaerobic species increases from the proximal to distal small intestine due to oxygen use.15 Small intestinal bacterial overgrowth (SIBO), an emerging condition that has been linked to up to 78% of irritable bowel syndrome cases, involves an excessive number of bacteria within the small intestine causing abnormal fermentation of nutrients, leading to the production of excessive gas and bloating.16 The colon has the most robust and populous microbiome, mostly containing obligate anaerobes; the most abundant bacteria in the colon are members of the genus Bacteroides, anaerobic gram-positive cocci, such as Peptostreptococcus, Eubacterium, Lactobacillus, and Clostridium.17 Through fermentation and the absorption and metabolism of metabolites such as short-chain fatty acids, the colonic microflora plays a key role in host digestive processes, especially when it comes to fiber, which is not broken down in any other section of the GI tract. Many microbiota studies use fecal samples that reflect the luminal “fecal” colonic microbiome. In addition, colonic-adherent microbiota exist that interact more directly with the host immune system and require biopsy during colonoscopy for study.18

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Phylum examples

Class examples

Order examples

Family examples

Genus examples

Actinomycetales

Corynebacteriaceae

Corynebacterium

Bifidobacteriales

Bifidobacteriaceae

Bifidobacterium

Actinobacteria Actinobacteria Coriobacteriia

Coriobacteriales

Coriobacteriaceae

Atopobium

Clostridium

Clostridium spp.

Lachnospiraceae

Roseburia

Roseburia intestinalis

Ruminococcaceae

Ruminococcus

Ruminococcus faecis

Veillonellaceae

Dialister

Dialister invisus

Lactobacillaceae

Lactobacillus

Lactobacillus reuteri

Enterococcaceae

Enterococcus

Enterococcus faecium

Bacillales

Staphylococcaceae

Staphylococcus

Staphylococcus leei

Sphingobacteriales

Sphingobacteriaceae

Sphingobacterium

Bacteroides fragilis

Bacteroidaceae

Bacteroides

Bacteroides vulgatus

Tannerella

Bacteroides uniformis

Parabacteroides

Parabacteroides distasonis

Rikenellaceae

Alistipes

Alisipes finegoldii

Prevotellaceae

Prevotella

Prevotella spp.

Escherichia

Escherichia coli

Shigella

Shigella flexneri

Desulfovibrio

Desulfovibrio intestinalis

Bilophila

Bilophilia wadsworthia

Clostridiales

Veillonellales

Lactobacillales Bacilli

Sphingobacteriia

Bacteroidetes

Tannerellaceae Bacteroidia

Gamma proteobacteria

Bifidobacterium bifidum Faecalibacterium prausnitzii

Firmicutes Negativicutes

Bifidobacterium longum

Faecalibacterium Clostridiaceae Clostridia

Species examples

Bacteroidales

Enterobacterales

Enterobacteriaceae

Delta proteobacteria

Desulfovibrionales

Epsilon proteobacteria

Campylobacterales

Helicobacteraceae

Helicobacter

Helicobacter pylori

Fusobacteria

Fusobacteriia

Fusobacteriales

Fusobacteriaceae

Fusobacterium

Fusobacterium nucleatum

Verrucomicrobia

Verrucomicrobiae

Verrucomicrobiales

Akkermansiaceae

Akkermansia

Akkermansia muciniphila

Proteobacteria

Desulfovibrionaceae

Figure.

Excerpted from Microorganisms. 2019;7(1):14. License creativecommons.org/licenses/by/4.0/.

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Microbiome-Associated Terms Commensal

Harmless microbes colonizing the gut that may provide a benefit to one another or to the host.

Microbiome

The microorganisms, their genes/ genomes, and the surrounding environmental conditions

Pathobiont

A potential pathogen that causes disease under certain circumstances such as microbiome disruption, eg, Clostridioides difficile

Pathogen

Any pathologic disease-causing organism

Postbiotic

Substances derived after the microorganisms are no longer alive, such as vitamins B and K, amino acids, and antimicrobial peptides

Prebiotic

A non-digestible substance (fiber) that stimulates the growth and/or activity of beneficial bacteria

