Gastroenterology & Endoscopy News (August 2020) by McMahon Group

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The Independent Monthly Newspaper for Gastroenterologists

Volume 71, Number 8 • August 2020

Race, Social Status Linked to Disparities In IBD Care

Clinicians Now Have Solid Guidance on COVID-19 And IBD Management

hen Maria Oliva-Hemker, MD, was training to be a pediatric gastroenterologist in the 1990s, the medical literature of the day indicated that inflammatory bowel disease overwhelmingly affected white patients. As she treated patients in Baltimore, however, it was clear to her a significant population of Black children had IBD, too. In fact, the incidence of IBD has been increasing in African American and Hispanic patients in recent decades. But it is harder for these patients, and Black patients in particular, to receive the care they need, experts say. Social and economic realities, including costly health insurance, low socioeconomic status, and a lack of medical services in minority neighborhoods, all likely contribute to inadequate care and worse outcomes. Experts say educating providers, diversifying the clinician community, and investing in research and initiatives to increase access to care are needed to improve care for everyone with IBD. “It is the time for us in IBD care to be looking at care in an inclusive, more multicultural way to our patients because that’s who they are,” Dr. Oliva-Hemker, the director of the Division of Pediatric Gastroenterology, Hepatology and Nutrition at the Johns Hopkins Children’s Center, in Baltimore, said.

s clinicians across the country continue to face alarming surges of COVID-19 cases, experts in inflammatory bowel disease say the gastroenterology community is now much more prepared for the care of IBD patients during the outbreak. “We have learned a ton since the pandemic started, and I feel confident in our management strategy for IBD in the COVID era,” Jordan Axelrad, MD, MPH, an assistant professor of medicine at the NYU Grossman School of Medicine and the IBD Center at NYU Langone Health, in New York City, said. “We now know what the risk factors are for severe outcomes of COVID-19 in IBD patients, and, importantly, we know that biologic and

small-molecule therapies are safe and likely do not increase the risk of COVID-19 acquisition or severe outcomes.” see Strategy, page 46

EHRs May Hold Keys to Practice Survival In the COVID Era

see IBD Disparities, page 22

he development of ancillary services is a crucial consideration for gastroenterology practices thinking about diversifying, particularly in the trying times of the COVID-19 pandemic. What service line should you develop? The answer may lie in the contents of your electronic health records (EHRs). Although often bemoaned as a bane of modern medical practice, the EHR holds a gold mine of patient data that can help practices identify ancillary service lines tailored to their own patient

population. These data, properly used, also can potentially identify gaps in care and drive significant improvement in patient outcomes. “Most groups still really don’t understand that EHRs contain a tremendous repository of data that can be used to identify subsets of patients who would benefit from specific ancillary services,” Scott Fraser, MBA, the managing director of Fraser Healthcare LLC, in Malvern, Pa., said. see EHR, page 12

COMMENTARY

EXPERT PICKS

HEP IN FOCUS

IN THE NEWS

AGA’s new probiotic guidelines: absence of evidence or evidence of absence?

Esophageal research from DDW 2020

EHR add-on predicts advanced fibrosis

IBD and the elderly: living with an IPAA

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REVIEW ARTICLE Cases From the Frontiers of Therapeutic Endoscopic Ultrasound in 2020

see insert at 24

In UC & Crohn's FOR ADULTS WITH MODERATELY TO SEVERELY ACTIVE UC OR CD FOR WHOM OTHER THERAPIES HAVE NOT WORKED WELL ENOUGH OR CANNOT BE TOLERATED Your decision to prescribe Entyvio for your appropriate patients may change the next chapter of their treatment journey

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

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

Entyvio combines:

LONG-TERM REMISSION

AND

UC and CD patients achieved remission at Week 52 vs placebo in study populations that included bio-naïve and anti-TNFα–experienced patients2,3 Individual results may vary.

IMPORTANT SAFETY INFORMATION (continued)

• Patients treated with ENTYVIO are at increased risk for developing infections. Serious infections have been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding ENTYVIO in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. • Progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIOtreated patient with multiple contributory factors has been reported in the postmarketing setting (e.g., human immunodeﬁciency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out.

Entyvio

vs HUMIRA® *

(adalimumab)

GUT SELECTIVITY4-9

AND

Entyvio helps address inﬂammation where it occurs—in the gut

Entyvio speciﬁcally binds to the α4β7 integrin and blocks the interaction between the α4β7 integrin and MAdCAM-1, which is mainly expressed on the GI tract endothelial cells3

IMPORTANT SAFETY INFORMATION (continued)

Monitor patients for any new or worsening neurological signs or symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue ENTYVIO dosing permanently. • There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury. • Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines and may receive live vaccines if the benefits outweigh the risks.

THE FIRST HEAD-TO-HEAD STUDY of biologic therapies in UC1,2 THE LA AND DMA ARK VARSITY STUDY available at Entyvio-VARSITY.com *HUMIRA® AbbVie Inc. North Chicago, IL. For more information related to adalimumab, please see AbbVie.com.

SAFETY

FOR THE LONG TERM Clinical trials evaluated safety in more than 3300 patients (UC and CD).3 A 5-year analysis, which included an open-label continuation study (UC and CD), has demonstrated consistent results across safety parameters10

IMPORTANT SAFETY INFORMATION (continued)

• Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo): nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, inﬂuenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities.

Please see Brief Summary of Full Prescribing Information on adjacent pages. CD = Crohn's disease; GI = gastrointestinal; MAdCAM-1 = mucosal addressin cell adhesion molecule-1; TNF = tumor necrosis factor; UC = ulcerative colitis. References: 1. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. N Engl J Med. 2019;381(13):1215-1226. 2. Data on ﬁle. Takeda Pharmaceuticals. 3. Entyvio (vedolizumab) prescribing information. Takeda Pharmaceuticals. 4. Briskin M, Winsor-Hines D, Shyjan A, et al. Am J Pathol. 1997;151(1):97-110. 5. Fedyk E, Wyant T, Yang LL, et al. Inﬂamm Bowel Dis. 2012;18(11):2107-2119. 6. Soler D, Chapman T, Yang LL, et al. J Pharmacol Exp Ther. 2009;330(3):864-875. 7. Wyant T, Fedyk E, Abhyankar B. J Crohns Colitis. 2016;10(12):1437-1444. 8. Wyant T, Leach T, Sankoh S, et al. Gut. 2015;64(1):77-83. 9. Milch C, Wyant T, Xu J, et al. J Neuroimmunol. 2013;264:123-126. 10. Colombel JF, Sands BE, Rutgeerts P, et al. Gut. 2017;66(5):839-851. ENTYVIO is a trademark of Millennium Pharmaceuticals, Inc., registered with the U.S. Patent and Trademark Office and is used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners. ©2020 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. Printed in U.S.A. US-VED-0198v2.0 07/20

Learn how you can help your patients reach remission—visit EntyvioHCP.com

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

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

FULL PRESCRIBING INFORMATION

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

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

ENTYVIO† (N=1434)

Placebo‡ (N=297)

Nasopharyngitis Headache

13% 12%

7% 11% 10%

Adverse Reaction

Arthralgia

12%

Nausea

Pyrexia

Upper respiratory tract infection

Fatigue

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

Inﬂuenza

Back pain

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

Rash

Pruritus

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

Cough

Bronchitis

Sinusitis

Oropharyngeal pain

Pain in extremities

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

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

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

Infusion-Related Reactions and Hypersensitivity Reactions

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

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

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

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

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

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

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

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

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

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

Liver Injury

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

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

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

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

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

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to vedolizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

U.S. License No. 1898

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

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

Postmarketing Experience The following adverse reactions have been identified during post-approval use of ENTYVIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Anaphylaxis [see Warnings and Precautions] DRUG INTERACTIONS Natalizumab Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab. TNF Blockers Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers. Live Vaccines Live vaccines may be administered concurrently with ENTYVIO only if the benefits outweigh the risks [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENTYVIO during pregnancy. Information about the registry can be obtained by calling 1-877-TAKEDA7 (1-877-825-3327). Risk Summary Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified an ENTYVIO associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy (see Clinical Considerations). No fetal harm was observed in animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and miscarriage is 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and embryo/fetal risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth. Fetal/Neonatal adverse reactions ENTYVIO administered during pregnancy could affect immune responses in the in utero exposed newborn and infant. The clinical significance of low levels of ENTYVIO in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Data Animal Data A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100 mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100 mg/kg (about 20 times the recommended human dosage).

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Vol. 71, No. 8

August 2020

Directions

EDITORIAL ADVISORY BOARD

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

ANDREW ALBERT, MD, MPH Chicago, Illinois

HARISH K. GAGNEJA, MD Austin, Texas

SATISH RAO, MD, PHD Augusta, Georgia

MANOOP S. BHUTANI, MD Houston, Texas

FRANK G. GRESS, MD New York, New York

JOEL E. RICHTER, MD Tampa, Florida

BROOKS D. CASH, MD Houston, Texas

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

DAVID ROBBINS, MD New York, New York

Legal pot spurs vomiting syndrome ➣ See page 10 The Regueiro Report: DDW highlights

AUSTIN CHIANG, MD, MPH Philadelphia, Pennsylvania

ELLEN J. SCHERL, MD New York, New York

GARY R. LICHTENSTEIN, MD Philadelphia, Pennsylvania

ALAN F. CUTLER, MD Farmington Hills, Michigan

JENIFER R. LIGHTDALE, MD, MPH Worcester, Massachusetts

PRATEEK SHARMA, MD Kansas City, Kansas

RONNIE FASS, MD Cleveland, Ohio

PETER R. MCNALLY, DO Fort Carson, Colorado

JEROME H. SIEGEL, MD New York, New York

DEBORAH FISHER, MD Durham, North Carolina

KLAUS MERGENER, MD, PHD, MBA ASHWANI K. SINGAL, MD, MS Tacoma, Washington Sioux Falls, South Dakota

➣ See page 20

Micronutrients in the ICU ➣ See page 34

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CHANGE OF ADDRESS

celiac disease. We think it is a combination of pollutants, plus genes, plus exposure to gluten that causes the disease.’

PHYSICIANS: If you are an MD, contact the AMA (you do not have to be a member of the AMA) at (800) 262-3211 or 515 N. State St., Chicago, IL 60610 or www.ama-assn.org. The following link will allow you to update your information online quickly and easily: • www.ama-assn.org/ama/pub/about-ama/physician-dataresources/online-data-collection-center.page If you are a DO, contact the AOA. Note that the AOA does not allow updating physician information online. • AOA: (800) 621-1773 or 142 E. Ontario St., Chicago, IL 60611 or www.osteopathic.org NURSE PRACTITIONERS AND PHYSICIAN ASSISTANTS: Send an email to circulation@mcmahonmed.com or fax to (815) 366-8297 or mail to 545 West 45th Street, 8th Floor, New York, NY 10036. Make sure to include the following information: name of the recipient, title of the publication, and the new and old addresses. If you are not a U.S. gastroenterologist, hepatologist or colorectal surgeon and would like to subscribe, send a check payable to Gastroenterology & Endoscopy News to Circulation Manager, Gastroenterology & Endoscopy News, 545 West 45th Street, 8th Floor, New

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page 25

COMMENTARY

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

New Probiotics Guidelines Highlight Need For Physician Awareness Elena Ivanina, DO E D Ivanina is an assistant Dr. professor at the Donald p and Barbara Zucker a School of Medicine at S Hofstra/Northwell, in New H York City. Y

he word “probiotic” derives from the L Latin pro and biota, meaniing “for life.” Long before tthe scientific community became aware of probiotic organisms, fermented products such as yogurt had frequently been used for traditional nutritional and therapeutic purposes. In 1905, Elie Metchnikoff was credited with making the association of health benefits not with yogurt itself, but rather with the lactobacilli used to ferment yogurt and the presence of these bacteria in the colon. Since then, probiotics have taken off in the direct-to-consumer market, with the medical science trailing behind. In 2000, journals published 176 papers about probiotics; in 2014, that figure was 1,476. Yet research on probiotics is still in its infancy.

In early June, the American Gastroenterological Association released new clinical guidelines on the use of probiotics for digestive conditions (Gastroenterology, in press). The only conditions for which the AGA determined probiotics were useful were during the course of antibiotic treatment to prevent infection with Clostridioides difficile, in patients with pouchitis, and the prevention of necrotizing enterocolitis in preterm infants. Although I applaud the association for combing through a lot of heterogeneous data to come up with these recommendations, I believe the group made the call too soon. How might these guidelines affect our patients? Recommendations, even those based on shaky evidence, that influence the decision making of many practitioners may prevent some patients from getting a safe therapeutic intervention and can create confusion.

Take IBS, for example. In 2018, the American College of Gastroenterology published its “Monograph on Management of Irritable Bowel Syndrome” by leaders in the field, such as Drs. Eamonn M. M. Quigley and Brian E. Lacy. They recommended to take probiotics, as a group, to improve global symptoms of IBS, as well as bloating and flatulence in these patients. The guidelines committee reviewed 53 randomized controlled trials involving 5,545 patients and found that probiotics were statistically superior to placebo, with a number needed to

antagonist with side effects including ischemic colitis and severe constipation, which led to the withdrawal of the drug from the market. Many patients may be helped by a trial of probiotics with their possible benefit and limited side effects, before advancing to a drug that requires a patient–physician agreement because the side effects are so severe.

Instead of blindly following each guideline paper that comes along, scrutinize the data for yourself. Make an individualized assessment and decision based on your patient’s unique condition.

treat of seven. They also found that the relative risk for experiencing any adverse event was not significantly higher with probiotics than sham therapy (1.09; 95% CI, 0.91-1.29). The AGA guidelines recommend the use of probiotics in IBS only in the context of a clinical trial. Although there was significant heterogeneity in study design, outcome measures and use of probiotic strains with different probiotics or probiotic combinations of variable duration, the results were promising. The guidelines refer to “significant … potential” and “some benefit.” However, following guidelines instead of making individual assessments carries potential dangers for patients, given the available alternative treatments. Eluxadoline, a mu-opioid receptor agonist and a deltaopioid receptor antagonist, has been associated with a high incidence of severe acute pancreatitis in patients with either biliary disorders (spasm of the sphincter of Oddi and biliary sludge) or alcohol use. And what about alosetron, a 5-hydroxytryptamine-3 receptor

It’s not just research on probiotics that’s in its infancy. Research on prebiotics, synbiotics and fecal microbiota transplantation (FMT) is lacking. Prebiotics are nondigestible carbohydrates that stimulate the growth and activity of beneficial colonic bacteria. Studies have shown they induce specific gut bacterial shifts and significantly reduce body weight, percentage of body fat, percentage of trunk fat, and serum interleukin. Synbiotics, a combination of prebiotics and probiotics, appear to have a benefit in inflammatory bowel disease. Lastly, FMT has proven helpful in Clostridioides difficile colitis and may have many other promising indications, including hepatic encephalopathy, IBS and obesity. I bring up these other microbiome-related therapies because we are still not exactly sure what works, how and for what conditions. For example, probiotics alone are less effective for IBS than synbiotics or an FMT. We know that in IBS, studies have shown the etiology is rooted in microbiome disruption so microbial therapy makes sense, but we just don’t know the details yet. Instead of blindly following each guideline paper that comes along, scrutinize the data for yourself. Make an individualized assessment and decision based on your patient’s unique condition. Weigh the risks and benefits compared with other existing therapies. Any blanket statements about all probiotics in GI conditions is premature, but probiotics and microbial therapy are going to be around “for life,” ■ and I would start learning about them today. Editor’s note: The views expressed in this commentary belong to the author and do not necessarily reflect those of this publication.

COMMENTARY

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Moneyball for Health Care: Why Hasn’t It Happened? Bruce Ramshaw, MD

“M

oneyball,” a book by Michael Lewis, and later made into a movie starring Brad Pitt, describes the success of applying the principles of data science to develop a winning strategy in baseball. It’s a transferable skill, so why hasn’t Moneyball happened in health care? You would think if data science can be used to win more games in baseball, it could be used to lower costs and improve outcomes. Data science is about measurement and improvement. In baseball, the measurement to be improved is runs scored with the lowest possible budget—producing the most wins per dollar spent. Similarly, if we want a sustainable health care system, we should measure and improve the value of care we provide, resulting in lower costs and better outcomes over time. If you can measure something, it can be improved. But if something is not being measured, it can’t be improved—and we’re not measuring the value of care in health care, in any organization, in any health care system in the world. For data science to work, there are basic rules. First, data require “context,” or a definable process. Attempting to apply data science without context doesn’t work. In sports, context is provided by the specific set of rules for a particular game, like baseball: nine players, three outs, three strikes, nine innings, etc. The insight from the application of data science tools applied to baseball will not work the same if applied to a different sport such as American football, with 11 players, four quarters, four downs, etc. In health care, context means defining each whole patient care process. The specific patient and treatment factors and outcome measures collected will be different for different types of patient care processes. For example, outcome measures used to define the value of care

Probably the most harmful habit of all, we’ve allowed health care leaders to continue to push the growth and volume model despite the harm done not only to patients, but to doctors and other caregivers as well.

for a breast cancer process will not be the same as those used for a ventral hernia process. Another principle of data science is it should be applied to measure and improve outcomes that matter most. In baseball, what matters most to improve the value of the team performance is combining salaries (financial measures) with factors that result in the most runs and wins (e.g., on-base percentage). Applying data science to measure and increase the number of pitches thrown will likely not help win more games. We’re not typically measuring outcomes that matter in health care. We tend to measure things that are easy to measure, such as if antibiotics are given before surgery, rather than the factors that improve the value of care the most. We document these easy-to-measure factors, often because of perverse financial incentives or penalties, without measuring to see what effect they have on outcomes. To truly measure value, we should be combining financial measures with outcome measures that matter in the context of each definable whole patient care process. Until we do, we can’t lower costs and improve patient outcomes at the same time. For over a century, baseball was using data the same as health care is today. At first, baseball statistics were based on the original development of one set of static measurements, like batting average, runs and runs batted in (RBIs). These statistics were invented in 1845, and presented in the “box score” for each game. The more these old statistics were examined, the less sense they made. They were not the best measures of player and team value, so they didn’t give the best insight into how to score more runs and win more games. In health care, we also use static measurements that don’t measure value well. Take wound infection, for example. Every hospital in the United States reports wound infection based on the CDC definition: superficial, deep or organ space. But when we asked patients who had wound infections what they thought, they said the CDC definition was not very helpful. Patients thought measuring wound infections by the invasiveness of the treatment and the length of time required to heal their wounds was a much better measurement. When we looked at the data for wound infections after open ventral hernia repairs, the patients were right: Some superficial infections took months or years to heal, requiring invasive surgical procedures, whereas some deep infections were resolved with a single course of oral antibiotics. We can learn to apply better measurements in health care. It wasn’t until the 1970s, when Bill James, a writer and night watchman at a Stokely Van Camp pork and beans cannery, began to question the status quo of baseball statistics. In 1977, James published a periodical called the “1977 Baseball Abstract: Featuring 18 Categories of Statistical Information That You Just Can’t Find Anywhere Else.” James developed new ways to measure baseball success and found that runs scored were highly correlated with wins. He developed weighted correlations that led to a formula that generated what he called “runs created.” As he developed momentum, he met with a small group of friends, including Sports Illustrated

writer Dan Okrent, at La Rotisserie Française restaurant, in New York City. That is where the concept of “Rotisserie” baseball was born. This has developed into a fantasy sports industry, which is worth nearly $10 billion annually. At that time, the only people interested in these new baseball measurements were the fans. As James continued to develop better measurements, there was one other group that showed interest: player agents. The agents wanted more statistics that validated the value of their clients, the professional baseball players, to justify negotiating larger salaries. Interestingly, the group of people who showed no interest in these better measurements and the application of data science to baseball were the owners and managers of the teams. The people most invested in the outcomes of the games had no interest in changing how they used their data and managed their teams. James, working with a company called STATS Inc., tried to persuade teams that they should use the new measures he had developed. Teams just weren’t interested. Part of the problem was that baseball already had its data company, Elias Sports Bureau. The company had the contract for managing all of baseball’s statistics. Like with the current generation of electronic health records in health care, baseball at that time did not think there was any need to change. The company certainly did not want to admit or believe that the statistics they were paid to collect and publish were poor indicators of player and team value. There was no appetite or incentive for innovation or improvement. The status quo was not challenged again until two entrepreneurs from the financial industry took what they learned about how to use data science applied to financial derivatives, and realized they could do the same thing in baseball. They started a company called AVM (Advanced Value Matrix) Systems in 1994, and approached teams to see if they could consult and apply their data science methods to baseball. Change did not come easily. It wasn’t until the Oakland Athletics were sold to a more frugal ownership group that there was enough financial pressure to make changes to the status quo. The inequities in baseball budgets rose to the level where some teams could afford the best individual players and others could not. Change usually only occurs when the pain of the status quo rises to a level greater than the discomfort of making a change. When the new owners refused to match the salary offers for star players who were plucked away by the wealthy teams, like the Yankees, then the A’s management, with Billy Beane in charge as the A’s general manager, felt the pressure to make changes in how they operated. Billy had read every one of Bill James’ “Baseball Abstract” publications, and he discovered that baseball was not using data appropriately. Paul DePodesta was an intern for the Cleveland Indians when Billy met him. Paul graduated from Harvard University with a degree in economics, but his real passion was the intersection between economics and psychology, a discipline now called behavioral economics. Paul had recently met the Wall Street traders-turnedbaseball data gurus during one of their initial sales calls see Moneyball, page 23