Probiotic

Live microorganisms that provide a health benefit to the host

Psychobiotic Probiotics with mental health benefits to the host Symbiont

An organism in a mutually beneficial relationship

Synbiotic

A combination of both prebiotics and probiotics to stimulate a specific beneficial microbe

steady state. A single course of antibiotics can transiently change the microbiome, but it often returns to the original state.20 A more persistent interference, such as long-term change in diet, recurrent antibiotic administration, or a disruption during a vulnerable time, such as infancy or peripartum, can result in microbiome reassembly that shifts to a disease-promoting state.21,22 Studies have revealed certain indicators of a healthy gut microbiome. For example, gut microbiome alpha-diversity has been linked to human health, with lower levels of diversity associated with several acute and chronic diseases.23 Another marker is the Firmicutes to Bacteroidetes (F/B) ratio. More commonly, certain species have stood out for their benefit, such as Faecalibacterium prausnitzii.

F. prausnitzii has been consistently reported as one of the main butyrate producers in the gut, with protective properties against colorectal cancer and inflammatory bowel diseases, and the ability to reduce gut mucosa inflammation. 24 Another important bacterium is Akkermansia muciniphila. A. muciniphilia has been shown to contribute to a healthy gut barrier, regulating immunity and modulating inflammation, and a lower abundance of this organism has been associated with multiple diseases.25

What Shapes the Adult Microbiome?

Several factors affect the adult gut microbiome, with diet seeming to have the most prominent effect. Given the role of diet, gastroenterologists can provide important counseling points during visits to help patients understand their ability to modify and optimize their microbiome.

•

Diet: Short- and long-term dietary habits influence the microbiome. Short-term diet changes can cause quick but reversible microbiome shifts with intermittent GI symptoms. Fiber is the key dietary nutrient for the microbiome, and specifically microbiota-accessible carbohydrates (MACs) feed gut microbes. When microbes ferment MACs, they produce short-chain fatty acids that have many health benefits, including improving GI transit by influencing serotonergic pathways. 26 Low-MAC diets cause negative microbial shifts that are mostly reversible with a high-MAC diet, unless the low MAC diet spans multiple generations causing a loss of microbial diversity that cannot be revived.27 Low-fiber diets essentially “starve” the gut microbes, causing them to turn to host epithelium and mucus for food, disrupting the epithelial barrier, and causing an increased risk for gut inflammation. Additives such as emulsifiers and artificial sweeteners also can have negative effects on the gut microbiome and increase the risk for metabolic and inflammatory disorders.28 Counseling patients on optimizing their fiber and MAC intake and minimizing their processed food intake can be a huge benefit to their overall health.

•

Exercise: Athletes have been found to have a more diverse gut microbiome and lower inflammatory marker levels. In animal studies, exercise-related gut microbiome changes reduced susceptibility to inflammation

‘Normal’ Versus Abnormal Microbiome A healthy microbiome is characterized by a diverse gut microbiota that develops from birth. By 3 years of age, a person’s microbiome resembles that of an adult but continues to change and develop functions such as vitamin synthesis.19 Although relative abundances of microbes can change, the overall community and function remain relatively intact and stable. Similarly, an unfavorable microbial community also can be stable and ultimately contribute to chronic disease. Resilience is an important property of the microbiome and reflects the amount of disturbance a microbial community can tolerate before it shifts to a new

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and weight gain. 29,30 Exercise-related changes in the intestinal microbiota can be similar in magnitude to, but different from, dietary changes, which is why although exercise is used to lose weight, it is very difficult to have sustained weight loss without changing diet as well.31 Exercise at moderate to high intensity for 30 to 90 minutes at least 3 times per week (or between 150 and 270 minutes weekly) for at least 8 weeks is likely to produce changes in the gut microbiota.32 •

Medications: Antibiotics, PPIs, laxatives, metformin, statins, hormones, benzodiazepines, antidepressants, nonsteroidal anti-inflammatory drugs, and antihistamines are just some examples of all the medications that are associated with changes in the composition of the gut microbiota. This information can help gastroenterologists make decisions such as using a limited course of PPIs and being more conservative with antibiotic use.

•

Other exposures: Smoking, alcohol consumption, and psychological stress have been associated with changes in the gut microbiota. Counseling about smoking cessation, minimizing alcohol, and gut–brain axis modulation is important for patient care.

Studying the Microbiome Methods of studying the microbiome have evolved in the past few years. Research into the microbiome started with microbial culture techniques that relied on specialized growth media to identify specific microbes. Culture techniques were very limited and, therefore, the field moved to 16S rRNA gene sequencing. This technique relies on the sequence of one gene (16S). Every organism has its own 16S signature that provides genus-level information but not specific species or strains of microbes. More recently, the shotgun metagenomics sequencing technique has been used. This approach, which evaluates DNA from the entire genome instead of only one gene, providing more specieslevel information as well as insight into microbial function.

The microbiome plays an important role in many health conditions, from metabolic disease such as obesity and type 2 diabetes to cardiovascular disease to GI conditions such as metabolic dysfunction-associated steatotic liver disease (formerly nonalcoholic fatty liver disease), IBD, celiac disease, and cancer. It influences the way that the body can respond to a specific drug therapy such as chemotherapy.

In addition, not only does it influence so many aspects of health, but evidence is accumulating that targeting the gut microbiome for therapeutic manipulation will be a cornerstone of therapy for GI disease and beyond.

References 1.

Rinninella E, Raoul P, Cintoni M, et al. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms. 2019;7(1):14.

8.

Willis JR, Gabaldón T. The human oral microbiome in health and disease: from sequences to ecosystems. Microorganisms.

2020;23;8(2):308.

2.

Hoffmann C, Dollive S, Grunberg S, et al. Archaea and fungi of the human gut microbiome: correlations with diet and bacterial residents. PLoS One. 2013;8(6):e66019.

9.

Lee K, Walker AR, Chakraborty B, et al. Novel probiotic mechanisms of the oral bacterium Streptococcus sp. A12 as explored with functional genomics. Appl Environ Microbiol.

2019;85(21):e01335-19.

3.

McKenzie H, Main J, Pennington CR, et al. Antibody to selected strains of Saccharomyces cerevisiae (baker’s and brewer’s yeast) and Candida albicans in Crohn’s disease. Gut. 1990;31(5):536-538.

4.

5.

10. Park CH, Lee SK. Exploring esophageal microbiomes in esophageal diseases: a systematic review. J Neurogastroenterol Motil. 2020;26(2):171-179.

Eriksson F, Tsagozis P, Lundberg K, et al. Tumor-specific bacteriophages induce tumor destruction through activation of tumor-associated macrophages. J Immunol. 2009;182(5):3105-3111.

11.

Dzidic M, Collado M, Abrahamsson T, et al. Oral microbiome development during childhood: an ecological succession influenced by postnatal factors and associated with tooth decay.

ISME J. 2018;12(9):2292-2306.

12. Brawner KM, Morrow CD, Smith PD. Gastric microbiome and gastric cancer. Cancer (Sudbury, Mass.). 2014;20(3):211-216.

13.

6.

Gomez A, Espinoza JL, Harkins DM, et al. Host genetic control of the oral microbiome in health and disease. Cell Host Microbe.

2017;22(3):269-278.

7.

Tanner ACR, Kressirer CA, Faller LL. Understanding caries from the oral microbiome perspective. J Calif Dent Assoc.

2016;44(7):437-446.

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Nardone G, Compare D. The human gastric microbiota: is it time to rethink the pathogenesis of stomach diseases?

United European Gastroenterol J. 2015;3(3):255-260.

Kastl AJ Jr, Terry NA, Wu GD, et al. The structure and function of the human small intestinal microbiota: current understanding and future directions. Cell Mol Gastroenterol Hepatol. 2020;9(1):33-45.

14. Hayashi H, Takahashi R, Nishi T, et al. Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism. J Med Microbiol. 2005;54(pt 11):1093-1101.

15. Thadepalli H, Lou MA, Bach VT, et al. Microflora of the human small intestine. Am J Surg. 1979;138(6):845-850.

16. Pimentel M, Saad RJ, Long MD, et al. ACG clinical guideline: small intestinal bacterial overgrowth. Am J Gastroenterol.

2020;115(2):165-178.

17. Canny GO, McCormick BA. Bacteria in the intestine, helpful residents or enemies from within? Infect Immun. 2008;76(8): 3360-3373.

18. Liu Y, Ajami NJ, El-Serag HB, et al. Dietary quality and the colonic mucosa-associated gut microbiome in humans. Am J Clin Nutr.