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Legalizing Recreational Marijuana May Be Associated With Uptick in Cyclic Vomiting

egalizing recreational use of marijuana may be related to increased hospitalizations for hyperemesis, researchers at Mayo Clinic have found. Reviewing state inpatient databases for Arizona, Kentucky, Maryland and Washington for 2010-2016, the Mayo ‘The health impacts of that are group found that legalization of recreational marijuana was associated unclear, and in GI, [cannabis with an increase of 0.68 hospitalizations per 100,000 people for canhyperemesis syndrome] is quite nabis hyperemesis syndrome (CHS) a distinctive side effect of heavy (P<0.05), about half of which were charged to Medicaid. This figure repcannabis use. We see it quite a resented a 61% increase in admissions bit in our practice.’ for CHS per 100,000 people over the study period, they said. —Isabel Hujoel, MD, Mayo Clinic In contrast, legalizing medical use of marijuana did not increase hospital admissions, according to the researchers, who submit- Kentucky had not legalized it throughout the study ted their findings to the 2020 Digestive Disease Week period. With no diagnostic code for CHS, investigators (abstract 275). tracked hospitalizations with a primary diagnosis of per“Over the past decade, there’s been a dramatic sistent or cyclical vomiting in conjunction with coding change in terms of legalization of marijuana, both rec- for marijuana abuse. The mean age of CHS hospitalizareational and medical,” Isabel Hujoel, MD, a gastroen- tions was 33 years; half of patients were men and 61% terology fellow at Mayo Clinic in Rochester, Minn., were white. The average length of stay was 2.6 days and and the leader of the study, said. “The health impacts the mean total admission charge was $14,930. of that are unclear, and in GI, CHS is quite a distincLegalization of recreational marijuana was associtive side effect of heavy cannabis use. We see it quite a ated with an increase of $17,474 in hospital charges bit in our practice.” per 100,000 people over the study period. By 2016, Arizona had legalized medical marijuana only, and the brunt of the cost of an admission was carried by

Medicaid, the payor for 50% of CHS admissions that year in all four states. In 2010, Medicaid was the primary payor for 44% of cases. “CHS is underrecognized both in the medical community and the public, and because of that people can go many years undiagnosed,” Dr. Hujoel said. In that time, patients can be subject to myriad tests such as CT scans or be prescribed antinausea medications that may not work. Implementing guidelines on the diagnosis and management of CHS may help minimize associated costs and harms, she said. Public policy initiatives that limit the potency of tetrahydrocannabinol in marijuana or direct state income tax from marijuana toward the cost of medical consequences of use may also be beneficial, she said. Thangam Venkatesan, MD, a professor of gastroenterology and hepatology at the Medical College of Wisconsin, in Milwaukee, and the chief medical advisor of the Cyclic Vomiting Syndrome Association, cautioned that the Mayo researchers may not have accurately defined CHS. “To make a diagnosis of CHS, you need to meet very specific criteria and you need to show that abstinence from cannabis causes cessation of symptoms,” Dr. Venkatesan said. see Legal, page 47

Study Finds Medical Cannabis Stronger Than Necessary for Pain Relief

edical cannabis contains two to three times the tetrahydrocannabinol (THC), the principal psychoactive agent in the drug, needed for effective chronic pain treatment, according to a study in PLoS One (2020;15[3]:e0230167). The researchers report that 90% of

legal cannabis, regardless of program type, contained THC in excess of 15%. “This is relevant because cannabis has demonstrated efficacy in neuropathic pain with low THC concentrations (less than 5% to 10%),” the study noted, which finds the vast majority of products contain recreational-level THC (i.e., >15%).

Researchers at Wake Forest Baptist Health, in Winston-Salem, N.C., collected data on 8,505 cannabis products from all chemotypes—including those rich in THC and cannabidiol (CBD) as well as THC/CBD flowers and pre-rolls—from 653 active, licensed dispensaries with an online presence in the Northeast and West. All northeastern states included in the study and New Mexico sold medicinal cannabis. California, Colorado and Washington legalized cannabis for recreational and medicinal use. “High-concentration products induce intoxicating effects and pose long-term risks if used regularly. Pharmacologically speaking, a treatment rarely starts with the highest dose possible,” lead author Edgar Alfonso Romero-Sandoval, MD, PhD, an associate professor of

anesthesiology at the Wake Forest School of Medicine, said. Kari L. Franson, PharmD, PhD, BCPP, a professor of clinical pharmacy at the University of Southern California, in Los Angeles, agreed. “It is concerning that a patient seeking cannabis may be presented only products with highpercentage THC. This goes against our typical therapeutic approach to start low and go slow with the dosing. “In addition, there can be adverse effects of using high-concentration THC cannabis products,” Dr. Franson, who was not involved with the study, said. “For the naive user, this may involve heart palpitations and anxiety, which may lead to a trip to the emergency department. Prolonged use can lead to cannabis use disorder, see Strong Cannabis, page 47

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

E-Consult Program Saves Time, Resources for GI Clinics

mplementing an enhanced electronic consultation protocol in which gastroenterologists review every outpatient referral and call most patients helps avoid unnecessary trips to the clinic and streamlines endoscopy, a new study has found. “Before we started the e-consult program, we had hundreds of patients on our clinical and endoscopy waiting lists,” Zhouwen Tang, MD, an assistant professor of medicine at the University of Texas at Austin Dell Medical School, said. “That was the impetus for us to start looking at other ways of delivering care. The concept of the e-consult is not new, but where we differed was that we did e-consults with everyone, not just patients [for whom] the referring provider felt it was appropriate.” The researchers evaluated all new outpatient GI referrals between Sept. 6, 2019, and Nov. 27, 2019. Each referral was characterized as leading to one of three outcomes: an endoscopy appointment without a clinic appointment, a clinic appointment only, or recommendations sent to referring provider without endoscopy or clinic visit. As part of the consult, patients were directly called by a physician or nurse. According to a poster submitted to the 2020 Digestive Disease Week (abstract Sa1031), the researchers tallied 759 e-consults during the 58-day study period. Clinic visits were avoided in more than 70% of patients. The e-consults were not particularly time-consuming, with two-thirds completed in less than 10 minutes of physician time, the researchers reported. The average time between a GI referral and the first completion of an e-consult was less than one day. “Approximately 85% of our e-consults were resolved on the same day of referral,” Dr. Tang told Gastroenterology & Endoscopy News. The study demonstrates that enhanced e-consult protocols can help avoid a significant number of unnecessary clinic visits, Dr. Tang said. “The vast majority were conducted without the need for an in-person clinic visit. Additionally, it didn’t take a whole lot of resources, and the time commitment is analogous to what an in-person clinic visit would be.” Dr. Tang encouraged other institutions to consider adopting similar protocols, but he recognized that may not be easy. “One of the major barriers is the payment model,” he said. “For this to be sustainable, you have to have some ways

for your providers to be reimbursed, especially if this were to be extended to a private practice model.” Christian A. Mayorga, MD, and Chenlu Tian, MD, GIs at Parkland Health and Hospital System in Dallas, have extensive experience with e-consultation programs and offered advice on their successful adoption. “We have to ensure primary care providers have confidence that the platform will deliver the quality care they

anticipated when they submitted an e-consult referral,” Dr. Tian said. “We also need specialists who are willing to answer e-consults. There also has to be very good communication between the specialists and the primary care providers to make it a success.” Sharing an electronic health record system is another important component, Dr. Mayorga added. “That way, you can see the e-consult order submitted by the referring provider, and then

the specialist’s response is recorded as an official note in the patient’s record.” While institutions may choose to adopt either a telephone or an electronic consultation model, Dr. Tian said the most important factor for patients is that they are receiving specialist input into their disease management. —Michael Vlessides Drs. Mayorga, Tang and Tian reported no relevant financial conflicts of interest. The abstract was named a DDW Poster of Distinction.

Table. Outco Outcome Avoided clinic Scheduled for without clinic

Recommended endoscopy

Scheduled in c

Scheduled in c patient could n

EHR continued from page 1

Safeguard Against Uncertainty Ancillary lines could help build resilience in a specialty that often derives the bulk of its revenue from procedural productivity, a business model whose vulnerabilities the COVID-19 pandemic starkly revealed. “We’re seeing an uptick in some patients returning to physician offices, but I would argue that most patients still have COVID-19–related reservations about entering a health care facility,” Mr. Fraser said. “If you combine that with the projected fall wave of infections, we could see another severe drop. That trend will reverse once we have a vaccine. In the interim, I think it’s critical for groups to mine their EHRs for other clinical service lines they can offer.” Reed Hogan, MD, is a gastroenterologist with GI Associates and Endoscopy Center in Jackson, Miss., a practice that relies heavily on its ancillary services.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Dr. Hogan credits that diversity of revenue sources for keeping his group afloat lately. “We never closed. Some places closed their endoscopy centers and are just now reopening, which is hard—next to impossible,” he said. With broad training in irritable bowel disease, inflammatory bowel diseases, nutrition and hepatology, gastroenterologists are well suited to diversify beyond screening for colorectal cancer, which, although important, is elective, Mr. Fraser said. “It’s critical for groups to understand their vulnerability, and to identify potential patient populations who may warrant follow-up, screening or treatment” for other conditions, he said. As an example, mining the EHR for data on patients with hepatitis B and C infections, alcoholism and fatty liver disease could identify those at high risk for nonalcoholic steatohepatitis, who can be screened easily in the office with FibroScan (Echosens). “The reimbursement isn’t substantial, but it identifies your at-risk patients for surveillance at appropriate intervals,” Mr. Fraser said. “Or you can enroll them into clinical trials for the 30-plus new NASH drugs

Data Mining By Disease State IBS Outsourcing to ModifyHealth to help patients with the low-FODMAP diet; ancillary income between $100 and $150 per patient enrolled

Fatty Liver FibroScan (Echosens) in office; ancillary income roughly $30-$40 per patient but activates at-risk patients for additional screening and potential clinical research protocols

NASH Clinical research; having formal clinical research entity or joint venture research entity. Ancillary income ranges between $100,000 and $500,000 annually or more, based on number of protocols and enrollment numbers. Joint venture structures are with ObjectiveGI and ideal for smaller groups

Hemorrhoids In-office banding or ablation, with ancillary income ranges that are substantial and dependent on treatment frequencies and severity of hemorrhoids

Advanced Imaging Cellvizio (Mauna Kea Technologies) in the ambulatory surgery center as an adjunct to esophagogastroduodenoscopy with biopsy nets $600-$650 additional facility fee for patients with high-grade dysplasia Source: Scott Fraser.

in development. This means establishing a separate research organization or partnering with a research group to create a joint venture research organization. It can be a lucrative ancillary line and is a huge valueadd for your patients.” Dietary management and hemorrhoid treatment are also services that, if warranted by your patient population, are easy to establish, he added.

Independent Revenue Stream Patient data, if extracted and de-identified, could prove attractive to third parties willing to pay for the information, according to Ian Strug, a co-founder of Virgo, a company that develops automation and artificial intelligence for endoscopy. “A patient’s medical history and the ways they’ve interacted with the health care system are valuable to health care firms working with technology. There are a number of players,” Mr. Strug said.

In pharmaceutical development, for example, EHR data may help companies evaluate phase 2 drugs in patients currently taking them, potentially speeding the path to a randomized controlled trial. “That sort of evidence has been considered anecdotal, but we haven’t had the computing power to look at hundreds of thousands of patients in one consolidated model,” Mr. Strug said. Insurance companies could use the data to better gauge the health of patients for actuarial purposes. Developers of AI technologies see EHR systems as a source for harvesting the immense volume of data they need to build their algorithms. “To get that data, you need a product that either feeds you that data or you need to buy it,” Mr. Strug said. In addition, entities involved in public health may be looking for ways to access EHRs for their own initiatives. “Any private company interested in building software that helps manage population health needs data,” he said. “For public health departments, it would be good to have access to data that goes beyond your Medicare/Medicaid population.” Dr. Hogan said he wasn’t aware of any practices selling their EHR data. “But it’s a smart idea—I like it. Our data banks are an intelligent resource. I’d be curious to learn how you would convert that into useful, revenue-generating information,” he said. A first step in figuring out what data to extract and how to extract them is to work with a technology representative. “Whoever sold you the software will be the best resource to help you start building customized reports, or point you in the direction of en suite software tools available to get that information,” Mr. Strug said. Formatting and packaging data sets may not be much of an issue. “The parties interested will help define the necessary data elements and format; the goal is to provide a holistic data set containing all the data points your consumer would want,” Mr. Strug said. A concern that people have is that their data could fall into the wrong hands. “Could someone reveal everyone in the data set? Theoretically, yes. But if you can ensure that you’ve anonymized a data set so that there is no string of data that can identify an individual, that seems unlikely,” Mr. Strug said. Other issues are up-front costs and finding a buyer. “Do I hire a salesperson? Do it myself ? All of these things take time and resources,” Mr. Strug said. At this point, however, capitalizing on patient data in this way may be more hypothetical than practical, for several reasons. “I’ve talked with pharmaceutical companies about exchanging data, but there are a lot of legal implications, kickback implications,” Jim Leavitt, MD, the president of Gastro Health, in Miami, said. “I’m not saying there’s no future for this data, but there are a lot of landmines. If you’re mining data for the right reasons—to develop programs to find and treat populations—then maybe, down the road, profiting from that data could be a byproduct. But to think of developing and selling big data primarily as an ancillary service is perverse.” Mr. Strug acknowledged that the ethics of data sharing and the murkiness of HIPAA requirements could be off-putting to physicians. “Folks are squeamish about it,” he said. —Monica J. Smith

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IMPORTANT SAFETY INFORMATION

Talicia contains omeprazole, a proton pump inhibitor (PPI), amoxicillin, a penicillin-class antibacterial, and rifabutin, a rifamycin antibacterial. It is contraindicated in patients with known hypersensitivity to any of these medications, any other components of the formulation, any other beta-lactams or any other rifamycin. Talicia is contraindicated in patients receiving rilpivirinecontaining products. Talicia is contraindicated in patients receiving delavirdine or voriconazole. Serious and occasionally fatal hypersensitivity reactions have been reported with omeprazole, amoxicillin and rifabutin. &ORVWULGLRLGHV GLŕ˘&#x201E; FLOH-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents and may range from mild diarrhea to fatal colitis. Talicia may cause fetal harm. Talicia is not recommended for use in pregnancy.

7DOLFLD PD\ UHGXFH WKH Hŕ˘&#x2021; FDF\ RI KRUPRQDO contraceptives. An additional non-hormonal method of contraception is recommended when taking Talicia. Talicia should not be used in patients with hepatic impairment or severe renal impairment. Acute Interstitial Nephritis has been observed in patients taking PPIs and penicillins. Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs. These events have occurred as both new onset and exacerbation of existing autoimmune disease. The most common adverse reactions (*1%) were diarrhea, headache, nausea, abdominal pain, chromaturia, rash, dyspepsia, oropharyngeal pain, vomiting, and vulvovaginal candidiasis. Please see Brief Summary of Prescribing Information on adjacent pages. 5()(5(1&( 'DWD RQ ŕ˘&#x2030; OH 5HG+LOO %LRSKDUPD k 5HG+LOO %LRSKDUPD /WG $OO ULJKWV UHVHUYHG 7$/

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Post-op NSAIDs Not Linked to GI Bleeding

ncreased risk for gastrointestinal bleeding was not related to use of nonsteroidal anti-inflammatory drugs (NSAIDs) following joint surgery, according to a new study. “While we were recommending that physicians prescribe longstanding, or several weeks of, NSAIDs after surgery, it became apparent to us that it was unclear that this was a safe practice,” Andrew Fleischman, MD, the lead author and a resident at the Sidney

Kimmel Medical College at Thomas Jefferson University, in Philadelphia, said. “While the risks of opioids are obvious, it is less clear what other risks NSAIDs may pose, especially since patients may be at increased risk for GI complications in the postoperative period due to the stress of surgery and use of venous thromboembolism prophylaxis.” In this retrospective study, Dr. Fleischman and his colleagues reviewed

the records of 28,794 patients who underwent hip or knee replacement surgery at their institution. Postdischarge medication use and any additional factors for bleeding were assessed. Nurse navigators made phone calls to patients at 11, 30 and 90 days after surgery to inquire about GI bleeding. The researchers also identified additional episodes of GI bleeding using call administrative codes, call logs and clinical dictations. The study was

BRIEF SUMMARY OF PRESCRIBING INFORMATION TALICIA® (omeprazole magnesium, amoxicillin and rifabutin) delayed-release capsules, for oral use 1 INDICATIONS AND USAGE 1.1 Helicobacter pylori Infection TALICIA is indicated for the treatment of Helicobacter pylori infection in adults. 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of TALICIA and other antibacterial drugs, TALICIA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 2 DOSAGE AND ADMINISTRATION Administer four (4) TALICIA capsules every 8 hours for 14 days with food. Instruct patients to swallow the TALICIA capsules whole, with a full glass of water (8 ounces). Each dose (4 capsules) of TALICIA includes rifabutin 50 mg, amoxicillin 1,000 mg and omeprazole 40 mg. Do not crush or chew TALICIA capsules. Do not take TALICIA with alcohol. If a dose is missed, patients should continue the normal dosing schedule until the medication is completed. Do not take two doses at one time to make up for a missed dose. 4 CONTRAINDICATIONS 4.1 Hypersensitivity Reactions TALICIA is contraindicated in patients with known hypersensitivity to the components of TALICIA: amoxicillin [or other ß-lactam antibacterial drugs (e.g., penicillins and cephalosporins)], omeprazole (or other benzimidazoles [e.g. proton pump inhibitors (PPIs) and anthelmintics]), rifabutin (or any other rifamycins), or to any other component of TALICIA. Hypersensitivity reactions may include anaphylaxis or Stevens Johnson Syndrome, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, rash and urticaria [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. 4.2 Rilpivirine-containing Products Proton pump inhibitors (PPIs), including omeprazole (a component of TALICIA), are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7.1)]. 4.3 Delavirdine The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving delavirdine [see Drug Interactions (7.1)]. 4.4 Voriconazole The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving voriconazole [see Drug Interactions (7.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and fatal hypersensitivity reactions, e.g. anaphylaxis, angioedema, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, interstitial nephritis, and serum sickness have been reported with the components of TALICIA: omeprazole, amoxicillin and rifabutin. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with TALICIA, inquire about history of hypersensitivity reactions to penicillins, cephalosporins, rifamycins, or PPIs. Discontinue TALICIA and institute immediate therapy, if hypersensitivity reactions occur. 5.2 Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of omeprazole, a component of TALICIA and nearly all antibacterial agents, including amoxicillin and rifabutin, which are components of TALICIA and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. CDAD must be considered in all patients who present with diarrhea following proton pump inhibitor and or antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is confirmed, TALICIA should be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.3 Reduced Efficacy of Hormonal Contraceptives TALICIA may reduce the efficacy of hormonal contraceptives. Therefore, an additional non-hormonal highly effective method of contraception should be used while taking TALICIA [see Drug Interactions (7.1)]. 5.4 Acute Interstitial Nephritis Acute interstitial nephritis (AIN) has been observed in patients taking PPIs including omeprazole as well as in patients taking penicillins such as amoxicillin, a component of TALICIA. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue TALICIA if AIN develops [see Contraindications (4.1)]. 5.5 Risk of Adverse Reactions or Loss of Efficacy Due to Drug Interactions Components of TALICIA have the potential for clinically important drug interactions [see Contraindications (4) and Drug Interactions (7)]. Avoid concomitant use of TALICIA with other CYP2C19 or CYP3A4 inducers (e.g. St. John’s Wort, rifampin) as they can substantially decrease omeprazole concentrations. Avoid concomitant use of TALICIA with CYP2C19 and/or CYP3A4 inhibitors (e.g. fluconazole, itraconazole) as it may significantly increase the plasma concentration of component (s) of TALICIA. Depending on the protease inhibitor, the concomitant use of TALICIA should be avoided (e.g. amprenavir, indinavir) or dose adjustments for a concomitantly administered protease inhibitor(s) may be required. Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. Avoid TALICIA in patients on high-dose methotrexate. Concomitant use of clopidogrel and omeprazole reduces the pharmacological activity of clopidogrel. Avoid TALICIA in patients on clopidogrel. When using TALICIA, consider alternative anti-platelet therapy [see Drug Interactions (7)]. 5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. If signs or symptoms consistent with CLE or SLE develop in patients receiving TALICIA, discontinue the drug and evaluate as appropriate. 5.7 Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Avoid TALICIA in patients with mononucleosis. 5.8 Uveitis Due to the possible occurrence of uveitis, patients should be carefully monitored when rifabutin, a component of TALICIA, is given in combination with clarithromycin (or other macrolides) and/or fluconazole and related compounds. If uveitis is suspected, refer for an ophthalmologic evaluation and, if considered necessary, suspend treatment with rifabutin [see Adverse Reactions (6.2)]. 5.9 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at least 14 days after TALICIA treatment and consider repeating the test if initial CgA levels are high [see Drug Interactions (7)]. 5.10 Development of Drug-Resistant Bacteria Prescribing TALICIA either in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling:

presented at the 2019 annual meeting of the American Society of Anesthesiologists (abstract A2226). There were 74 patients (0.26%) who experienced GI bleeding within 90 days of surgery, and 34 of them were hospitalized. Median duration of NSAID use was 3.5 weeks. Patients who experienced GI bleeds were older and more likely to have a history of GI reflux or ulceration than those without these characteristics. Variables that

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)] • Clostridioides difﬁcile-Associated Diarrhea [see Warnings and Precautions (5.2)] • Acute Interstitial Nephritis [see Warnings and Precautions (5.4)] • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6)] • Rash in Patients with Mononucleosis [see Warnings and Precautions (5.7)] • Uveitis [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience with TALICIA 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 safety of TALICIA was assessed in adult patients who were screened and found to be positive for H. pylori infection in one active-controlled (Study 1) and one placebo-controlled (Study 2) clinical trial. Patients received TALICIA, amoxicillin and omeprazole, or placebo every eight hours for 14 consecutive days taken with food. A total of 305 patients received TALICIA in Studies 1 and 2, 227 patients received amoxicillin and omeprazole (as omeprazole magnesium) in Study 1, and 41 patients received placebo in Study 2. These patients had a mean age of 46.4 years (range 18 to 70 years); 62.3% were female, 80.3% were white with 64.2% Hispanic or Latino. Adverse Reactions Leading to Discontinuation Treatment discontinuation due to an adverse reaction occurred in 1% (4/305) of patients receiving TALICIA, <1% (1/227) of patients receiving amoxicillin and omeprazole, and 2% (1/41) of patients receiving placebo. Adverse reactions leading to discontinuation of TALICIA were nausea and vomiting, nausea, nasal congestion, and nasopharyngitis, in one patient each. Most Common Adverse Reactions Selected adverse reactions occurring in *1% of patients receiving TALICIA in Study 1 and 2 are described in Table 1. Table 1: Selected Adverse Reactions Occurring in 1% or Greater of Patients Receiving TALICIA in Studies 1 and 2 Study 1 Study 2 Amoxicillin and TALICIA Placebo Omeprazole (N=77) (N=41) (N=227) n (%) n (%) n (%) Diarrhea 23 (10.1) 18 (7.9) 11 (14.3) 4 (9.8) 17 (7.5) 16 (7.0) 12 (15.6) 4 (9.8) Headachea Nausea 11 (4.8) 12 (5.3) 3 (3.9) 1 (2.4) Abdominal painb 8 (3.5) 11 (4.8) 3 (3.9) 2 (4.9) Chromaturiac 0 0 10 (13.0) 1 (2.4) 6 (2.6) 2 (0.9) 4 (5.2) 0 Rashd Dyspepsiae 5 (2.2) 3 (1.3) 1 (1.3) 0 Vomiting 5 (2.2) 5 (2.2) 1 (1.3) 2 (4.9) Oropharyngeal pain 2 (0.9) 2 (0.9) 3 (3.9) 0 Vulvovaginal candidiasisf 5 (2.2) 5 (2.2) 0 0 a Headache includes: headache and migraine. b Abdominal pain includes: abdominal pain, abdominal pain upper, and abdominal pain lower. c Riboflavin was administered in Study 1 to prevent unintentional unblinding and may have contributed to under-reporting of chromaturia. d Rash includes: rash, rash maculo-papular, rash morbilliform, and urticaria. e Dyspepsia includes: dyspepsia and epigastric discomfort. f Vulvovaginal candidiasis includes: vulvovaginal candidiasis, vulvovaginal mycotic infection, fungal infection, and vaginal discharge + vulvovaginal burning sensation + vulvovaginal pruritus. 6.2 Other Important Adverse Reactions from the Labeling of the Individual Components of TALICIA Additional adverse reactions that occurred in 1% or greater of patients treated with omeprazole or rifabutin alone in clinical trials were as follows: Omeprazole Flatulence, acid regurgitation, upper respiratory infection, constipation, dizziness, asthenia, back pain, and cough. Rifabutin Flatulence, asthenia, chest pain, fever, pain, leucopenia, anemia, anorexia, eructation, myalgia, insomnia, and taste perversion. The following selected adverse reactions occurred in less than 1% of patients treated with rifabutin alone: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, dyspnea, skin discoloration, thrombocytopenia, pancytopenia, and jaundice. 6.3 Post-Marketing Experience with Components of TALICIA Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure. Omeprazole Cardiovascular: angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema Endocrine: gynecomastia Gastrointestinal: pancreatitis including fatal pancreatitis, anorexia, irritable colon, fecal discoloration, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis, fundic gland polyps, gastroduodenal carcinoids in patients with Zollinger-Ellison syndrome on long-term treatment as a manifestation of the underlying condition associated with such tumors Hepatic: fatal hepatic failure or necrosis, hepatic encephalopathy, hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice Metabolism and Nutritional disorders: hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain Musculoskeletal: muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture. Nervous System/Psychiatric: depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, dream abnormalities, tremors, paresthesia, vertigo Respiratory: epistaxis Skin: photosensitivity, urticaria, pruritus, petechiae, purpura, alopecia, dry skin, hyperhidrosis Special Senses: tinnitus, taste perversion Ocular: optic atrophy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision Urogenital: hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain Hematologic: Agranulocytosis, hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis Amoxicillin Gastrointestinal: black hairy tongue Liver: hepatic dysfunction, cholestatic jaundice, cholestasis, acute cytolytic hepatitis Renal: crystalluria Adverse Reaction

TALICIA (N=228) n (%)

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

‘While physicians need to consider the clinical scenario and use good clinical judgment, NSAIDs can be administered safely for an extended duration after surgery.’ —Andrew Fleischman, MD, Thomas Jefferson University

Hemic and Lymphatic Systems: anemia, hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis Central Nervous System: hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness Rifabutin Blood and lymphatic system disorders: agranulocytosis, lymphopenia 7 DRUG INTERACTIONS 7.1 Interactions with Other Drugs and Diagnostics Drug interaction studies with TALICIA have not been conducted. The drug interaction information described here is based on the prescribing information of individual TALICIA components: omeprazole, amoxicillin, and rifabutin. Rifabutin is a substrate and inducer of cytochrome P450 (CYP) 3A enzymes. Omeprazole is a substrate and an inhibitor of CYP2C19, and a substrate of CYP3A4. Co-administration of TALICIA and other drugs that are substrates, inhibitors, or inducers of these enzymes may alter concentrations of rifabutin/omeprazole or other co-administered drugs [See Table 2 below]. Omeprazole magnesium is a PPI. Refer to the prescribing information of the drugs used concomitantly with TALICIA for further information on their interactions with PPIs. Table 2: Interactions with TALICIA When Co-Administered with Other Drugs and Diagnostics CYP2C19 or CYP3A4 Inducers Clinical Impact Decreased exposure of omeprazole when used concomitantly with strong inducers. Prevention or St. John’s Wort, rifampin: Avoid concomitant use with TALICIA [see Warnings and Precautions (5.5)]. Management Ritonavir-containing products: See prescribing information for specific drugs. CYP2C19 or CYP3A4 Inhibitors Clinical Impact Increased blood levels of omeprazole and rifabutin. Voriconazole: Concomitant use with TALICIA is contraindicated [see Contraindications (4)]. Prevention or Fluconazole, posaconazole, and itraconazole: Avoid concomitant use with TALICIA. If Management coadministration cannot be avoided, monitor patients for rifabutin associated adverse events, and lack of anti-fungal efficacy. CYP2C19 Substrates (e.g., Clopidogrel, citalopram, cilostazol, phenytoin, diazepam) plasma concentrations of CYP2C19 substrate drugs or decreased/increased plasma Clinical Impact Increased concentrations of its active metabolite(s). Prevention or Clopidogrel: Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.5)]. Management Avoid concomitant use with TALICIA. Antiretrovirals/Protease Inhibitors Antiretrovirals/protease inhibitors may increase rifabutin blood levels. The effect of PPIs (such as omeprazole in TALICIA) on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development Clinical Impact of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. Delavirdine: Combination treatment with TALICIA and delavirdine is contraindicated [see Contraindications (4)]. Rilpivirine-containing products: Concomitant use with TALICIA is contraindicated [see Prevention or Contraindications (4)]. Management Avoid concomitant use of TALICIA with amprenavir, indinavir, lopinavir/ritonavir, saquinavir/ritonavir, ritonavir, tipranavir/ritonavir, fosamprenavir/ritonavir, or nelfinavir [see Warnings and Precautions (5.5)]. Other antiretrovirals: See prescribing information for specific antiretroviral drugs. Probenecid Clinical Impact Increased and prolonged blood levels of amoxicillin. Allopurinol Increase in the incidence of rashes is reported in patients receiving both allopurinol and amoxicillin Clinical Impact together compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. Prevention or Discontinue allopurinol at the first appearance of skin rash. Assess benefit-risk of continuing TALICIA Management treatment. Warfarin, and Other Oral Anticoagulants Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been in patients receiving amoxicillin and oral anticoagulants and in patients receiving PPIs, Clinical Impact reported including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Prevention or Monitor INR and prothrombin time and adjust the dose of warfarin or other oral anticoagulants to Management maintain the desired level of anticoagulation. Methotrexate Concomitant use of omeprazole with methotrexate (primarily at high doses) may elevate and Clinical Impact prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities [see Warnings and Precautions (5.5)]. Prevention or Avoid concomitant use of TALICIA in patients receiving high-dose methotrexate. Management Digoxin Clinical Impact Potential for increased digoxin blood levels. Prevention or Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug Management concentrations. See digoxin prescribing information. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) can alter the absorption of other drugs due to its effect of reducing intragastric acidity Clinical Impact Omeprazole thereby increasing gastric pH.

Prevention or Management Tacrolimus

predicted GI bleeding included anticoagulant use (odds ratio [OR], 2.0; 95% CI, 1.2-3.4), non-aspirin antiplatelet agent use (OR, 3.3; 95% CI, 1.4-7.7), and aspirin use (OR, 1.7; 95% CI, 1.02.7). Rates of GI bleeding were not associated with type of surgery, comorbidities or body mass index.

New Confidence in NSAIDs Dr. Fleischman offered advice on the optimal dosages of NSAIDs. “In order

Mycophenolate mofetil (MMF): Use TALICIA with caution in transplant patients receiving MMF. See the prescribing information of other drugs dependent on gastric pH for absorption.

Potential for increased tacrolimus blood levels, especially in patients who are intermediate or poor metabolizers of CYP2C19. Prevention or Monitor tacrolimus whole blood levels and adjust dose as per the prescribing information for Management tacrolimus. Drugs Metabolized via the CYP450 Enzymes (e.g., cyclosporine, disulﬁram) Clinical Impact Interactions are reported with omeprazole and other drugs metabolized via the CYP450 enzymes. Prevention or Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when Management taken concomitantly with TALICIA. Oral Contraceptives Concomitant use of amoxicillin and rifabutin with hormonal contraceptives may lead to loss of its Clinical Impact efficacy due to lower estrogen reabsorption and decreased ethinylestradiol and norethindrone concentrations, respectively [see Warnings and Precautions (5.3)]. Prevention or Patients should be advised to use additional or alternative non-hormonal methods of contraception. Management Diagnostic Investigations for Neuroendocrine Tumors PPI-induced decrease in gastric acidity may lead to increased serum chromogranin A (CgA) levels, Clinical Impact which may cause false positive results in diagnostics for neuroendocrine tumors [see Warnings and Precautions (5.9)]. CgA levels at least 14 days after stopping TALICIA treatment and consider repeating the test Prevention or Assess initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial Management iflaboratory should be used for testing, as reference ranges between tests may vary. Urine Glucose Test High urine concentrations of ampicillin or amoxicillin may result in false-positive reactions when Clinical Impact using glucose tests based on the Benedict’s copper reduction reaction that determines the amount of reducing substances like glucose in the urine. Prevention or Glucose tests based on enzymatic glucose oxidase reactions should be used. Management Interaction with Secretin Stimulation Test in gastrin secretion in response to secretin stimulation test may falsely suggest Clinical Impact Hyper-response gastrinoma. Prevention or Test should be performed at least 14 days after stopping TALICIA treatment to allow gastrin levels Management to return to baseline. False Positive Urine Tests for Tetrahydrocannabinol (THC) Clinical Impact There have been reports of false positive urine screening tests for THC in patients receiving PPIs. Prevention or Management An alternative confirmatory method should be considered to verify positive results. Other Laboratory Tests Following administration of ampicillin or amoxicillin to pregnant women, a transient decrease Clinical Impact in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. Clinical Impact

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal reproduction studies, TALICIA may cause fetal harm when administered to pregnant women. There are no adequate and well controlled studies of amoxicillin, omeprazole, or rifabutin (used separately or together) in pregnant women. Use of TALICIA is generally not recommended for use in pregnancy. If TALICIA is used during pregnancy, advise pregnant women of the potential risk to a fetus. 8.2 Lactation Risk Summary Data from a published clinical lactation study reports that amoxicillin is present in human milk. Published adverse effects with amoxicillin exposure in the breast-fed infant include diarrhea. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TALICIA and any potential adverse effects on the breast-fed child from TALICIA or from the underlying condition. 8.3 Females and Males of Reproductive Potential Contraception Both rifabutin and amoxicillin components of TALICIA interact with hormonal contraceptives resulting in lower levels of these contraceptives. Therefore, female patients taking hormonal contraceptives should use an additional non-hormonal highly effective method of contraception while taking TALICIA. 8.5 Geriatric Use Clinical studies of TALICIA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients. 8.6 Renal Impairment It is recommended to avoid the use of TALICIA in patients with severe renal impairment (GFR < 30 mL/min). Amoxicillin is primarily eliminated by the kidney. 8.7 Hepatic Impairment It is recommended to avoid the use of TALICIA in patients with hepatic impairment. In patients with hepatic impairment (Child-Pugh Class A, B, or C) exposure to omeprazole substantially increased compared to healthy subjects. 10 OVERDOSAGE No information is available on accidental overdosage of TALICIA in humans. In case of an overdose, patients should contact a physician, poison control center, or emergency room.

TALICIA is distributed by RedHill Biopharma Inc. Raleigh, NC TALICIA is manufactured in Sweden for RedHill Biopharma Ltd. Tel Aviv, Israel TALICIA is a trademark registered with the U.S. Patent and Trademark Office and used under license by RedHill Biopharma Inc. ©2020 RedHill Biopharma Ltd. All rights reserved. TAL/0050 04/2020

to get the most benefit from adjunct analgesic medications, especially acetaminophen and NSAIDs in the postoperative period, it is important to prescribe these medications on a standing-dose schedule to be taken every day. Instead of attempting to treat pain as needed, the goal is to prevent onset of pain with nonopioid medications.” For providers who may be concerned about NSAID use in the postoperative setting, Dr. Fleischman said the data should give them confidence that increasing NSAID prescribing postoperatively will not come with increases in GI complications. “While there are certain patients who may not be good candidates for extended prescription of NSAIDs, it is not difficult to identify these patients and adjust prescribing practices,” he said. Dr. Fleischman noted that patients with a history of peptic ulcer disease, as well as those taking non-aspirin antiplatelet agents and anticoagulants, demonstrated the highest rates of GI bleeding. “While physicians need to consider the clinical scenario and use good clinical judgment, NSAIDs can be administered safely for an extended duration after surgery,” Dr. Fleischman said. Edward R. Mariano, MD, MAS, an anesthesiologist and a professor of anesthesiology in the Department of Perioperative and Pain Medicine at Stanford University School of Medicine, in California, said “NSAIDs are effective analgesics even after major surgery such as lower-extremity arthroplasty. When given in the right patient population, meaning [those patients] not at elevated risk for GI bleeding, NSAIDs are not associated with an increased odds of GI bleed according to this study. This doesn’t mean give NSAIDs to everyone, but it does provide assurance that the current level of screening for contraindications to NSAIDs may be working.” Dr. Mariano added that, while multimodal analgesic protocols are now commonly recommended for surgical patients, “they should be considered checklists and not recipes.”