2019;110(3):701-712.

19. Lim ES, Zhou Y, Zhao G, et al. Early life dynamics of the human gut virome and bacterial microbiome in infants. Nat Med. 2015;21(10):1228-1234.

20. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A. 2011;108(suppl 1):4554-4561.

21. Schulfer AF, Battaglia T, Alvarez Y, et al. Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice. Nat Microbiol. 2018;3(2):234-242.

22. Miyoshi J, Bobe AM, Miyoshi S, et al. Peripartum antibiotics promote gut dysbiosis, loss of immune tolerance, and inflammatory bowel disease in genetically prone offspring. Cell Rep. 2017;20(2):491-504.

23. Pickard JM, Zeng MY, Caruso R, et al. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol. Rev. 2017;279(1):70-89.

24. Lopez-Siles M, Duncan SH, Garcia-Gil L, et al. Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics.

ISME J. 2017;11(4):841-852.

25. Cani PD, Depommier C, Derrien M. et al. Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol. 2022;19(1)):625-637.

26. Sonnenburg ED, Sonnenburg JL. Starving our microbial self: the deleterious consequences of a diet deficient in microbiotaaccessible carbohydrates. Cell Metab. 2014;20(5):779-786.

27. Sonnenburg ED, Smits SA, Tikhonov M, et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature.

2016;529(7585):212-215.

28. Chassaing B, Koren O, Goodrich JK, et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature. 2015;519(7541):92-96.

29. Allen JM, Mailing LJ, Cohrs J, et al. Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice. Gut Microbes. 2018;9(2):115-130.

30. Evans CC, LePard KJ, Kwak JW, et al. Exercise prevents weight gain and alters the gut microbiota in a mouse model of high fat diet-induced obesity. PLoS One. 2014 26;9(3):e92193.

31. Kang SS, Jeraldo PR, Kurti A, et al. Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition. Mol Neurodegener. 2014;13;9:36.

32. Boytar AN, Skinner TL, Wallen RE, et al. The effect of exercise prescription on the human gut microbiota and comparison between clinical and apparently healthy populations: a systematic review. Nutrients. 2023;15(6):1534.

Dr. Ivanina reported no relevant financial disclosures.

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Improving the Safety of Endoscopy Procedures in Pregnant Patients WAQAR QURESHI, MD, FRCP (UK), FACG, FASGE Professor of Medicine Baylor College of Medicine Houston, Texas

A

lthough about 20,000 gastrointestinal endoscopies (0.4% of all endoscopies) are

performed in pregnant patients in the United States each year,1 endoscopy in this setting often causes anxiety and hesitation for both the physician and patient. These reactions are understandable given the paucity of safety data on endoscopy for the fetus during the procedure. Both mother and baby are at risk during the procedure, and it is difficult to reliably monitor fetal well-being.

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However, data showing the procedure’s safety have started to accumulate, particularly when there is a strong indication and providers take the appropriate precautions to enhance safety. The indications for endoscopy in the pregnant patient are listed in the table.

A rational approach to these patients involves a higher threshold for the decision to perform endoscopy and informed consent about what is known and unknown about risk to the fetus.

This review discusses the safety precautions that apply to all pregnant patients, regardless of gestational age.

Sedation The fetus is particularly sensitive to maternal hypoxia and hypotension, either of which may cause fetal hypoxia that can lead to fetal distress or demise. Maternal oversedation, with resulting hypoventilation or hypotension, also can cause

reduced placental perfusion and hypoxia. Pregnant patients are prone to aspiration, regardless of stage of pregnancy, and require intubation for most procedures.2 Preoxygenation should precede intubation to decrease the likelihood of transient fetal hypoxia. A systematic review of 54 studies and 12,452 patients who underwent surgery, and therefore sedation, during pregnancy showed that they had no increase in congenital anomalies compared with the general population.3 However, if sedation is required, endoscopists should use the lowest possible medication doses and minimize procedure time.