—Naveed Saleh, MD, MS Dr. Fleischman reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Expert Picks From DDW: Esophageal Disorders C OMPILED

AND WRITTEN BY

K ATE O’R OURKE

n this installment of “Expert Picks,” Joy Chang, MD, MS, a clinical lecturer in the Division of Gastroenterology and Hepatology at the University of Michigan, in Ann Arbor, highlights research on esophageal disorders submitted to the 2020 Digestive Disease Week.

Abstract 15. Clinical-Physiologic Phenotypes of Laryngopharyngeal h l Reflux: Exploratory Latent Class Analysis (Yadlapati et al) ‘This challenging patient population may be best served with a multidisciplinary approach to laryngeal symptom management, including care from gastroenterologists, otolaryngologists and speechlanguage pathologists.’

EXPERT PICKS Abstract 54. Clinical Success After Per-Oral Endoscopy Myotomy (POEM) Correlates With Distensibility Index on Endoluminal Functional Lumen Imaging Probe (EndoFLIP) Assessment: A Prospective Study

—Joy Chang, MD, University of Michigan

‘Post-POEM endoscopy with EndoFLIP may offer an advantage over highresolution manometry as a more tolerable modality to assess treatment response.’ —Joy Chang, MD, University of Michigan

Abstract 932. Histologic And Symptomatic Improvement Across Multiple Forms of Eosinophilic Gastrointestinal Diseases in ENIGMA, a Randomized, Double-Blind, Placebo-Controlled Trial

‘To date, the pathophysiology of these distal EGIDs is not well understood, and the ENIGMA study highlights important new insights for selecting therapeutic targets for these diseases.’

—Joy Chang, MD, University of Michigan

The aim of this prospective single-center study, performed over 20 months, was to characterize the clinical and physiologic phenotypes of laryngopharyngeal reflux. The study enrolled 43 adults with chronic laryngeal symptoms (dysphonia, sore throat, cough) that lasted more than eight weeks, and for whom data on esophageal high-resolution impedance manometry were available. Subjects completed validated questionnaires (GerdQ, Reflux Symptom Index [RSI]) and provided saliva for pepsin analysis. The mean age was 59.9 years and 24% were men; the mean body mass index was 25.9 kg/m2; and the mean RSI score was 23.8. The researchers identified three distinct subgroups—A, B and C—and 88% of subjects fell into one of these subgroups. All subgroups reported cough (group A, 55%; group B, 95%; group C, 70%). Dysphonia or sore throat were not reported by group A, were infrequent in group B (10%), and were frequent in group C (80%-90%). Heartburn was most frequently reported in group B (48%) compared with group A (9%) and group C (20%). Regurgitation was frequently reported in group A (64%) and infrequent in groups B (19%) and C (10%). The median integrated relaxation pressure in the lower esophageal sphincter was lower in group A (mean, 7 mm Hg) than in groups B (mean, 17 mm Hg) or C (mean, 14 mm Hg). The mean pressure in the upper esophageal sphincter was normal in group A (3 mm Hg) and group B (0 mm Hg), and elevated in group C (20 mm Hg). The researchers observed other distinct patterns across subgroups. For example, patients in group A, compared with group B or C, had higher mean BMI (29 vs. 25 kg/m2 for both groups), higher

proportion of ineffective swallows (30% vs. 12.6% vs. 7.5%, respectively), and higher salivary pepsin (74 vs. 40 vs. 64 ng/mL, respectively). Group A presented with typical symptoms of gastroesophageal reflux. Group B’s presentation suggested a cough reflex physiology, and group C’s was muscle tension hypertonicity with isolated laryngeal symptoms. Distinct physiologic differences might explain variability in treatment response and could help guide phenotype-driven management, the researchers said. Dr. Chang: This exploratory study highlights a common condition and constellation of symptoms frequently shuttled between gastroenterologists and otolaryngologists. The authors identified three distinct phenotypes of suspected laryngopharyngeal reflux based on symptoms and physiologic measures. Patients with laryngeal symptoms of dysphonia, sore throat and cough were clustered into a typical reflux group, and two additional nonreflux groups representing cough reflex physiology and muscle tension hypertonicity. From a practical standpoint, this study points out physiologic differences in patients with laryngeal symptoms and provides preliminary evidence regarding the use of clinical phenotypes to identify the underlying mechanism of a patient’s laryngeal symptoms. This study also suggests this challenging patient population may be best served with a multidisciplinary approach to laryngeal symptom management, including care from gastroenterologists, otolaryngologists and speech-language pathologists. see Picks, page 18

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Picks continued from page 16

Abstract 54. Clinical Success After Per-Oral Endoscopy Myotomy (POEM) Correlates With Distensibility Index on Endoluminal Functional Lumen Imaging Probe (EndoFLIP) Assessment: A Prospective Study (Kolb et al) Per-oral endoscopic myotomy (POEM) is safe and effective for the treatment of achalasia and other spastic esophageal motility disorders. Clinical improvement after POEM can be measured by Eckardt score (ES) and with objective data from high-resolution esophageal manometry and/or a timed barium esophagram, both of which are associated with poor patient tolerance and compliance. The use of an endoluminal functional lumen imaging probe (EndoFLIP) during upper endoscopy is an alternative method of diagnosis that has a potential role in the follow-up of patients after POEM and may be more tolerable for patients. This study sought to prospectively assess the distensibility index (DI) on EndoFLIP after POEM and to determine if ES and DI are correlated. The prospective study included all patients who had undergone assessment with EndoFLIP between November 2017 and November 2019 as part of routine follow-up after undergoing POEM at a tertiary academic medical center. All patients had high-resolution esophageal manometry confirming the diagnosis of achalasia or obstruction of the esophagogastric junction prior to POEM. Clinical success of POEM

was defined as a postprocedural ES of 3 or less, with a dysphagia component of 2 or lower. All patients had endoscopy with EndoFLIP at approximately three months after POEM. A postprocedural DI greater than 2.8 mm2/mm Hg was considered adequate treatment. The study enrolled 33 patients (55% female; mean age, 54 years); 85% had undergone previous therapy including dilation, botulinum toxin or Heller myotomy. Clinical success after POEM was 97%, with significant improvement in ES (mean decreased from 6.91 before POEM to 0.88 after POEM; P<0.001), according to the researchers. All patients achieved a postprocedural DI at 60 mL greater than 2.8 (mean DI, 5.41 mm2/mm Hg) and DI measurements with EndoFLIP correlated with ES. One patient who did not meet criteria for clinical success reported improvement in symptoms (ES, 10 to 4) and had a post-POEM DI of 6 mm2/mm Hg. Reflux esophagitis was reported in 36% of patients; no difference was observed in mean DI in those with or without esophagitis (5.73 vs. 5.22; P=0.78). Two adverse events (6.06%) related to POEM were reported, but none was associated with EndoFLIP.

Dr. Chang: This novel study leveraged EndoFLIP technology to assess clinical improvements in patients with achalasia and esophagogastric outflow obstruction undergoing POEM, many of whom had failed prior endoscopic or surgical therapies. At three months after POEM, nearly all patients experienced significant symptom improvement measured by ES and adequate treatment response measured by DI. Reduction in symptoms correlated with greater post-POEM DI. On post-POEM endoscopy, reflux esophagitis was appreciated in one-third of patients, however, few with Los Angeles grade C-D esophagitis. This study shows improved symptoms after POEM correlate well with normalized DI, and post-POEM endoscopy with EndoFLIP may offer an advantage over high-resolution manometry as a more tolerable modality to assess treatment response. As intraoperative EndoFLIP is now more widely used to determine potential predictors of response, a future application may be the use of EndoFLIP to assess the durability of these responses after POEM.

Abstract 932. Histologic and Symptomatic Improvement Across Multiple Forms of Eosinophilic Gastrointestinal Diseases in ENIGMA, a Randomized, Double-Blind, Placebo-Controlled Trial Of Antolimab (AK002) (Dellon et al) Antolimab (Allakos), an anti‒Siglec-8 antibody, is a novel targeted therapy that depletes eosinophils and inhibits mast cells. This first prospective, randomized controlled trial included 59 patients with eosinophilic gastritis and/or eosinophilic enteritis with or without eosinophilic esophagitis. The researchers found that treatment with antolimab was associated with a significant depletion of tissue eosinophils throughout the GI tract and significant improvement of symptoms, and was generally well tolerated, indicating that further development is warranted, they said. Treatment with antolimab led to significant depletion of GI eosinophils across all compartments investigated, regardless of number of sites involved or site of highest eosinophil infiltration. Overall, patients who received the experimental agent had a 95% mean reduction of tissue eosinophils relative to baseline, versus a 10% mean increase in those who

received placebo (P<0.0001). Total symptom severity improved significantly (–53%) in patients who received antolimab compared with placebo (–24%; P=0.0012). This effect was consistent across patient groups. Among patients with comorbid eosinophilic esophagitis, antolimab treatment resulted in significant depletion of esophageal eosinophils and substantial improvement in dysphagia (–53% mean reduction; –17% in the placebo group). The most common adverse event reported for antolimab was mild to moderate reactions to the infusion, most frequently with the first dose. Dr. Chang: With the rising prevalence, incidence and awareness of eosinophilic esophagitis, interest has been increasing in characterizing eosinophilic GI disorders (EGIDs) affecting the stomach (eosinophilic gastritis), small bowel (eosinophilic

enteritis), and colon (eosinophilic colitis). To date, the pathophysiology of these distal EGIDs is not well understood, and the ENIGMA study highlights important new insights for selecting therapeutic targets for these diseases. Antolimab is a novel therapy that effectively targets eosinophil apoptosis and inhibits mast cells. Treatment resulted in dramatic depletion of tissue eosinophilia and significantly improved symptoms. These findings are encouraging, as the symptoms of eosinophilic gastritis and enteritis can be challenging to manage. Patients with comorbid eosinophilic esophagitis also experienced improvement in dysphagia. As we look forward to the phase 3 study, this drug’s effect on histopathology and symptoms not only presents a promising therapeutic target, but also sheds light on the roles of eosinophils and mast cells ■ in this group of diseases.

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eath rates from liver cancer have increased steadily from 2000 to 2016 among adults aged 25 years and older, bucking a trend of decreasing overall cancer death rates since the 1990s, according to new reports from the CDC. Liver cancer, which was the ninth-leading cause of cancer death in 2000, became the sixth-leading cause in 2016. Jiaquan Xu, MD, from the National Center for Health Statistics, used data from the National Vital Statistics System to determine overall trends in liver cancer deaths, as well as trends in various subpopulations based

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Yearlong Trial Shows SubQ Infliximab Holds Up Against IV Form for IBD

atients with inflammatory bowel disease are one step closer to having a subcutaneous version of infliximab. According to data from a yearlong, randomized crossover trial, the subcutaneous formulation of the biosimilar CT-P13 (Pfizer) was as effective as the IV version in treating both Crohn’s disease and ulcerative colitis. The biosimilar was associated with more injection site reactions than the IV version but was otherwise similar in safety, according to the researchers. They presented the results at the 2020 Congress of the European Crohn’s and Colitis Organisation (oral presentation 24).

The benefits of shifting to a subcutaneous version of infliximab are significant, according to Samir A. Shah, MD, a clinical professor of medicine at the Alpert Medical School of Brown University and the chief of gastroenterology at The Miriam Hospital, in Providence, R.I. “Not only is it inconvenient for many patients to receive an infusion, the actual costs of infusion are higher and it takes time to travel to the infusion clinic,” Dr. Shah, who was not involved in the study, said. “I think subcutaneous infliximab would be good for new outpatient starts see Subcutaneous, page 22

Table. Clinical and Endoscopic Efficacy at Week 54 For Subcutaneous and IV CT-P13 Crohn’s Disease

Subcutaneous CT-P13

IV CT-P13

Clinical responsea at week 54

71.4%

68%

Clinical remissionb at week 54

57.1%

56%

81.6%

71.8%

Ulcerative Colitis Clinical responsec at week 54 d

Clinical remission at week 54

68.4%

61.5%

Mucosal healing for both diseases 66.7% at week 54

69.8%

a Clinical response for Crohn’s disease defined as a decrease of at least 70 points on the Crohn’s Disease Activity Index (CDAI) compared with baseline. b Clinical remission defined as a CDAI score of less than 150 points. c Clinical response for UC defined as a decrease of at least 2 points on the partial Mayo score, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point, or an absolute rectal bleeding subscore of 0 or 1. d

Clinical remission for ulcerative colitis defined as a partial Mayo score of 1 point or lower.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

The Regueiro Report: Best of DDW Part 2 n Part 2 of the two-part edition of The Regueiro Report, Miguel Regueiro, MD, a professor of medicine and the chair of the Department of Gastroenterology, Hepatology and Nutrition at Cleveland Clinic in Cleveland, highlights several abstracts submitted to the 2020 Digestive Disease Week.

Resection Rates Decline In the Era of Biologics Widespread use of biologics has reduced the need for surgery in both adult and pediatric IBD patients, as two DDW studies showed. In one study (abstract Su1961), a team led by Cleveland Clinic researchers examined data from electronic health records of IBD patients treated between 1999 and 2019, at 26 large tertiary health care systems across the country. Of the 165,720 patients with Crohn’s disease and 131,260 patients with ulcerative colitis, 25,170 and 8,520, respectively, received a biologic. None of the patients had a previous bowel resection. Nearly 11% of CD patients and 11.3% of those with UC treated with biologics required a bowel resection during the study period (at least two months after starting treatment), whereas first-time resection rates among people with CD and UC not treated with a biologic were 14.2% and 13.7%, respectively (P<0.001 for both, compared with biologic users). In a separate abstract (Mo1836), French investigators examined data from 1,061 children with IBD treated during three eras of modern IBD therapy: pre-immunosuppressants (1988-1993), pre–anti-TNF (1994-2000), and after anti-TNF agents (2001-2011). They found that resection rates within five years of diagnosis fell from 35% to 30% and then to 20% over the three treatment eras, respectively. However, the use of corticosteroids, hospitalizations and disease progression did not change over this time, according to the researchers. Dr. Regueiro: The message with these two studies is that achieving mucosal healing, in this case through use of biologics early in the course of IBD, can improve the course of disease. Many physicians still take a stepwise approach to pharmacologic treatment with medications that may be less effective at controlling inflammation, but these studies suggest doing so can lead to complications that can be avoided by using more aggressive therapies, such as biologics, early.

Dr. Regueiro: In-person conferences may not resume until 2021, and scheduled conferences likely will convert to some kind of virtual format. The silver lining is that accessing educational content is now easier than ever. DDW has done a great job at converting its in-person program to the virtual setting, and the abstracts I chose touch on a variety of aspects of the medical and surgical management of inflammatory bowel disease.

After Ileocecal Anastomosis, Ring Inflammation Not Huge Concern (Abstract Su1895)

Inflammation at the site of an anastomotic ring is common, but how clinically significant is it? To answer this question, investigators retrospectively examined 93 patients with CD who had undergone ileal resection and had an ileocecal anastomosis. None of the patients were experiencing significant inflammation in the bowel proximal to the anastomosis at the time of surgery. After a median follow-up of 55 months, they found 35.5% of patients developed anastomotic ring inflammation and 42% experienced exacerbation of their disease. The researchers observed no association between the presence of anastomotic ring inflammation and disease worsening. Changing medication resolved anastomotic ring inflammation in 26% of patients. Ring inflammation resolved spontaneously in 11% of cases. Dr. Regueiro: This study is very important. It’s not uncommon to see inflammation along the ileocolonic anastomotic “ring,” and there has always been the question of whether this represents a recurrence of CD. These findings reflect what I have seen in my own practice, namely that inflammation confined to the anastomotic ring does not make a big difference clinically.

Ulcerative Colitis Flares During Pregnancy Treatable (Abstract Su1940) An acute episode of severe UC can be managed successfully and does not typically affect pregnancy outcomes, as this retrospective study found in 20 pregnant women with the condition treated over a 15-year period at two large medical centers. The women had a median pregnancy duration of 21 weeks when they experienced an acute episode of severe UC. Following inpatient treatment with IV corticosteroids—and in half of cases, an anti-TNF agent—90% were colectomyfree six months after hospital admission, 84% after one year, and 64% at four years. Regarding pregnancy outcome, 90% had successful live births, six infants were premature, four infants were of low birth weight, and there were two spontaneous abortions. When the authors pooled their data with the slim body of literature on the topic, they found that 7.7% of pregnant women admitted for an acute episode of severe UC required colectomy during hospitalization.

Dr. Regueiro: Patients with IBD are often young and otherwise healthy, so there’s been a long-standing question of what happens if they have a flare during pregnancy. In this study, researchers looked at patients exposed to medications while pregnant and what they found is reassuring: These hospitalized UC patients can be safely and successfully treated with IV steroids and antiTNF agents.

—David Wild

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Research Strengthens Role Of Environmental Factors in IBD Etiology

ecent data have bolstered the idea that the environment plays a key role in the development of inflammatory bowel disease. Researchers have found that the risk for developing IBD increases over time in immigrants from countries that have low rates of the condition. In a Denmark study, after just one generation, the odds that their Danish-born children will be diagnosed with IBD is the same as that of the country’s population as a whole. “The food these individuals eat and the environment they live in are some of the external factors that could be associated with their IBD risk,” said lead researcher Manasi Agrawal, MD, an advanced IBD fellow at the Icahn School of Medicine at Mount Sinai, in New York City. Dr. Agrawal and her colleagues examined IBD rates between 1997 and 2018 in immigrants to Denmark. They chose that country because of the high prevalence of IBD and the availability of a “well-designed and continuously updated” government-run national registry that is linked to medical data, she said. Using the registry data, the investigators identified over 1.5 million immigrants to Denmark whose country of birth was known. They analyzed the data according to rates of IBD in the immigrants’ country of origin, their age at immigration and their duration of stay in their adopted country. The data set included information from nearly 1.3 million first-generation immigrants and 208,826 second-generation immigrants. The results, which were presented at the 2020 Congress of the European Crohn’s and Colitis Organisation (oral presentation 7), revealed that the incidence of IBD among first-generation immigrants reflected the rates of IBD in their parents’ country of origin for a long period. However, after an average of 20 years of living in Denmark, the risk for Crohn’s disease and ulcerative colitis among first-generation immigrants increased by 26% and 11%, respectively (risk ratio [RR] for Crohn’s disease, 1.26; 95% CI, 1.08-1.46; P<0.0001 and RR for ulcerative colitis, 1.11; 95% CI, 0.99-1.23; P=0.0004). While IBD rates rose slowly among first-generation immigrants, for secondgeneration immigrants Dr. Agrawal’s team found the risk for IBD to be similar to that in the Danish general

population, regardless of the IBD rates in their parents’ country of birth. Ashwin Ananthakrishnan, MD, an associate professor of medicine at Massachusetts General Hospital, in Boston, said the study points to the important role “behavior and lifestyle” play in the etiology of IBD. For example, similar rates of IBD in second-generation immigrants

indicate that “early life exposures, which would be seen only in second-generation immigrants, are particularly relevant in IBD pathogenesis.” Dr. Ananthakrishnan was not involved in the research. At the same time, the rising rate of IBD among first-generation immigrants points to the role of “later-life environmental exposures, most plausibly diet,

but certainly not exclusively restricted to that,” in the onset of IBD, he said. —David Wild Drs. Agrawal and Ananthakrishnan reported no relevant financial conflicts of interest.

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IBD Disparities continued from page 1

This year, long-persistent injustices in the United States have been thrown into sharp relief by the murder of George Floyd, a Black man, by police in Minneapolis, and the COVID-19 pandemic. Mr. Floyd’s death sparked weeks of protests across the country and the world over police brutality and racism, while the SARS-CoV-2 has disproportionately infected and killed people of color in the United States. The CDC reported in June that Blacks and Latinos were five and four times as likely, respectively, as whites, to be hospitalized with the virus. In response to these events, the leading four gastroenterology societies—the American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy and American Association for the Study of Liver Diseases— issued a joint statement in early June condemning racism and discrimination and pledging to invest in and work to reduce inequity in health care. Pfizer and the Crohn’s and Colitis Foundation also announced a request for proposals for projects that would address health disparities among patients with IBD. While the incidence of IBD remains high in the white population, the difference between white and minority patients has been narrowing, Dr. OlivaHemker said. A 2020 review of Medicaid data from four states (California, Georgia, North Carolina and Texas) identified 14,735 patients with IBD, 32% of whom were Black (Inflamm Bowel Dis 2020 May 14. [Epub ahead of print]. https://doi.org/10.1093/ibd/ izaa090). From 1970 to 2010, incidence rates for IBD increased by 39% for white patients and 135% for nonwhite patients, according to research published last year (Therap Adv Gastroenterol 2019;12:1-8).

Subcutaneous continued from page 19

after the first two induction IV doses, and for stable outpatients already on IV infliximab who wish to transition to subcutaneous administration.” Results presented at the United European Gastroenterology Week 2019 (late breaker 02) showed comparable efficacy and safety for subcutaneous and IV CT-P13 in patients with active Crohn’s disease and ulcerative colitis over 30 weeks of treatment. In the current trial, lead researcher Shomron Ben-Horin, MD,

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

The shifting epidemiology could be partly due to increased awareness of the disease in minority groups, leading to more patients receiving a diagnosis, according to Adjoa Anyane-Yeboa, MD, MPH, who recently completed the Commonwealth Fund Fellowship in Minority Health Policy at Harvard University and is joining the staff at Massachusetts General Hospital, in Boston. For some patients, environmental factors also may play a role. For example, Dr. Oliva-Hemker has noticed that the children of immigrants from Latin America and Asia develop IBD at rates similar to their white peers, suggesting that living in the industrialized United States increases the risk for developing IBD (see story, page 21). While the research is limited, studies d e m onstrate that Black patients often suffer more serious consequences from IBD than white patients with the condition. IBD-related hospitalizations (7.3% in nonHispanic Black patients, 3.0% in non-Hispanic white patients, and 2.7% in Hispanic patients) and IBD-related mortality (0.061% in non-Hispanic Black patients, 0.036% in non-Hispanic white patients, and 0.026% in Hispanic patients) were higher in non-Hispanic Black patients compared with non-Hispanic white patients, although the overall disease burden is still lower among minority groups (J Crohns Colitis 2014;8[4]:288-295). These disparities appear to be tied to economics. Patients with IBD who are minorities, have public health insurance, or have a household income below $50,000 annually are two to three times more likely to report moderate or severe disability from the illness, according to a 2019 study (Aliment Pharm Ther 2019; 1-8). Medicaid coverage and lower socioeconomic status were associated with increased in-hospital mortality for patients with IBD in a 2013 review (Inflamm Bowel Dis 2013;19[3]:627-643). Research suggests this disparity also extends to children. the director of the Institute of Gastroenterology at the University of Tel Aviv Sheba Medical Center, and colleagues reported one-year data from the same study in 131 of the study participants. Following two loading doses of 5 mg/kg of IV CT-P13 two weeks apart, 66 patients were randomized to receive subcutaneous CT-P13 beginning at six weeks. Patients whose body weight was less than 80 kg received 120 mg and heavier patients received 240 mg, both every two weeks. Another 65 participants continued on 5 mg/kg of IV CT-P13 every eight weeks until 30 weeks, at which point they were switched to

“I think at the end of the day, a lot of this doesn’t have to do with there being biologic differences,” Dr. OlivaHemker said. “It’s really more environmental, social determinants of disease.” This includes where patients live and work, Dr. Anyane-Yeboa said. Black people with IBD are less likely to receive regular specialty care from a gastroenterologist, she said. Many people can’t take two days off work to get regular colonoscopies, lack child care support needed to attend doctors’ appointments, have to travel long distances to reach specialists, or have no one to drive them regularly to the visits, she said. When Black patients do seek care, they often have to contend with racial bias among doctors and health care workers. “We are all aware there is unconscious bias in how minority patients are treated compared to white patients,” Aline Charabaty, MD, AGAF, the clinical director of gastroenterology and director of the the weight-dependent subcutaneous version of the drug. Four patients who had responded to induction IV treatment but subsequently lost response by week 30 also received the 240-mg dose of subcutaneous CT-P13. According to Dr. Ben-Horin, of the 105 people who completed the full 54 weeks of the study, disease behavior and rates of mucosal healing were similar in each group of patients (Table). Mean predose serum concentrations were higher in the subcutaneous arm, he reported, and switching from IV infusion to subcutaneous injection increased those predose serum concentrations. Roughly three-fourths of patients who received subcutaneous CT-P13 had a treatment-related adverse event, compared with 58.5% of those receiving the IV formulation, but the difference was not significant, the researchers reported. Infection rates were similar between the two groups, at 31.8% and 29.2% for subcutaneous and IV administration, respectively. More localized injection site reactions occurred in patients who received subcutaneous CT-P13, at 22.7%, than in the IV treatment group, at 4.6%. These reactions were grade 1 or 2, and most patients recovered without any treatments, the authors reported. —David Wild

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

AGA Expands Diversity Efforts n response to the ongoing national reckoning over historic racial injustices, gastroenterology organizations are pledging to take transformative action. On July 1, the American Gastroenterological Association announced a multiyear project to address and eradicate disparities among digestive disease patients and practitioners. Members of the AGA Equity Project are working to create a multiyear strategic plan to address six broad, ambitious goals. The effort includes promoting truly equal access to health care, funding innovative research on multicultural patient populations, and creating an inclusive AGA membership and leadership committed to eradicating racism and prejudice

Inflammatory Bowel Disease Center at Johns HopkinsSibley Memorial Hospital, in Washington, D.C., said. Fully understanding and addressing these disparities will take action on many levels, Dr. Anyane-Yeboa said. From an individual provider perspective, telehealth services could provide an avenue for physicians to reach their patients more regularly, according to Dr. Charabaty, who has been using these platforms successfully with her patients throughout the COVID-19 pandemic. Virtual visits can cut down on missed work and other factors that can make in-person visits challenging for some patients. Dr. Charabaty said she also takes time to understand the social and cultural situation of each patient and create an atmosphere of trust in order to identify and address the barriers to care for each patient. However, more systemic solutions are required to fully address these systemic disparities. This starts with

Moneyball continued from page 8

and he was intrigued. Soon after that, Billy Beane hired Paul, and Paul convinced Billy to hire AVM Systems. With the help of Paul and AVM Systems, Billy began to apply data science to the Oakland A’s. Moneyball was the result. Today our health care system’s use of data is similar to where baseball was in the 1990s. We’ve learned many wrong lessons. From reductionist tools, like prospective randomized controlled trials, we’ve learned to apply treatments that seem best for the average patient to all patients, regardless of differences in each local environment and the biologic variability of patient subpopulations. We’ve learned that training to be a doctor should allow us to use our training and experience, without appropriate data, to make treatment recommendations. Probably the most harmful habit of all, we’ve allowed health care leaders to continue to push the growth and volume model despite the harm done not only to

toward “patients, colleagues, and communities.” Sandra Quezada, MD, MS, the co-chair of the AGA Equity Task Force and assistant dean for academic and multicultural affairs at the University of Maryland School of Medicine, in Baltimore, said the initiative seeks to address across the gamut of gastrointestinal diseases. “While it is certainly true that health disparities in many diseases including GI have existed for many years, despite some awareness of these issues, there is a need for greater breadth and depth of knowledge and understanding of not only what disparities in GI health outcomes and health care delivery are

education, cultural sensitivity and mandatory implicit bias training for everyone who interacts with patients, Dr. Oliva-Hemker said. Increased outreach from academic health centers also could proactively engage patients in an underserved community with care services, Dr. Anyane-Yeboa said. And actively cultivating and investing in a more diverse provider community and medical leadership will be crucial, she said.

patients, but to doctors and other caregivers as well. The financial constraints and inequities in health care are worsening and are contributing to more and more harm for patients, employers and in some cases, even for doctors themselves. Tragically, there are reports in the United States of young people dying because they can’t afford insulin. Doctors are dying by suicide at a rate greater than in the general population. A main challenge to make necessary changes in health care is to let go of the pride and the belief that we (doctors, hospitals, insurers, even patients sometimes) know what is best for any given situation. Billy Beane describes the mindset required to make this change in the book: “The hardest thing … is there is a certain pride, or lack of pride to do this right.” Letting go of beliefs and the way we’ve always done things is hard and uncomfortable. But discomfort is a normal and necessary part of learning, and transformation can’t occur without changing our mindsets

experienced by various communities, but also of the underlying explanations for how these disparities developed, in order to disrupt these patterns,” Dr. Quezada said. “The AGA will increase its advocacy work to dismantle the policies and systems that perpetuate health disparities and inequities. Heightened national awareness of racial and social injustice has galvanized the AGA Governing Board to redouble the organization’s efforts to combat disparities and achieve equity. The AGA is committed to providing resources to these efforts, and values collaboration with external organizations to achieve this goal.” —J.M.

“As health care professionals, we need to talk openly about how racism affects our patients and their health outcomes,” Dr. Anyane-Yeboa said. “If we can have these conversations and develop policies and practices to address them, then we can start to dismantle the structures that leave certain patient populations at a disadvantage.”

and the structure for how we care for patients and manage data. There is a major difference between applying data science to baseball and to health care. Ultimately, baseball is a competitive sport—it’s about winning, beating another team. When other major league teams learned to apply data science to their organizations, the advantage for the Oakland A’s was diminished. In fact, just two years after the A’s had tied the Yankees for the most wins during the 2002 season with one of the lowest budgets in baseball, the Boston Red Sox won their first World Series in almost 100 years using the same principles of data science. This data-driven effort was led by Theo Epstein, the new general manager, and Bill James, who was hired by Boston’s owner, John Henry, in 2003. In health care, we should not be competing. We should be focused on a goal that aligns all of us: improving the value of care for all patients with any disease or health problem. When we align around the goal of value and work collaboratively to improve value for patients, we can

—Jillian Mock

apply one of the most important tools of data science: the ensemble model for learning. If every clinical team in each local environment were to implement a value-based continuous learning model and then network the learnings from each clinical team, we could improve value forever. Data science is real, but very different from the reductionist science paradigm we’ve been taught and are functioning under in health care today. Until we feel that the pain of continuing to suffer in this reductionist status quo is worse than the discomfort of learning and applying a new data science paradigm, like Moneyball did for baseball, we will continue to suffer the consequences. I believe the inequities and harm resulting from our current system structure are enough to commit to making this change now. ■ Dr. Ramshaw is a general surgeon and data scientist in Knoxville, Tenn., and a managing partner at CQInsights. You can read more from him on his blog: www.bruceramshaw.com/blog. Editor’s note: The views expressed in this commentary belong to the author and do not necessarily reflect those of this publication.

Complete archives Web-only content Multimedia And more â&#x20AC;Ś

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Nutritional Deficits Confound Celiac Diets Montreal—Nutritional deficiencies are common in celiac patients on a gluten-free diet, regardless of their level of dietary compliance or length of time they’ve adhered to the diet, a new study shows. The findings indicate such deficiencies may be related more to the relative nutritional inadequacy of a gluten-free diet than to malabsorption among these patients, according to the researchers. “Celiac disease is associated with quite a few nutritional deficiencies, which may be explained by malabsorption when the disease is active,” Aseera Jivraj, an undergraduate student at McMaster University in Hamilton, Ontario, said. “We wanted to understand how prevalent these deficiencies are, and how they’re influenced by patients’ compliance with gluten-free diets.” To help evaluate the presence of nutritional deficiencies in celiac disease patients on short- and long-term glutenfree diets, Ms. Jivraj’s group enrolled 169 consecutive patients (median age, 37 years; 76% female) into the study. All participants had biopsy-proven celiac disease. Adherence to a gluten-free diet was validated using the Celiac Dietary Adherence Test and a dietary review by a dietitian. At the time of patient enrollment, the researchers also measured levels of anti-tissue transglutaminase antibody, immunoglobulin A, and a variety of vitamins and minerals.

Of the participants, 63 had been on a short-term gluten-free diet defined as two years or less, and 106 were on a long-term diet defined as longer than two years. Patients in the short-term group had been on a gluten-free diet for a median of one year, compared with a median of five years for those in the

long-term group. Overall, dietary adherence was rated as excellent in 50% of the participants, good in 36% and fair in 14%. However, compliance was superior among patients on the long-term diet: excellent/good, 92% versus 74%, and fair, 8% versus 26%, according to the researchers.

‘I try to educate my celiac patients that just because a diet is gluten-free doesn’t necessarily mean it’s healthy. I think that’s a common misconception, even among physicians. Also, I think physicians should know that deficiencies may develop and [they should] check up on their patients regularly, even if [they] don’t have any GI symptoms.’ —Dawn W. Adams, MD, MS, Vanderbilt University

Yet the analysis found that 82% of patients had persistent symptoms at follow-up, with no differences between the groups, despite the fact that 81% had normal antibody levels (Table). “So, it didn’t matter whether people were on a short-term diet or long-term diet, they still had nutritional deficiencies,” Ms. Jivraj, who presented the findings at the 2020 Canadian Digestive Diseases Week (abstract A23), said. “Each nutrient had a predetermined range,” said Ms. Jivraj, who conducted the study under the supervision of senior author Maria I. Pinto-Sanchez, MD, an assistant professor of gastroenterology at McMaster University. “When patients’ levels fell outside the lower end of the range, they were considered deficient. Likewise, if it fell outside on the upper end, they were considered to have increased levels.” The only mineral that showed consistently high levels in the study’s participants, irrespective of the length of their gluten-free diet, was chromium, which was increased in 74% of patients. Given these findings, the researchers concluded that nutritional deficiencies are frequent in celiac disease patients on gluten-free diets, regardless of their compliance with or duration of the regimen. “It’s incredible to have the high level of adherence that we saw, but see Deficiencies, page 32

Certain Pollutants Associated With Celiac

hile previous research has demonstrated that the origins of celiac disease are largely genetic, a new study reveals that an underlying cause of the disease also may be environmental. The study, submitted to the 2020 Digestive Disease Week (abstract 1120), found that levels of toxic chemicals found in pesticides, nonstick cookware and fire retardants are increased in young people with celiac. “It is not that our study shows that pollutants cause celiac disease. We think it is a combination of pollutants, plus genes, plus exposure to gluten that causes the disease,” said Jeremiah Levine, MD, a pediatric gastroenterologist at NYU Langone Health, in New York City, and the senior investigator on the research project. “Our study establishes the first measurable tiein between environmental exposure to toxic chemicals and celiac disease.” Dr. Levine said he launched the study because of the unexplained increase in the incidence of celiac disease, which affects roughly one in 100 adults worldwide. He has had a long-standing interest in whether environmental issues could be contributing to the increased incidence of gastrointestinal diseases.

While the HLA-DQ2 and HLA-DQ8 genotypes play a clear and important role in the pathology of celiac disease, evidence from mouse models suggests that genetic predisposition and exposure to gluten are not the only factors contributing to the condition, Dr. Levine said. To conduct the study, Dr. Levine’s group prospectively evaluated all children who presented at NYU Langone Hassenfeld Children’s Hospital with

complaints that would raise concerns about the possibility of celiac disease. The researchers then followed the children to determine who had celiac disease and who did not and evaluated their exposure to persistent organic pollutants (POPs). These halogenated, synthetic organic compounds are used in a variety of manufacturing and industrial processes, and are known endocrine disruptors with a plausible link to celiac disease, given the interplay between the endocrine and immune systems, according to the researchers. The study cohort included 30 children and young adults, aged 3 to 21 years, who were newly diagnosed with celiac disease, and 60 other young people without the disease of similar age, sex and race. The researchers found that after controlling for sex, race, age, BMI and genetic susceptibility, patients with higher concentrations of serum p,p’-dichlorodiphenyldichloroethylene (DDE) had double the risk for celiac disease (95% CI, 1.08-3.84). After stratifying by sex, the researchers found higher odds of celiac disease in females with serum concentrations of DDE (odds ratio [OR], 13; 95% CI, 1.54-110), perfluorooctanesulfonic see Pollutants, page 32

THE FIRST AND ONLY FDA-APPROVED ORAL JAK INHIBITOR FOR MODERATELY TO SEVERELY ACTIVE UC1,2

XELJANZ/XELJANZ XR

A MARK OF

R APID, POWERFUL , AND SUSTAINED RESULTS IN UC 1,2

Not an actual patient. Pill not to scale.

INDICATION • XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response or who are intolerant to TNF blockers. • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. IMPORTANT SAFETY INFORMATION SERIOUS INFECTIONS Patients treated with XELJANZ/XELJANZ XR are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids. If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use. • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Avoid use of XELJANZ/ XELJANZ XR in patients with an active, serious infection, including localized infections, or with chronic or recurrent infection. FDA=US Food and Drug Administration; JAK=Janus kinase; UC=ulcerative colitis; XR=extended release.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages.

In the UC population, XELJANZ 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily. The risks and beneﬁts of treatment with XELJANZ/XELJANZ XR should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection, or those who have lived or traveled in areas of endemic TB or mycoses. Viral reactivation including herpes virus and hepatitis B reactivation have been reported. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infection. MORTALITY Rheumatoid arthritis (RA)* patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with XELJANZ 5 mg given twice daily or TNF blockers in a large, ongoing, postmarketing safety study. XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or PsA†. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. *RA=rheumatoid arthritis. XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. XELJANZ 10 mg twice daily is not approved for use in RA. † PsA=psoriatic arthritis. XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs). Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. XELJANZ 10 mg twice daily is not approved for use in PsA.

■ ORAL 2

Not an injection, not an infusion2 • XELJANZ is available in 5 mg or 10 mg twice-daily doses • XELJANZ XR is available in 11 mg or 22 mg once-daily doses See dosage adjustments in XELJANZ/XELJANZ XR full prescribing information.