Propofol appears to be safe in the second and third trimesters of pregnancy, and there has been a trend toward increased use of this agent for endoscopy in pregnant patients. Although sufficient data are lacking, propofol can be used in the first trimester if a procedure cannot be postponed to the second trimester.4,5 Meperidine and

Table. Indications for Endoscopy In the Pregnant Patient Significant GI bleeding (hematemesis or melena) Cholangitis and choledocholithiasis Liver cirrhosis Severe abdominal pain from suspected peptic ulcer disease or malignancy Dysphagia or odynophagia Suspected gastric outlet obstruction

Figure 1. The pregnant uterus compressing the aorta and inferior vena cava against the vertebral column can decrease placental perfusion.

Figures 2 and 3. A pillow placed under the right hip causes the uterus to roll off the spine and great vessels, improving blood flow through the aorta and inferior vena cava.

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midazolam also appear to be safe, but are used less commonly.4,5 Diazepam was thought to increase the risk for congenital malformations, but this has not been borne out on closer scrutiny in more recent studies.6 However, diazepam does cross the placenta and blood–brain barrier, and is excreted in breast milk, so it should be avoided close to delivery.

Some pregnant patients prefer to avoid sedation and may benefit from lidocaine gargles or IV promethazine for calming effects. Sigmoidoscopy can be done safely without sedation with tap water enema preparation.

Patient Positioning The pregnant uterus can compress the aorta or inferior vena cava (IVC) and reduce venous return, which, in turn, can lead to placental hypoperfusion and fetal hypoxia (Figure 1).

Thus, it is recommended that patients not lie supine for endoscopic procedures after 20 weeks of gestation.7 Aortic and IVC compression can be prevented by placing a pillow under the patient’s right hip to create a leftward pelvic tilt, so the uterus is not lying directly on top of the aorta or IVC (Figures 2 and 3).

Pregnant Patients With Liver Cirrhosis Bleeding from esophageal varices is a serious complication in pregnant patients that can result in death of both the mother and fetus.8 Esophageal varices may worsen in pregnancy, in part because of the increased vascular volume that occurs. It is common practice to screen for varices before pregnancy and then at around 20 weeks of gestation so that large varices can be banded.

Safely Features Unique To ERCP In Pregnancy When choledocholithiasis is suspected, magnetic resonance cholangiopancreatography (MRCP) is useful for determining the size and number of stones before a decision is made regarding endoscopic retrograde cholangiopancreatography (ERCP) (Figure 4). In some cases, the stone will have been passed, making ERCP unnecessary.

The risk for post-ERCP pancreatitis is higher in pregnant women than in nonpregnant women,9 and for this reason it is important to have an experienced endoscopist perform the procedure. This also helps keep the procedure time short. Before any fluoroscopy, the literature recommends wire-first cannulation and aspiration of bile through a sphincterotome.10 Snapshot digital imaging and preprocedural MRCP minimize the amount of radiation used when investigating the number of stones or other pathology to be addressed.10 In the setting of multiple common bile duct stones or a large stone requiring lithotripsy, it is acceptable to insert a plastic stent with a plan to remove the stones postpartum.11 Unless the procedure is done in the first trimester of pregnancy, it usually is done in the supine position. It is important to remember that the lead apron shield is placed beneath the patient since the x-rays originate below the table.

When an endoscopic sphincterotomy is necessary, it is important to have the grounding pad above the diaphragm, preferably on the patient’s right shoulder (Figure 5).

This placement ensures that any stray current does not go through the pregnant uterus and harm the fetus (amniotic fluid is a good conductor of electrical current).

Periprocedural Antibiotic Use When an antibiotic is needed, such as in the setting of cholangitis, providers should avoid using the quinolone

Figure 4. MRCP shows a stone in the distal common bile duct, confirming the need for ERCP. MRCP, magnetic resonance cholangiopancreatography; ERCP, endoscopic retrograde cholangiopancreatography.

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Figure 5. Grounding pad placement over right shoulder blade for endoscopic sphincterotomy reduces the risk for stray electrical current affecting the fetus.

antibiotics, streptomycin, and tetracyclines because they can pose risks to the developing fetus.12 Antibiotics that are considered safe in pregnancy include the penicillins, cephalosporins, erythromycin (except estolate), and clindamycin.12 Metronidazole should be avoided in the first trimester, and sulfonamides and nitrofurantoin avoided in the third trimester.12

Conclusion Applying the following principles will help gastroenterologists optimize outcomes when endoscopy is needed in obstetric patients. Always have a strong indication when performing endoscopy in pregnant patients, and defer endoscopic procedures to the second trimester whenever

possible. If sedation is required, use the lowest effective dose of medication and minimize procedure time. Position pregnant patients in the left pelvic tilt or left lateral position to avoid compression of the vena cava or aorta. Confirm the presence of fetal heart sounds before sedation is begun and after the endoscopic procedure, and consider continuous monitoring of the fetal heartbeat and contractions once the fetus is past 22 weeks gestational age. Make sure obstetric staff are aware and available in case there is a complication, and remember that endoscopy is contraindicated in the setting of obstetric complications such as placental abruption, imminent delivery, ruptured membranes, and eclampsia.