■ RAPID 1,2

In two 8-week induction studies1,2,a • OCTAVE 1: 18% of patients taking XELJANZ 10 mg twice daily achieved remissionb vs 8% on placebo; P<0.01 (primary endpoint) • OCTAVE 2: 17% of patients taking XELJANZ 10 mg twice daily achieved remissionb vs 4% on placebo; P<0.001 (primary endpoint) Reductions in rectal bleeding and stool frequency2 • Decreases in rectal bleeding and stool frequency Mayo subscores were observed as early as Week 2 in patients treated with XELJANZ (exploratory endpoint)

■ POWERFUL AND

SUSTAINED 1,2

In a 52-week maintenance study1,2,c • 41% on XELJANZ 10 mg twice daily and 34% on XELJANZ 5 mg twice daily achieved remissionb (primary endpoint) vs 11% on placebo; P<0.0001d • 47% on XELJANZ 10 mg twice daily and 35% on XELJANZ 5 mg twice daily achieved sustained corticosteroid-free remissione (key secondary endpoint) vs 5% on placebo; P<0.0001f

LEARN MORE AT XELJANZRESULTS.COM Study Designs for OCTAVE 1, OCTAVE 2, and OCTAVE Sustain (UC-I, UC-II, and UC-III)2: The OCTAVE clinical program included 3 phase 3, randomized, double-blind, placebo-controlled clinical trials. In OCTAVE 1 and 2, two identical, 8-week induction studies, 1139 patients with moderately to severely active UC (598 and 541 patients, respectively) were randomized to XELJANZ 10 mg twice daily or placebo (4:1 ratio). Patients were required to have experienced treatment failure with or intolerance to at least 1 of the following agents: oral or intravenous corticosteroids, azathioprine, 6-MP, or TNF blocker. Patients were permitted to use stable doses of oral aminosalicylates and corticosteroids (prednisone daily dose up to 25 mg equivalent). Concomitant immunosuppressants (immunomodulators or biological therapies) were not permitted. The primary endpoint was remission.b In OCTAVE Sustain, a 52-week maintenance study, 593 patients who had completed the induction studies and achieved clinical response were rerandomized to XELJANZ 10 mg twice daily, XELJANZ 5 mg twice daily, or placebo (1:1:1 ratio). Patients were permitted to use stable doses of oral aminosalicylates, but initiation of corticosteroid tapering was required upon entrance into this study for patients who were receiving corticosteroids at baseline. Concomitant immunosuppressants (immunomodulators or biological therapies) were not permitted. The primary endpoint was remission.b Sustained corticosteroid-free remissione was a key secondary endpoint. XELJANZ 5 mg twice daily is the recommended dosage for maintenance therapy. For patients with loss of response during maintenance treatment, a dosage of 10 mg twice daily may be considered and limited to the shortest duration.

IMPORTANT SAFETY INFORMATION (cont’d) MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. Consider the risks and beneﬁts of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ/ XELJANZ XR in patients who develop a malignancy. Malignancies (including solid cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg twice daily dosing in the UC long-term extension study. Other malignancies were observed in clinical studies and the post-marketing setting including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and

XELJANZ 10 mg twice daily (n=905); placebo (n=234).1 Remission was stringently deﬁned as a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0.2 c Use the lowest effective dose to maintain response.2 d XELJANZ 10 mg twice daily (n=197); XELJANZ 5 mg twice daily (n=198); placebo (n=198).2 e Sustained corticosteroid-free remission was deﬁned as remission (a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0) and not taking corticosteroids for at least 4 weeks prior to the visit at both Week 24 and Week 52 among patients in remission at baseline.2 f XELJANZ 10 mg twice daily (n=55); XELJANZ 5 mg twice daily (n=65); placebo (n=59).2 b

6-MP=6-mercaptopurine; TNF=tumor necrosis factor; UC=ulcerative colitis; XR=extended release.

pancreatic cancer. NMSCs have been reported in patients treated with XELJANZ. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. THROMBOSIS Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inﬂammatory conditions. RA patients who were 50 years of age and older with at least one CV risk factor treated with XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers in a large, ongoing postmarketing safety study had an observed increase in incidence of these events. Many of these events were serious and some resulted in death. Avoid XELJANZ/XELJANZ XR in patients at risk. Discontinue XELJANZ/XELJANZ XR and promptly evaluate patients with symptoms of thrombosis. For patients with UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

IMPORTANT SAFETY INFORMATION (cont’d) THROMBOSIS (cont’d) XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or PsA. In a long-term extension study in UC, four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer. GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. XELJANZ/ XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). HYPERSENSITIVITY Angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ/XELJANZ XR and some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction. LABORATORY ABNORMALITIES Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Monitor lymphocyte counts at baseline and every 3 months thereafter. Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ/XELJANZ XR dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Anemia: Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ/XELJANZ XR should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. If drug-induced liver injury is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until this diagnosis has been excluded. Routine monitoring of liver tests and prompt investigation of the

causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. Lipid Elevations: Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. Manage patients with hyperlipidemia according to clinical guidelines. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR therapy. VACCINATIONS Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy. PATIENTS WITH GASTROINTESTINAL NARROWING Caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation. HEPATIC and RENAL IMPAIRMENT Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. For patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 5 mg twice daily, reduce to XELJANZ 5 mg once daily. For UC patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 10 mg twice daily, reduce to XELJANZ 5 mg twice daily. ADVERSE REACTIONS The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in patients with RA with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infection, nasopharyngitis, diarrhea, headache, and hypertension. The safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in RA patients. Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials for UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster. USE IN PREGNANCY Available data with XELJANZ/XELJANZ XR use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy. In animal studies, tofacitinib at 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings. The relevance of these findings to women of childbearing potential is uncertain. Consider pregnancy planning and prevention for females of reproductive potential.

References: 1. Data on file. Pfizer Inc., New York, NY. 2. XELJANZ [prescribing information]. New York, NY, Pfizer Inc., December 2019.

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

XELJANZ® (tofacitinib)/XELJANZ® XR (tofacitinib) BRIEF SUMMARY OF PRESCRIBING INFORMATION. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, AND THROMBOSIS SERIOUS INFECTIONS Patients treated with XELJANZ/XELJANZ XR are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt XELJANZ/ XELJANZ XR until the infection is controlled. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use. • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens. The risks and beneﬁts of treatment with XELJANZ/ XELJANZ XR should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/ XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MORTALITY Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with XELJANZ 5 mg given twice daily or TNF blockers in a large, ongoing, postmarketing safety study. MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virusassociated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. THROMBOSIS Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inﬂammatory conditions. Rheumatoid arthritis patients who were 50 years of age and older with at least one CV risk factor treated with XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers in a large, ongoing postmarketing safety study had an observed increase in incidence of these events. Many of these events were serious and some resulted in death. Avoid XELJANZ/XELJANZ XR in patients at risk. Discontinue XELJANZ/XELJANZ XR and promptly evaluate patients with symptoms of thrombosis. For patients with ulcerative colitis, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. INDICATIONS AND USAGE Rheumatoid Arthritis XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. Psoriatic Arthritis XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs). • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. Ulcerative Colitis XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response or who are intolerant to TNF blockers. • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biological therapies for UC or with

potent immunosuppressants such as azathioprine and cyclosporine is not recommended. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids. In the UC population, XELJANZ treatment with 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis). Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections. The risks and beneﬁts of treatment should be considered prior to initiating XELJANZ/XELJANZ XR in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR. XELJANZ/ XELJANZ XR should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ/XELJANZ XR should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored. Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are recommended. Tuberculosis Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ/XELJANZ XR. Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ/XELJANZ XR in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be conﬁrmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ/XELJANZ XR. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan and Korea. Mortality Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with XELJANZ 5 mg given twice daily or TNF blockers in a large, ongoing, postmarketing safety study. A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or PsA. For the treatment of UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Malignancy and Lymphoproliferative Disorders Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a malignancy. Malignancies were observed in clinical studies of XELJANZ. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. During the 2 PsA controlled clinical studies there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ. During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1220 patients, 0 cases of solid cancer or lymphoma were observed in XELJANZ-treated patients. In the long-term extension study, malignancies (including solid cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg twice daily. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine. Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC. Thrombosis Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Patients with rheumatoid arthritis 50 years of age and older with at least one CV risk factor treated with XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers in a large, ongoing postmarketing study had an observed increase in incidence of these events. Many of these events were serious and some resulted in death. A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or PsA. In a long-term extension study in patients with UC, four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer. Promptly evaluate patients with symptoms of thrombosis and discontinue XELJANZ/XELJANZ XR in patients with symptoms of thrombosis. Avoid XELJANZ/XELJANZ XR in patients that may be at increased risk of thrombosis. For the treatment of UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids. XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation. Hypersensitivity Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ/XELJANZ XR. Some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections • Mortality • Malignancy and Lymphoproliferative Disorders

• Thrombosis • Gastrointestinal Perforations • Hypersensitivity • Laboratory Abnormalities Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. Rheumatoid Arthritis The clinical studies described in the following sections were conducted using XELJANZ. Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not a recommended regimen for the treatment of rheumatoid arthritis. The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure. The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies.The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment.This limits the interpretation of the long-term safety data with respect to dose. The most common serious adverse reactions were serious infections. The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients. Overall Infections In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively). Serious Infections In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo. In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patientyears) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection. Tuberculosis In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days). Opportunistic Infections (excluding tuberculosis) In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per

100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days). Malignancy In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patientyears for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo. In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily. The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma. Laboratory Abnormalities Lymphopenia In the controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure. Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Neutropenia In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure. There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections. In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials. Liver Enzyme Elevations Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes. In the controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups. In the controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy. Lipid Elevations In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm. • Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm. • Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients. In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy. In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials. Serum Creatinine Elevations In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum

creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-speciﬁed discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical signiﬁcance of the observed serum creatinine elevations is unknown. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in the table below. Common Adverse Reactions* in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis With or Without Concomitant DMARDs (0-3 Months) XELJANZ XELJANZ 5 mg 10 mg Twice Placebo Twice Daily Daily** Preferred Term Upper respiratory tract infection

N = 1336 (%)

N = 1349 (%)

N = 809 (%)

Nasopharyngitis

Diarrhea

Headache

Hypertension

N reflects randomized and treated patients from the seven clinical trials. * reported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo. ** the recommended dose of XELJANZ for the treatment of rheumatoid arthritis is 5 mg twice daily. Other adverse reactions occurring in controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia Infections and infestations: Diverticulitis Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal) Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema Clinical Experience in Methotrexate-Naïve Patients Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients. The safety experience in these patients was consistent with Studies RA-I through V. Psoriatic Arthritis XELJANZ 5 mg twice daily and 10 mg twice daily were studied in 2 double-blind Phase 3 clinical trials in patients with active psoriatic arthritis (PsA). Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of PsA. Study PsA-I (NCT01877668) had a duration of 12 months and enrolled patients who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months. Study PsA-II (NCT01882439) had a duration of 6 months and enrolled patients who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo controlled period. In these combined Phase 3 clinical trials, 238 patients were randomized and treated with XELJANZ 5 mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. All patients in the clinical trials were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (9.5%) patients aged 65 years or older and 66 (13.9%) patients with diabetes at baseline. The safety profile observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety profile observed in rheumatoid arthritis patients. Ulcerative Colitis XELJANZ has been studied in patients with moderately to severely active UC in 4 randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose ranging UC-V) and an open-label long term extension study (UC-IV). Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in

patients receiving placebo in either the induction or maintenance clinical trials were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster. Induction Trials (Study UC-I, UC-II, and UC-V): Common adverse reactions reported in ≥2% of patients treated with XELJANZ 10 mg twice daily and ≥1% greater than that reported in patients receiving placebo in the 3 induction trials were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia. Maintenance Trial (Study UC-III): Common adverse reactions reported in ≥4% of patients treated with either dose of XELJANZ and ≥1% greater than reported in patients receiving placebo are shown in the table below. Common Adverse Reactions* in UC Patients during the MaintenanceTrial (Study UC-III) XELJANZ XELJANZ 5 mg 10 mg Placebo Twice Daily Twice Daily Preferred Term

N = 198 (%)

N = 196 (%)

N = 198 (%)

Nasopharyngitis

Elevated cholesterol levels**

Headache

Upper respiratory tract infection

Increased blood creatine phosphokinase

Rash

Diarrhea

Herpes zoster

Gastroenteritis

Anemia

Nausea

* reported in ≥4% of patients treated with either dose of XELJANZ and ≥1% greater than reported for placebo. ** includes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased. In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed more often in patients treated with XELJANZ 10 mg twice daily. Four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer. Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to 5 mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC. Postmarketing Experience Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed). DRUG INTERACTIONS The table below includes drugs with clinically important drug interactions when administered concomitantly with XELJANZ/XELJANZ XR and instructions for preventing or managing them. Clinical Relevant Interactions Affecting XELJANZ and XELJANZ XR When Coadministered with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ/ XELJANZ XR is recommended

Moderate CYP3A4 Inhibitors Coadministered with Strong CYP2C19 Inhibitors (e.g., ﬂuconazole) Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ/ XELJANZ XR is recommended

Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact

Decreased exposure to tofacitinib and may result in loss of or reduced clinical response

Intervention

Coadministration with XELJANZ/ XELJANZ XR is not recommended

Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact

Risk of added immunosuppression; coadministration with biologic DMARDs or potent immunosuppressants has not been studied in patients with rheumatoid arthritis, psoriatic arthritis, or UC.

Intervention

Coadministration with XELJANZ/ XELJANZ XR is not recommended

USE IN SPECIFIC POPULATIONS All information provided in this section is applicable to XELJANZ and XELJANZ XR as they contain the same active ingredient (tofacitinib). Pregnancy Pregnancy Exposure Registry There is a pregnancy

exposure registry that monitors pregnancy outcomes in women exposed to XELJANZ/XELJANZ XR during pregnancy. Patients should be encouraged to enroll in the XELJANZ/XELJANZ XR pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call the toll free number 1-877-311-8972. Risk Summary Available data with XELJANZ/XELJANZ XR use in pregnant women are insufﬁcient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy (see Clinical Considerations). In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dose of 5 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily, respectively (see Data). The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or ulcerative colitis. 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. Data Animal Data In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, ﬁbula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats). In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits). In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats). Lactation Risk Summary There are no data on the presence of tofacitinib in human milk, the effects on a breastfed infant, or the effects on milk production. Tofacitinib is present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in adults treated with XELJANZ/XELJANZ XR, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours after the last dose of XELJANZ or 36 hours after the last dose of XELJANZ XR (approximately 6 elimination half-lives).

Data Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured. Females and Males of Reproductive Potential Contraception Females In an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dose of 5 mg twice daily and 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings. However, there is uncertainty as to how these animal findings relate to females of reproductive potential treated with the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential. Infertility Females Based on findings in rats, treatment with XELJANZ/XELJANZ XR may result in reduced fertility in females of reproductive potential. It is not known if this effect is reversible. Pediatric Use The safety and effectiveness of XELJANZ/ XELJANZ XR in pediatric patients have not been established. Geriatric Use Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older.The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65. Of the 1156 XELJANZ-treated patients in the UC program, a total of 77 patients (7%) were 65 years of age or older. The number of patients aged 65 years and older was not sufficient to determine whether they responded differently from younger patients. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly. Use in Diabetics As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes. Renal Impairment Moderate and Severe Impairment XELJANZ-treated patients with moderate or severe renal impairment had greater tofacitinib blood concentrations than XELJANZ-treated patients with normal renal function. Therefore, dosage adjustment of XELJANZ/XELJANZ XR is recommended in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis). • Rheumatoid arthritis and psoriatic arthritis patients with moderate or severe renal impairment receiving XELJANZ XR should switch to XELJANZ and adjust the dosage. Mild impairment No dosage adjustment is required in patients with mild renal impairment. Hepatic Impairment Severe Impairment XELJANZ/XELJANZ XR has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. Moderate Impairment XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib blood concentration than XELJANZ-treated patients with normal hepatic function. Higher blood concentrations may increase the risk of some adverse reactions. Therefore, dosage adjustment of XELJANZ/XELJANZ XR is recommended in patients with moderate hepatic impairment. • Rheumatoid arthritis and psoriatic arthritis patients receiving XELJANZ XR should switch to XELJANZ and adjust the dosage. Mild Impairment No dosage adjustment of XELJANZ/XELJANZ XR is required in patients with mild hepatic impairment. Hepatitis B or C Serology The safety and efficacy of XELJANZ/XELJANZ XR have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology. OVERDOSAGE There is no specific antidote for overdose with XELJANZ/ XELJANZ XR. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. In a study in subjects with end stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) = 0.73 (0.15)]. However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus limits the value of hemodialysis for treatment of overdose with XELJANZ/ XELJANZ XR. This brief summary is based on XELJANZ®/XELJANZ® XR (tofacitinib) Prescribing Information LAB-0445-19.0 Issued: December 2019 © 2020 Pfizer Inc. All rights reserved. January 2020

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Table. Nutritional Deficiencies in Celiac Disease Patients On Short- and Long-Term Gluten-Free Diets

Deficiencies

Nutrient

Short-Term Diet (n=63)

Long-Term Diet (n=106)

Copper High Low

2 (2%) 27 (21%)

1 (2%) 5 (11%)

1 (1%) 22 (27%)

0.29

Ferritin High Low

1 (1%) 35 (21%)

0 (0%) 16 (26%)

1 (1%) 19 (18%)

0.36

Albumin High Low

0 (0%) 9 (6%)

0 (0%) 3 (5%)

0 (0%) 6 (6%)

0.52

Selenium High Low

5 (3%) 20 (13%)

2 (4%) 8 (15%)

3 (3%) 12 (12%)

0.99

Zinc High Low

3 (2%) 78 (50%)

0 (0%) 32 (55%)

3 (3%) 46 (47%)

0.15

Iron High Low

2 (1%) 20 (15%)

1 (2%) 9 (18%)

1 (1%) 11 (13%)

0.89

continued from page 25

nutritional deficiencies were commonly seen, even in people who are strictly adherent to the diet,” Ms. Jivraj added. Dawn W. Adams, MD, MS, the medical director of the Center for Human Nutrition at Vanderbilt University Medical Center, in Nashville, Tenn., said the results suggest that nutritional deficiencies may be related more to nutritional shortcomings in gluten-free diets than malabsorption in patients with celiac disease. “I think the gluten-free diet can be restrictive for a couple of reasons,” Dr. Adams said. “First, gluten-free products aren’t necessarily fortified and supplemented, like the gluten-containing products can be. And generally, by avoiding whole grains, you’re likely going to miss out on some essential vitamins and minerals.” Some data also indicate that people with celiac disease might restrict their diets in other ways as well. “Perhaps their diets aren’t as diverse or they’re afraid of eating certain foods because they have a legitimate fear of getting sick,” Dr. Adams added.

P Value

Overall (n=169)

Consequently, gastroenterologists have an important role in suggesting alternative nutrient-rich foods for these patients. “I try to educate my celiac patients that just because a diet is gluten-free doesn’t necessarily mean it’s healthy,” Dr. Adams said. “I think that’s a common misconception, even among physicians. Also, I think physicians

Pollutants continued from page 25

acid (OR, 12.8; 95% CI, 1.17-141), and perfluorooctanoic acid (OR, 20.6; 95% CI, 1.13-375) and in males with serum BDE153, a polybrominated diphenyl ether (PBDE) congener (OR, 2.28; 95% CI, 1.01-5.18). DDE is the main metabolite of dichlorodiphenyltrichloroethane, which was predominately used as an insecticide until U.S. regulators banned the substance in 1972. Perfluoroalkyl substances including perfluorooctanesulfonic acid and perfluorooctanoic acid are commonly used as surfactants and polymers for consumer products and building materials. PBDEs are ingredients in flame retardants in upholstered furniture, mattresses and electronic products. Although many of these substances have been or are being phased out of use, they are resistant to degradation and can accumulate in animal and human tissue. Dr. Levine said the new findings may help to explain why some children with genetic susceptibility develop celiac disease while others remain disease-free. Dr. Levine said the POPs his group analyzed may act by altering tight junctions in the gut, allowing for gliadin—a key protein in gluten—to more easily cross the small intestinal epithelium. Alternatively, POPs may act in an endocrine-disrupting manner by enhancing the immune response after gliadin has crossed the intestinal barrier, he said.

should know that deficiencies may develop and [they should] check up on their patients regularly, even if [they] don’t have any GI symptoms.” —Michael Vlessides Dr. Adams and Ms. Jivraj reported no relevant financial conflicts of interest.

“This study suggests that there may be a role in environmental exposure predisposing patients who are otherwise predisposed to develop celiac disease because of genetics to developing celiac disease, potentially through the effect on the gut barrier or on immune disruption,” Dr. Levine said. “One should look further with regard to the association between exposure to organic pollutants and the development of celiac disease, and in addition, potentially look for other autoimmune diseases that similarly may have underlying environmental triggers.” “This study is not proof of causality, and that is an important point,” said Joseph Murray, MD, a professor of medicine and celiac expert at Mayo Clinic in Rochester, Minn., who was not involved in the research. “This study raises the possibility that maybe these [POPs] are not safe, at least in this example of an autoimmune condition. There is no question that a lot more work will be needed to confirm the association and then to identify or determine if there is a causal relationship between them.” Dr. Murray provided an alternative explanation for the findings. “There is the possibility of what is called reverse causality, that having celiac disease makes your body take up more of these organic substances,” he said. —Kate O’Rourke Drs. Levine and Murray reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

IBD Linked to Depression and Anxiety

100 70 Proportion of patients, %

linically active inflammatory bowel disease is positively correlated with symptoms of depression and anxiety, researchers have found. Previous studies proposed a relationship between depression, anxiety and IBD, but its directionality and causality remain unknown. For the new study, researchers at a tertiary IBD clinic screened consecutive patients for depression and anxiety using the validated Computerized Adaptive Test for Mental Health (CAT-MH), a novel computerized testing technology in which patients used a smart device to take a short test that adapted in length and content based on their previous answers. The screening results were then compared with the patients’ disease activity. Disease activity was assessed through chart review, and the senior author, blinded to the CAT-MH results, determined clinical remission

P=0.016 60% P=0.05

50 40

40% 34%

30 21% 20 10 0 Depression ■ Active disease

Anxiety ■ Clinical remission

Figure. Comparison of proportions of patients with depression and anxiety with clinically active disease and those in remission. status. The researchers also reviewed other disease and patient characteristics, including sex, race, past surgeries, type

of IBD, smoking status and number of discontinued medications. The study involved 100 patients. The

Osteoporosis Underappreciated Risk in Microscopic Colitis

creening for and treating osteoporosis should be routine in the management of microscopic colitis, but is not, a recent study shows. Almost half of the patients in one of the largest registries of microscopic colitis had never been evaluated for bone density even prior to initiating treatment with corticosteroids, the researchers found. “Eighty-two percent of patients with available bone density evaluations were found to have a significant degree of bone loss, fulfilling criteria for either osteoporosis or osteopenia,” Ian Greenberg, MD, an internal medicine resident at the University of Chicago NorthShore, in Evanston, Ill., who helped conduct the study, said. The presence of microscopic colitis is not necessarily the problem. A previously published case-control study failed to show a causative relationship between microscopic colitis and osteoporosis, but recommended that clinicians screen for bone density given the increased prevalence of osteoporosis in these patients (Postgrad Med 2018;130[3]:348-354). “A substantial proportion of these patients have many risk factors for osteoporosis including being female, older and postmenopausal, and having a lower body mass index. Additionally, active smoking is often observed in microscopic colitis,” Dr. Greenberg said. The use of corticosteroids, which often are prescribed for osteoporosis, is a significant risk factor for loss of bone density. For the new study, Dr. Greenberg and his colleagues analyzed data from 192 men and women in a microscopic colitis registry at NorthShore University HealthSystem, in Illinois. Of these patients, 94 (49%) had ever undergone a bone density assessment.

Most patients (91%) were female, with a mean age at diagnosis of 69 years. The majority of patients (76%) had been treated with corticosteroids, typically a long course of budesonide. When compared with age- and sex-matched controls, microscopic colitis patients’ odds ratio (OR) for osteoporosis was more than 50% greater (1.58), but the difference was not statistically significant. However, according to Dr. Greenberg, the selected control group had significantly more bone loss than U.S. estimates of 45% to 55%. The U.S. Preventive Services Task Force (USPSTF) strongly recommends screening for osteoporosis with bone density measurement to prevent osteoporotic fractures in women aged 65 years and older. There is no current guideline for bone scans specifically in people with microscopic colitis. Dr. Greenberg said this gap presents an opportunity to improve screening for osteoporosis through consistently evaluating patients who already fulfill established criteria, in addition to screening patients with multiple risk factors for osteoporosis. Evaluating bone density before initiating long-term corticosteroids would provide the opportunity to try steroidsparing treatments that could reduce the impact of bone loss in these highrisk patients. “Patients with microscopic colitis tend to have multiple risk factors for osteoporosis. Although important, increased bone loss remains an underappreciated problem in this

researchers identified 40 patients with mild and two with moderate depression. Of the mildly depressed patients, 25 (62.5%) were previously undiagnosed, as was one (50%) moderately depressed patient, they reported. Twenty-seven patients tested positive for anxiety, 21 mild and six moderate; 11 of the 21 (52.38%) and three of the six (50%) cases were previously undiagnosed. One patient out of the 100 participants tested positive for suicidal ideation within the preceding month. The researchers found clinically active IBD to be significantly associated with the severity of depression. Patients with clinically active disease had a significantly higher relative risk (RR) for depression (RR, 1.8; 95% CI, 1.1-2.7) (Figure). They also had a higher risk for anxiety, but this increase was not statistically significant (RR, 1.9; 95% CI, see Depression, page 34

condition,” Dr. Greenberg said. He said bone density scans should be a routine evaluation step in this population, but the data from patients at his own institution indicate this step is not being taken with most patients. Hamed Khalili, MD, an assistant professor of medicine at Massachusetts General Hospital and Harvard School of Medicine, in Boston, who has published frequently on microscopic colitis and its risks for other gastrointestinal diseases and mortality, said the new findings, while “interesting,” do not definitively demonstrate that bone density screening is necessary on the basis of microscopic colitis alone. “As microscopic colitis primarily affects postmenopausal women, we know this population is already at high risk of developing osteopenia and osteoporosis,” Dr. Khalili said. But he questioned how treatments for microscopic colitis affect the potential for clinical events related to bone density. “It will be interesting to see if in larger studies, significant differences are observed [for fracture], particularly among patients that require frequent dosing with steroids.” —Ted Bosworth Dr. Greenberg reported no relevant financial conflicts of interest. Dr. Khalili reported financial relationships with Pfizer and Takeda.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Micronutrients as Therapy in the ICU

icronutrient supplementation as a therapy for critically ill patients is receiving increasing attention. However, although excellent mechanistic data support potential benefits, clinical trial data are lacking, according to a presentation at the ASPEN20 Virtual Conference in March.

Stoppe, MD, a critical care consultant at Aachen University in Germany, and another session presenter, told the online attendees. Phil Ayers, PharmD, the chief of clinical pharmacy services at Baptist Medical Center, in Jackson, Miss., said there may be a legitimate role for some micronu-

‘‘Vitamin C, vitamin D, selenium and thiamine are s promising micronutrients for p adjuvant therapy in severe a acute illness. a [But] dosing should be interpreted in light of the limitations of the primary literature.’ —Phil Ayers, PharmD, Baptist Medical Center

“Everyone was super excited about the potential for vitamin D, vitamin C, selenium, thiamine and other micronutrients to improve outcomes in the ICU. But it’s been very difficult to demonstrate the benefits that everyone believed there was going to be,” Keith Miller, MD, a trauma and critical care surgeon at the University of Louisville Hospital, in Kentucky, said. “There have been a lot of big, expensive trials with less than exciting results” (N Engl J Med 2019;381[26]:25292540; N Engl J Med 2013;368[16]:1489-1497). Dr. Miller and other session presenters highlighted some data that suggest improved outcomes with supplementation of certain micronutrients for some subgroups of patients. “With any nutrition study, it is hard to see positive effects of an intervention for all patients,” Christian

trients in critically ill ICU patients—particularly when used in higher than recommended daily doses of some micronutrients. “Vitamin C, vitamin D, selenium and thiamine are promising micronutrients for adjuvant therapy in severe acute illness,” Dr. Ayers, who was not involved in the session, said. “Early supplementation should be considered to prevent or treat deficiency.” But he added that “dosing should be interpreted in light of the limitations of the primary literature.”

Dialing in Vitamin D Vitamin D is known to be critical for bone health and metabolism of calcium and phosphorus. Research over the past 15 years has elucidated several additional roles for vitamin D in human health, particularly related to the immune response during illness. “There

are vitamin D receptors on nearly every cell in the body,” Dr. Miller said. Growing enthusiasm for the vitamin has resulted in studies of its potential role in critical illness. “There are nutrients that have excellent theoretical benefit that have not been well flushed out in trials,” Dr. Miller said. “Vitamin D, however, has been extremely well studied.” Vitamin D deficiency, defined as calcifediol, or 25(OH)D, less than 20 ng/mL, is extremely common in the general population: More than 40%, according to a U.S. study in 2005 and 2006 (Nutr Res 2011;31[1]:48-54). Not surprisingly, it is more common among critically ill patients, and is “certainly associated with poor outcomes,” Dr. Miller noted (Crit Care 2014;18[6]:660). A handful of randomized clinical trials have evaluated the effect of vitamin D supplementation, generally administered enterally as a bolus dose of 540,000 IU. In the VIOLET trial, investigators found no difference in 90-day all-cause mortality for vitamin D– deficient patients given a dose of vitamin D compared with a placebo (N Engl J Med 2019;381[26]:25292540). An earlier trial found that administration of high-dose vitamin D did not reduce mortality overall compared with placebo, but did result in a significant decrease in patients with severe vitamin D deficiency—defined as 25(OH)D less than 12 ng/mL (JAMA 2014;312[15]:1520-1530). “A big problem in critical care trials is the heterogeneity of the ICU patient population,” Dr. Miller said, noting how young patients who may have gunshot injury or had surgery are grouped with older patients, such as those with pneumonia. “Because vitamin D deficiency is so common, you may be less likely to see a benefit if you give the vitamin to everyone in the ICU. You are more likely to see a benefit in specific subgroups.” Another trial investigating the role of the vitamin, VITDALIZE, is ongoing (ClinicalTrials.gov Identifier: NCT03188796). “That will help clarify and target in on some of the subgroups that a lot of clinicians

Depression continued from page 33

0.99-3.5). No other variables were significantly associated with depression or anxiety, the researchers said. The researchers, who presented their findings at the 2020 Crohn’s & Colitis Congress (abstract P038), concluded that gastroenterologists “should consider patients with clinically active disease at higher risk for psychological comorbidities, and include such screening in their routine care.” “The important point here is the fact that inflammatory burden is associated with depression and anxiety and that controlling disease might improve patients’ mental health,” Cindy Traboulsi, MD, the research coordinator at the Rubin Lab, University of

Chicago Medicine, who helped conduct the study, said. “We are currently working on a longitudinal study to see if the patients’ response to the questionnaire changes through different points in time. This way, we can use the patients as their own controls and compare their scores to their disease states and see if this changes.” The findings also point to the need for closer collaboration between GIs and mental health specialists, Dr. Traboulsi added. “A multidisciplinary approach is important to ensure all aspects of patient care are targeted. Mental well-being is a very important aspect of patient care and a closer collaboration can hopefully improve this,” she said.

Laurie Keefer, PhD, the director of psychobehavioral research in the Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, in New York City, called the study “novel in that it offers a faster, technology-based screening option that can be done in clinic with results given in real time. This could empower clinicians to bring up emotional concerns earlier on in treatment.” Dr. Keefer, who was not involved in the study, said she agreed that GIs should screen patients with clinically active IBD for depression and anxiety, “as long as the information is used by the provider in real time to drive a deeper discussion around mental health.”

She noted that the questionnaires administered through CAT, like most screening tools, identify symptoms but do not make a diagnosis of depression or anxiety. “Diagnosis should be done by a qualified mental health professional using standardized criteria that also requires observation of and interview with the patient,” Dr. Keefer said. “The authors are not alone in this conundrum. Using screening cutoffs to reflect diagnoses is commonly done in IBD studies and is a major confounder to our complete understanding of the true link between depression, anxiety and IBD.” —Ajai Raj

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

believe would benefit from supplementation,” Dr. Miller said. “Enterally administered vitamin D is cheap and amazingly safe,” he added. Except for a few cases of hypercalcemia, researchers have not noted many adverse events. “A large, randomized clinical trial demonstrating broad clinical benefit is not yet out there,” he added. “But I think there’s a place for it.”

Vitamin C, Thiamine Data A Mixed Bag Despite the proven importance of vitamin C in immune function and as an antioxidant, research also is mixed on whether supplementation with the vitamin may improve outcomes in critically ill patients, according to Todd Rice, MD, an associate professor of medicine in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt University School of Medicine, in Nashville, Tenn. A 2017 study stirred interest when the authors reported that supplementation with hydrocortisone, thiamine and vitamin C lowered hospital mortality rates compared with a placebo in patients with severe sepsis and septic shock: 8.5% versus 40.4% (P<0.05) (Chest 2017;151[6]:1229-1238). But the study was criticized for its methods that may not have adjusted for all potential confounders. The VITAMINS trial, a more recent randomized study conducted in Australia, did not show any differences in vasopressor-free days, mortality or ICU length of stay between patients receiving hydrocortisone, thiamine and vitamin C and those given hydrocortisone alone (JAMA 2020;323[5]:423-431). “There are some not very good data that says vitamin C improves outcomes in patients with septic shock,” Dr. Rice told the online attendees. “There are other data, also generally flawed, that has not been able to demonstrate improved outcomes. That leaves us in a bit of an area of unknown.” While the medical community awaits further data, should these micronutrients be supplemented in the ICU? Dr. Rice said no supplementation is totally free of risk. Too much vitamin C can cause kidney stones in the urinary tract, for example. “But the bigger issue is that vitamin C interferes with a bunch of assays,” Dr. Rice said. Vitamin C can elevate the glucose readings of some glucometers due to ascorbate oxidation on the surface of electrochemical strips contained in these devises. This can force lab tests and risk a non-hyperglycemic patient receiving insulin (Chest

2018;154[1]:228-229). Dr. Rice noted that this accuracy issue does not occur with the spectrophotometric or calorimetric-based methods used in clinical core laboratories. The role of thiamine level alone in critical care also is murky. “We don’t know a ton about thiamine supplementation in critical illness,” said Dr. Rice, pointing to one study that found a lower mortality rate among patients given thiamine for septic shock (Crit Care Med 2018;46[11]:1747-1752). “But we need a prospective trial to see if

thiamine really works.” Meanwhile, thiamine, also known as vitamin B1, does not appear to pose any risk for adverse effects. “So giving thiamine is probably not unreasonable,” Dr. Rice said. “But with the conflicting data, we don’t use it as a treatment.”

Uncertainty Over Selenium Yet more uncertainty surrounds supplementation with selenium, according to Dr. Stoppe. Research has linked low selenium levels with organ failure in ICU patients (R2=0.42; P<0.01) (Br

J Anaesth 2007;98[6]:775-784). The relationship was more pronounced when organ failure was associated with an infection such as severe sepsis. A 2013 review found selenium supplementation reduced the relative risk (RR) for death by 17% among critically ill patients with sepsis (RR, 0.83; 95% CI, 0.70-0.99; P=0.04) (PLoS One 2013;8[1]:e54431). A more recent meta-analysis found no significant differences in mortality among ICU patients (Crit Care 2016;20[1]:356) in see Micro, page 46

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

EHR Add-on Could Help Predict Advanced Fibrosis lthough no guidelines exist for primary care physicians to refer patients with non-alcoholic fatty liver disease to a specialist, more than one in four patients presenting to a hepatologist for the condition may already have advanced fibrosis. A new formula added to electronic health records could help. “Patients are referred to us for fatty liver due to random reasons, such as elevated alanine aminotransferase [ALT] or abnormal imaging,” said Dina Halegoua-DeMarzio, MD, the director of the Jefferson Fatty Liver Center at the Sidney Kimmel Medical College at Thomas Jefferson University, in Philadelphia. “But there didn’t seem to be any standard reason why they would be referred to us, so we wanted to look more closely at it. And it was shocking that so many patients presented to us already with advanced stages of fibrosis that could have possibly been treated much more easily at an earlier stage.”