References 8.

van der Slink LL, Scholten I, van Etten-Jamaludin FS, et al. Pregnancy in women with liver cirrhosis is associated with increased risk for complications: a systematic review and meta-analysis of the literature. Br J Obstet Gynecol. 2022;129(10):1644-1652.

9.

Inamdar S, Berzin TM, Sejpal DV, et al. Pregnancy is a risk factor for pancreatitis after endoscopic retrograde cholangiopancreatography in a national cohort study. Clin Gastroenterol Hepatol.

2016;14(1):107-114.

1.

Cappell MS. The fetal safety and clinical efficacy of gastrointestinal endoscopy during pregnancy. Gastroenterol Clin North Am. 2003;32(1):123-179.

2.

Cheek TG, Baird E. Anesthesia for nonobstetric surgery: maternal and fetal considerations. Clin Obstet Gynecol. 2009;52(4):535-545.

3.

Lim G, Facco FL, Nathan N, et al. A review of the impact of obstetric anesthesia on maternal and neonatal outcomes.

Anesthesiology. 2018;129(1):192-215.

4.

Neuman G, Koren G. Safety of procedural sedation in pregnancy.

J Obstet Gynaecol Can. 2013;35(2):168-173.

10. Samara ET, Stratakis J, Enele Melono JM, et al. Therapeutic ERCP and pregnancy: is the radiation risk for the conceptus trivial?

Gastrointest Endosc. 2009;69(4):824-831.

5.

Beilin Y. Anesthesia for nonobstetric surgery during pregnancy.

Mt Sinai J Med. 1998;65(4):265-270.

11.

6.

Ban L, West J, Gibson JE, et al. First trimester exposure to anxiolytic and hypnotic drugs and the risks of major congenital anomalies: a United Kingdom population-based cohort study.

PLoS One. 2014;9(6):e100996.

7.

Qureshi WA, Rajan E, Adler DG, et al; American Society for Gastrointestinal Endoscopy. Guidelines for endoscopy in pregnant and lactating women. Gastrointest Endosc. 2005;61(3):357-362.

Cappell MS, Stavropoulos SN, Friedel D. Systematic review of safety and efficacy of therapeutic endoscopic-retrograde-cholangiopancreatography during pregnancy including studies of radiation-free therapeutic endoscopic-retrograde-cholangiopancreatography. World J Gastrointest Endosc. 2018;10(10):308-321.

12. Bookstaver PB, Bland CM, Griffin B, et al. A review of antibiotic use in pregnancy. Pharmacotherapy. 2015;35(11):1052-1062.

Dr. Qureshi reported no relevant financial disclosures. Dr. Qureshi, who completed obstetrics/gynecology residency training in addition to internal medicine and gastroenterology training, is the lead author of the American Society of Gastrointestinal Endoscopy’s guidelines on endoscopy in pregnancy.

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Endoscopy System Elevating the Standard of Endoscopy

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Image provided by Prof. Dr. Jürgen Pohl using a GIF-1100 gastroscope

The EVIS X1 endoscopy system is not designed for cardiac applications. Other combinations of equipment may cause ventricular fibrillation or seriously affect the cardiac function of the patient. Improper use of endoscopes may result in patient injury, bleeding, and/or perforation. Complete indications, contraindications, warnings, and cautions are available in the Instructions for Use (IFU).

TXI™ and RDI™ technologies are not intended to replace histopathological sampling as a means of diagnosis.

The EVIS X1™ endoscopy system introduces a range of new technologies that aim to revolutionize the way physicians can detect, characterize and treat gastrointestinal and interoperative disorders.

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Scan the QR code or visit the Olympus booth at ACG to learn more.

TXI

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TXI™ Technology See Things in a New Light

Image provided by Prof. Dr. Jürgen Pohl using a GIF-1100 gastroscope

©2023 Olympus America Inc. Registered Trademark of Olympus or its affiliates. TXI and RDI are trademarks of Olympus Corporation and/or their affiliates. medical.olympusamerica.com I OAIGI0923AD49938

Between the Guidelines

ACG Issues Updated Guidance On Lower GI Bleeding

T

he American College of Gastroenterology recently released an updated clinical guideline on the management of acute lower gastrointestinal bleeding (Am J Gastroenterol 2023;118[2]:208-231). GEN’s Sarah Tilyou spoke with lead author Neil Sengupta, MD, a gastroenterologist and associate professor at the University of Chicago Medicine, about the impetus for the guideline and what it means to GI practice.

GEN: What prompted the guideline?

Dr. Sengupta: Lower GI bleeding is one of the most common reasons patients are hospitalized in this country for a digestive disorder. It’s a very common scenario that clinicians deal with on a daily basis. The prior American College of Gastroenterology guidelines on this topic were published in 2016. Since that time, there have been numerous updates related to the diagnosis and management of lower GI bleeding. So, we felt it was important to provide clinicians with a set of updated evidencebased recommendations for the diagnosis and management of this very common condition.

GEN: What’s new in the guideline that clinicians need to know?

Dr. Sengupta: We provide 12 evidence-based recommendations that provide an overview of the diagnosis and management of patients with lower GI bleeding. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework to develop a list of practical, evidence-based recommendations that clinicians hopefully will find useful.

Pertinent updates since the last iteration of this guideline include a focus on the role of reversal agents for patients who are on anticoagulation when they present with lower GI bleeding, including management of patients on vitamin K antagonists as well those taking direct oral anticoagulants.

We also provide updated guidance on the increasing role of radiologic tests in lower GI bleeding, in particular CT angiography. In addition, we discuss the role of risk stratification tools

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Neil Sengupta, MD

for patients who present with lower GI bleeding, with a focus on trying to identify patients who are at low risk for requiring a hospital-based intervention. Finally, we also provide updated guidance on resumption of anticoagulant and antiplatelet therapies after bleeding has subsided.

Some of the recommendations in the updated guideline are somewhat different from the prior iteration in 2016. One example is that the previous guideline had recommended performing colonoscopy urgently (within 24 hours of presentation) for patients with severe hematochezia. Since the 2016 guideline was published, several randomized controlled trials have shown that urgent colonoscopy is not associated with improved clinical outcomes compared with elective colonoscopy. So, in our updated document, we specifically do not recommend urgent colonoscopy for most patients, simply because it hasn’t been shown to improve clinical outcomes such as rebleeding and mortality compared to doing an elective, or next-available colonoscopy.

GEN: How might the guideline change practice?

Dr. Sengupta: One change relates to the role of reversal agents for patients with life-threatening bleeding who don’t respond to traditional resuscitation. Specific targeted reversal agents weren’t in existence in 2016. Now, we’re increasingly dealing with patients taking warfarin or direct oral anticoagulants, some of whom may present with life-threatening bleeding. The guideline includes a flowchart of when to consider those reversal drugs versus when patients should

be managed conservatively, so that’s somewhat different compared with the prior guideline.

There also is an increasing role for radiology testing, both diagnostic and therapeutic, in the setting of lower GI bleeding. In patients who have active bleeding with hemodynamic instability, we recommend CT angiography as the initial diagnostic test, not a colonoscopy, because of its ability to rapidly obtain images without requiring a bowel preparation.

CT angiography has pretty high sensitivity and specificity for diagnosing the cause and location of lower GI bleeding. For patients who have a CT angiography that shows where the bleeding is coming from, we recommend referral to interventional radiology for treatment via embolization.

In the guideline, we try to provide guidance for scenarios in which conservative management without endoscopic procedures is a reasonable strategy. For example, if a patient with a history of diverticular bleeding and a colonoscopy within a year or two that shows diverticulosis presents with typical bleeding that is highly consistent with diverticular bleeding based on the patient’s clinical history, inpatient colonoscopy likely could be avoided.

The patient could be monitored conservatively, and if their bleeding subsides spontaneously, they can be discharged with outpatient follow-up because the clinical history is so highly consistent with diverticular bleeding based on their prior presentations.

Once bleeding has stopped, then the management really shifts to prevention of recurrent bleeding. That’s when we start thinking about what we can do to decrease the risk for recurrent bleeding. We should consider discontinuing the patient’s nonsteroidal anti-inflammatory drugs, which has been shown to decrease the risk for recurrent lower GI bleeding. If a patient is on aspirin but does not have an established history of coronary artery disease, we should consider stopping their aspirin. If they are on clopidogrel or nonaspirin antiplatelets and they don’t necessarily need to be on it (e.g., maybe they had a stent placed many years ago), then we should be proactive and potentially discontinue the clopidogrel or the other nonaspirin antiplatelets. Those are the things that we should do to reduce the risk for recurrent diverticular bleeding, rather than going into the cycle of repeating a colonoscopy every time a patient experiences bleeding because the rates of intervention during inpatient colonoscopy are relatively low.

GEN: What were some of the hottest points of debate among the guideline panelists?

Dr. Sengupta: In terms of the controversial points, one was when not to do an inpatient colonoscopy. As providers who deal with these patients in the hospital, we often go through

the cycle of feeling the need to do an inpatient colonoscopy each time a patient experiences bleeding. However, the rates of endoscopic intervention are very low, particularly for patients with diverticular bleeding. The bleeding may have subsided by the time we insert the colonoscope, and it’s not clear whether we’re really benefiting the patient with the procedure.

So, one recommendation that we included in the guideline was to consider not doing a colonoscopy in certain patients in whom bleeding has clinically subsided, who have a high pretest probability of diverticular disease as a cause of their bleeding, and who’ve had a recent outpatient colonoscopy excluding something like colon cancer or a vascular lesion.

That’s relatively controversial, because in the past, the recommendation was to consider doing colonoscopy in most, if not all, patients with lower GI bleeding.

GEN: What are some of the biggest remaining gaps in evidence?

Dr. Sengupta: There definitely are a lot. Unfortunately, there haven’t been a lot of randomized controlled trials to help guide management—despite how common lower GI bleeding is. That limited the strength of many of our recommendations. When we did the GRADE evidence review process, a lot of our recommendations are low quality, or very low quality, simply because there aren’t any randomized controlled trials to help guide management. Despite that, we still wanted to include recommendations just because this is a very, very common clinical condition that providers deal with on a daily basis.

A few of the gaps that we highlight include gaps in data on when to use reversal agents versus when to hold the drugs in patients who come in with lower GI bleeding while on anticoagulation. There simply is no evidence to help guide which patients benefit from a conservative strategy versus which patients need reversal of their anticoagulation. We also need more evidence on using risk stratification tools to identify low-risk patients. It would be helpful if we could get a better sense of which patients actually require an intervention and which patients can be triaged to an outpatient management pathway. That would save resources and money. And then we need more evidence on which patients do better with a colonoscopy pathway versus an angiographic pathway.

There are not a lot of data on what the risks are for rebleeding for patients who are treated through a colonoscopy versus patients who are treated with angiography.

We have a section of our guideline where we discuss future directions, and I hope that the topics that we mentioned will be a call to action and spur investigators to focus on these important topics because there simply is not a lot of evidence to help guide us.

Dr. Sengupta reported a relationship with Alexion.

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one & done

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1 Jensen DM, Kovacs T, Ghassemi KA, Kaneshiro M, Gornbein J. Clin Gastroenterol Hepatol. 2021 Nov;19(11):2315-2323 2 Meier B, Wannhoff A, Denzer U, Stathopoulos P, Schumacher B, Albers D, Hoffmeister A, Feisthammel J, Walter B, Meining A, Wedi E, Zachäus M, Pickartz T, Küllmer A, Schmidt A, Caca K. Gut. 2022 Jul;71(7):1251-1258.

3 Lau J, Tan CH, Sun X, Song H, Li L, Li R, Li P, Feng J, Wang B, Leung WK, Hartley I, Moss AC, Suen BY, Yu Y, Chan FK. Over-the-scope clips versus standard endoscopic treatment. UEG Week Virtual (October 3-5) 2021

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OTSC® is a registered brand of Ovesco Endoscopy AG.