HEPATOLOGY IN FOCUS Progress against biliary artesia slow page 37 but steady ‘Studies have shown that the sooner you have the Kasai procedure after diagnosis of biliary atresia, the better your five-year survival rates.’ —Cara Lynn Mack, MD

Vax status poor in liver patients page 41 ‘That’s something that can begin with primary care physicians and community gastroenterologists.’ —Kenneth E. Sherman, MD, PhD

Noninvasive test may predict outcomes of liver disease page 43 ‘We think the biggest benefit of the test is in early cirrhosis. In those patients, MELD doesn’t really help stratify them as low or high risk.’ —Mohammad Amin Fallahzadeh, MD

Dr. Halegoua-DeMarzio and her colleagues used Endoscopy News. “Also, a diagnosis of diabetes—as noted vibration-controlled transient elastography (VCTE) by elevated A1c—was significantly associated with havwith FibroScan (Echosens) to examine patients’ fibrosis ing advanced fibrosis on presentation.” stage upon their initial presentation to hepatologists for NAFLD. They then used logistic regression analysis of serum metabolic markers to identify a formula that could help predict the likelihood of a patient with NAFLD having severe fibrosis. In a study submitted to the 2020 Digestive Disease Week (abstract Sa1569), the researchers examined the charts of 116 men ‘It was shocking that so many patients presented and women with NAFLD presenting to Jefferson Fatty Liver to us already with advanced stages of fibrosis Center between July 2015 and April 2018. that could have possibly been treated much more They also performed unieasily at an earlier stage.’ variate and multivariate analy—Dina Halegoua-DeMarzio, MD, Jefferson Fatty Liver Center sis of serum metabolic markers between patients who were found The researchers also created a formula that comon VCTE to have minimal fibrosis (F0-F2) and their bines the two variables to calculate the probability of counterparts with severe fibrosis (F3-F4). At the first documented hepatology visit, FibroScan fibrosis: probability = eR/(1+eR), where R = –8.56 + screening predicted 53.5% of patients with F0 or F1 0.052*AST + 0.89*A1c. “We tried to take it a step further to see if there was NAFLD, 19.8% with F2 NAFLD, 12.9% with F3 NAFLD, and 13.8% with F4 NAFLD. Among 35 some way we could make this useful to primary care docpatients who also had a liver biopsy, FibroScan and tors,” she said. “There are a few other calculations out biopsy results were found to be consistent in terms of there, but they can be a bit complicated.” Rohit Loomba, MD, MHSc, the director of the F0-F2 and F3-F4 groupings in 68.6% of cases. Univariate analysis showed that several factors dif- NAFLD Research Center at the University of Califorfered significantly between the F0-F2 and F3-F4 groups, nia at San Diego, said he was impressed with the potenincluding high-density lipoprotein (P=0.03), hemoglo- tial utility of the formula, although the data requires bin (Hb)A1c (P=0.0001), aspartate aminotransferase validation in larger studies. (AST; P=0.0001), and ALT (P=0.0009). “This study provides data on the use of noninvasive On logistic regression multivariate analysis, only biomarkers in clinical settings and how clinicians can AST (odds ratio, 1.13; P=0.01) and HbA1c (odds ratio, utilize these in their clinical practice to risk-stratify 2.18; P=0.05) were significantly different between the patients with NAFLD,” Dr. Loomba said. “More importwo groups. The optimal cutoffs to identify advanced tantly, it provides cut-points for AST and HbA1c that liver fibrosis on FibroScan for these two factors were may be clinically actionable.” —Michael Vlessides greater than 43 U/L for AST and greater than 6.6% for HbA1c. “It’s interesting because AST is sometimes not as Drs. Halegoua-DeMarzio and Loomba reported no relevant financial conflicts of interest. focused on as much as ALT within the medical community,” Dr. Halegoua-DeMarzio told Gastroenterology &

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Research Cracking Hard Case Of Pediatric Biliary Atresia

evastating though it is, the grip of biliary atresia may be lessening on pediatric populations around the world, thanks to recent scientific advances. The etiology of the condition remains unknown, but it is currently believed that children with a genetic predisposition to the disease suffer a prenatal bile duct injury triggered by either a viral infection or toxin. Such an injury is followed shortly after birth by autoinflammatory and autoimmune responses that further damage the biliary tree, leading to fibrosis. “Upon diagnosis of biliary atresia, extrahepatic remnants are removed and a Kasai hepatoportoenterostomy is performed in an attempt to reestablish bile flow,” Cara Lynn Mack, MD, a professor of pediatrics and gastroenterology, hepatology and nutrition at the University of Colorado Anschutz Medical Campus School of Medicine, in Aurora, said. “The sooner you intervene with the Kasai procedure, the better the outcomes.” Risk factors for the development of biliary atresia are numerous and are influenced by geography. Certain indigenous people in New Zealand have the world’s highest rates of occurrence, with an incidence of one in every 920 live births. In contrast, the disease

is least common in Europe, affecting one in every 12,000 live births. “The reasons for these differences in geographic occurrence are not well understood and likely reflect both genetic and environmental susceptibilities,” Dr. Mack said. Other risk factors include female sex, genetic mutations associated with laterality defects for splenic malformation, and preterm birth or low birth weight. Currently, liver biopsy is a mainstay of diagnosing biliary atresia, although emerging diagnostic biomarkers may soon obviate the need for biopsy. One biomarker is direct bilirubin level, which a 2011 investigation (Pediatrics 128[6]:e1428-e1433) of 61 infants with biliary atresia found was significantly higher in newborns with the disease than in healthy ones (1.4 vs. 0.19 mg/dL; P<0.0001). In addition, matrix metalloproteinase-7 (MMP-7) has been shown to be a sensitive diagnostic biomarker for biliary atresia. In a 2017 trial in Science Translational Medicine (9[417]:eaan8462), researchers used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia to identify potential biomarkers of disease.

“They found that patients with biliary atresia had significantly higher levels of MMP-7 compared with other liver diseases and normal controls,” Dr. Mack said. “When they combined MMP-7 levels with gamma-glutamyl transpeptidase, there was a 95% positive predictive value for the diagnosis of biliary atresia.” A study showed MMP-7 also may be correlated with severity of liver fibrosis and the risk for liver transplantation (J Pediatr 2019;208:30-37.e1). Researchers have found that levels of serum autotaxin predict outcomes in patients with biliary atresia, Dr. Mack said. Finally, research has identified the utility of the infant stool color card as a potential diagnostic modality for biliary atresia. In a 2011 article in Hepatology (53[1]:202-208), a team in Taiwan reported that a screening program using the card significantly increased the percentage of infants with biliary atresia who underwent a Kasai procedure in the first 60 days of life, compared with historical controls. “As part of the screening, the mother is given the stool color card at the time of discharge from the nursery,” Dr. Mack said. “If the baby develops the acholic stool colors, the mother is advised to contact the physician and be seen immediately to work up for biliary atresia.” Several clinical and molecular markers of outcome have also been identified. One of the most robust is the timing of the Kasai procedure. “Studies have shown that the sooner you have the Kasai procedure after diagnosis of biliary atresia, the better your five-year survival rates,” Dr. Mack said. In addition, serum total bilirubin level at three months after the Kasai procedure has been found to predict two-year outcome in biliary atresia (J Pediatr 2016;170:211-7.e1-2). That trial concluded that transplant-free survival at two years was significantly greater among infants with serum total bilirubin below 2 mg/dL than above that value (86% vs. 20%; P<0.0001). Like Dr. Mack, Douglas Mogul, MD, PhD, recognized the importance of diagnosing the disease as early as possible. “In biliary atresia, time to diagnosis and intervention through the Kasai procedure is one of the biggest predictors for outcomes in this terrible disease,” Dr. Mogul, an assistant professor in pediatric gastroenterology at Johns Hopkins School of Medicine, in Baltimore, said. “Identifying these patients at the earliest possible moment is one of the few things we can do to change the trajectory for children with biliary atresia. Consequently, there is a tremendous need for rapid, sensitive and specific biomarkers for this disease, and it’s exciting to learn that MMP-7 may fit these criteria.” —Michael Vlessides

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DIFFERENT QUESTIONS. SAME ANSWER. EPCLUSA.

IS HE TREATMENTa EXPERIENCED WHAT IS HIS GENOTYPE

IS SHE TREATMENT-NAïVE

DOES SHE HAVE COMPENSATED CIRRHOSIS

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In EPCLUSA clinical trials, treatment-experienced patients had failed a Peg-IFN + RBV–based regimen with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir). Peg-IFN = peginterferon alfa; RBV = ribavirin.

INDICATION EPCLUSA is indicated for the treatment of adults with chronic hepatitis C virus (HCV) GT 1-6 infection without cirrhosis or with compensated cirrhosis.

IMPORTANT SAFETY INFORMATION BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with EPCLUSA. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment

with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV coinfected patients for hepatitis ﬂare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. WARNINGS AND PRECAUTIONS • Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with EPCLUSA due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvircontaining regimen. In patients without alternative viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

CHALLENGES MATTER WHEN CHOOSING AN HCV TREATMENT

CONFIDENTLY TREAT WITH EPCLUSA

% overall cure rate in clinical trials GT 1-6 NC/CC patients1 (n=1015/1035; ASTRAL-1, -2, -3 studies)b

Sustained virologic response (SVR12) was the primary endpoint and was deﬁned as HCV RNA <15 IU/mL at 12 weeks after the end of treatment.1 Achieving SVR12 is considered a virologic cure.2

DURATION

PILL

ONCE A DAY

• 12 weeks with or without food1 • Protease inhibitor-free1

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Randomized trials in TN and TEa subjects without cirrhosis or with compensated cirrhosis1 ASTRAL-1: Double-blind, placebo-controlled trial in GT 1, 2, 4, 5, or 6 subjects (N=740). GT 1, 2, 4, or 6 subjects were randomized 5:1 to receive EPCLUSA or placebo for 12 weeks; GT 5 subjects received EPCLUSA for 12 weeks. ASTRAL-2: Open-label trial in GT 2 subjects (N=266). Subjects received EPCLUSA or SOF + RBV for 12 weeks. ASTRAL-3: Open-label trial in GT 3 subjects (N=552). Subjects received EPCLUSA for 12 weeks or SOF + RBV for 24 weeks. CC = compensated cirrhosis; GT = genotype; NC = non-cirrhotic; SOF = sofosbuvir; TE = treatment-experienced; TN = treatment-naïve. References: 1. EPCLUSA [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2019. 2. US Department of Health and Human Services, Center for Drug Evaluation and Research. Guidance for industry. Chronic hepatitis C virus infection: developing direct-acting antiviral drugs for treatment. November 2017.

WARNINGS AND PRECAUTIONS (cont’d) • Risk of Reduced Therapeutic Effect Due to Concomitant Use of EPCLUSA with P-gp Inducers and/or Moderate to Potent Inducers of CYP2B6, CYP2C8 or CYP3A4: Rifampin, St. John’s wort, and carbamazepine are not recommended for use with EPCLUSA as they may signiﬁcantly decrease sofosbuvir and/or velpatasvir plasma concentrations. ADVERSE REACTIONS • The most common adverse reactions (≥10%, all grades) with EPCLUSA were headache and fatigue. DRUG INTERACTIONS • Coadministration of EPCLUSA is not recommended with topotecan due to increased concentrations of topotecan. • Coadministration of EPCLUSA is not recommended with proton-pump inhibitors, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine,

DRUG INTERACTIONS (cont’d) efavirenz, and tipranavir/ritonavir due to decreased concentrations of sofosbuvir and/or velpatasvir. Consult the full Prescribing Information for EPCLUSA for more information on potentially signiﬁcant drug interactions, including clinical comments. Please see Brief Summary of full Prescribing Information for EPCLUSA, including BOXED WARNING on the following page.

EPCLUSA® (sofosbuvir 400 mg and velpatasvir 100 mg) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only. BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with EPCLUSA. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and posttreatment follow up. Initiate appropriate patient management for HBV infection as clinically indicated.

INDICATIONS AND USAGE EPCLUSA is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection: • Without cirrhosis or with compensated cirrhosis • With decompensated cirrhosis for use in combination with ribavirin (RBV) CONTRAINDICATIONS EPCLUSA and RBV combination regimen is contraindicated in patients for whom RBV is contraindicated. Refer to the RBV prescribing information for a list of contraindications for RBV.

WARNINGS AND PRECAUTIONS Risk of HBV Reactivation in Patients Coinfected with HCV and HBV: HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV DAAs and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients with serologic evidence of resolved HBV infection (HBsAg negative and hepatitis B core antibody (anti-HBc) positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increase in aminotransferase levels; and, in severe cases, increases in bilirubin levels, liver failure, and death can occur. Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with EPCLUSA. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with EPCLUSA and during posttreatment follow up. Initiate appropriate patient management for HBV infection as clinically indicated. Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen (HARVONI [ledipasvir/sofosbuvir]). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown. Coadministration of amiodarone with EPCLUSA is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered EPCLUSA: Counsel patients about the risk of serious symptomatic bradycardia; and cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who are taking EPCLUSA who need to start amiodarone therapy due to no other alternative viable treatment options should undergo similar cardiac monitoring as outlined. Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting EPCLUSA should also undergo similar cardiac monitoring as outlined. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems. Risk of Reduced Therapeutic Effect Due to Concomitant Use of EPCLUSA With Inducers of P-gp and/or Moderate to Strong Inducers of CYP: Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to potentially reduced therapeutic effect of EPCLUSA. The use of these agents with EPCLUSA is not recommended. Risks Associated with RBV and EPCLUSA Combination Treatment: If EPCLUSA is administered with RBV, the warnings and precautions for RBV apply to this combination regimen. Refer to the RBV prescribing information for a full list of the warnings and precautions for RBV.

ADVERSE REACTIONS Subjects without Cirrhosis or with Compensated Cirrhosis: The adverse reactions data for EPCLUSA in patients without cirrhosis or with compensated cirrhosis were derived from three Phase 3 clinical trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3) which evaluated a total of 1035 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV, who received EPCLUSA for 12 weeks. The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received EPCLUSA for 12 weeks. The most common adverse reactions (at least 10%) were headache and fatigue in subjects treated with EPCLUSA for 12 weeks. Adverse reactions (all grades) reported in ≥5% of subjects receiving 12 weeks of treatment with EPCLUSA in ASTRAL-1 were: headache (22%), fatigue (15%), nausea (9%), asthenia (5%), and insomnia (5%). Of subjects receiving EPCLUSA who experienced these adverse reactions, 79% had an adverse reaction of mild severity (Grade

1). The adverse reactions observed in subjects treated with EPCLUSA in ASTRAL-2 and ASTRAL-3 were consistent with those observed in ASTRAL-1. Irritability was also observed in ≥ 5% of subjects treated with EPCLUSA in ASTRAL-3. Subjects Coinfected with HCV and HIV-1: The safety assessment of EPCLUSA in subjects with HCV/HIV-1 coinfection was based on an openlabel trial (ASTRAL-5) in 106 subjects who were on stable antiretroviral therapy. The safety profile in HCV/HIV-1 coinfected subjects was similar to HCV mono-infected subjects. The most common adverse reactions (at least 10%) were fatigue (22%) and headache (10%). Subjects with Decompensated Cirrhosis: The safety assessment of EPCLUSA in subjects infected with genotype 1, 2, 3, 4, or 6 HCV with decompensated cirrhosis was based on one Phase 3 trial (ASTRAL-4) including 87 subjects who received EPCLUSA with RBV for 12 weeks. All 87 subjects had Child-Pugh B cirrhosis at screening. On the first day of treatment with EPCLUSA with RBV, 6 subjects and 4 subjects were assessed to have Child-Pugh A and Child-Pugh C cirrhosis, respectively. The most common adverse reactions (all grades with frequency of 10% or greater) in the 87 subjects who received EPCLUSA with RBV for 12 weeks were fatigue (32%), anemia (26%), nausea (15%), headache (11%), insomnia (11%), and diarrhea (10%). Of subjects who experienced these adverse reactions, 98% had adverse reactions of mild to moderate severity. A total of 4 (5%) subjects permanently discontinued EPCLUSA with RBV due to an adverse event; there was no adverse event leading to discontinuation that occurred in more than 1 subject. Decreases in hemoglobin to < 10 g/dL and < 8.5 g/dL during treatment were observed in 23% and 7% of subjects treated with EPCLUSA with RBV for 12 weeks, respectively. RBV was permanently discontinued in 17% of subjects treated with EPCLUSA with RBV for 12 weeks due to adverse reactions. Less Common Adverse Reactions Reported in Clinical Trials: Rash: In ASTRAL-1, rash occurred in 2% of subjects without cirrhosis or with compensated cirrhosis treated with EPCLUSA for 12 weeks and in 1% of subjects treated with placebo. In ASTRAL-4, rash occurred in 5% of subjects with decompensated cirrhosis treated with EPCLUSA with RBV for 12 weeks. No serious adverse reactions of rash occurred, and all rashes were mild or moderate in severity. Depression: In ASTRAL-1, depressed mood occurred in 1% of subjects without cirrhosis or with compensated cirrhosis treated with EPCLUSA for 12 weeks and was not reported by any subject taking placebo. No serious adverse reactions of depressed mood occurred, and all events were mild or moderate in severity. Laboratory Abnormalities: Lipase Elevations: In ASTRAL-1, isolated, asymptomatic lipase elevations of > 3xULN were observed in 3% and 1% of subjects treated with EPCLUSA and placebo for 12 weeks, respectively and in 6% and 3% of subjects treated with EPCLUSA in ASTRAL-2 and ASTRAL-3, respectively. In the Phase 3 trial of subjects with decompensated cirrhosis (ASTRAL-4), lipase was assessed when amylase values were ≥ 1.5xULN. Isolated, asymptomatic lipase elevations of > 3xULN were observed in 2% of subjects treated with EPCLUSA with RBV for 12 weeks. Creatine Kinase: In ASTRAL-1, isolated, asymptomatic creatine kinase elevations of ≥ 10xULN were observed in 1% and 0% of subjects treated with EPCLUSA and placebo for 12 weeks, respectively; and in 2% and 1% of subjects treated with EPCLUSA in ASTRAL-2 and ASTRAL-3, respectively. In the Phase 3 trial with decompensated cirrhosis (ASTRAL-4), isolated, asymptomatic creatine kinase elevations ≥ to 10xULN were reported in 1% of subjects treated with EPCLUSA with RBV for 12 weeks. Indirect Bilirubin: Increases in indirect bilirubin up to 3 mg/dL above baseline were noted among HIV-1/HCV coinfected subjects treated with EPCLUSA and an atazanavir/ritonavir-based antiretroviral regimen. The elevated indirect bilirubin values were not associated with clinical adverse events and all subjects completed 12 weeks of EPCLUSA without dose adjustment or treatment interruption of either EPCLUSA or HIV antiretroviral agents. Adverse Reactions in Adults with Severe Renal Impairment Requiring Dialysis: In an open-label trial (Trial 4062), in which a total of 59 adults with HCV with compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis received EPCLUSA for 12 weeks, the most common adverse reaction was nausea (7%). Postmarketing Experience: Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with a sofosbuvir containing regimen. Skin and Subcutaneous Tissue Disorders: Skin rashes, sometimes with blisters or angioedema-like swelling; angioedema.

DRUG INTERACTIONS Sofosbuvir and velpatasvir are substrates of P-gp and breast cancer resistance protein (BCRP) while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not. Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic effect of EPCLUSA. The use of these agents with EPCLUSA is not recommended. EPCLUSA may be coadministered with P-gp, BCRP, and CYP inhibitors. Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1. Coadministration of EPCLUSA with drugs that are substrates of these transporters may increase the exposure of such drugs. Established and Potentially Significant Drug Interactions: Clearance of HCV infection with DAAs may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment. Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. The drug interactions listed below are based on studies conducted with either EPCLUSA, the components of EPCLUSA (sofosbuvir and velpatasvir) as individual agents, or are predicted drug interactions that may occur with EPCLUSA. This list includes potentially significant

interactions but is not all inclusive. Interactions with carbamazepine, rifabutin, rifampin, efavirenz, rosuvastatin, and atorvastatin have been studied in healthy adults. Alteration in Dose or Regimen May Be Recommended for the Following Drugs When Coadministered with EPCLUSA: • Acid Reducing Agents: Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of velpatasvir. Antacids: Separate antacid and EPCLUSA administration by 4 hours. H2-receptor antagonists: Doses comparable to famotidine 40 mg twice daily or lower may be administered simultaneously with or 12 hours apart from EPCLUSA. Proton-pump inhibitors: Coadministration of omeprazole or other proton pump inhibitors is not recommended. If considered medically necessary to coadminister, EPCLUSA should be administered with food and taken 4 hours before omeprazole 20 mg. Use with other proton pump inhibitors has not been studied. • Antiarrhythmics (amiodarone; digoxin): Amiodarone: Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia and is not recommended. Mechanism of effect is unknown. If coadministration is required, cardiac monitoring is recommended. Digoxin: Increased concentration of digoxin. Monitor digoxin therapeutic concentration during coadministration with EPCLUSA. Refer to digoxin prescribing information for monitoring and dose modification recommendations for concentration increases of <50%. • Anticancers (topotecan): Increased concentration of topotecan. Coadministration is not recommended. • Anticonvulsants (carbamazepine; phenytoin; phenobarbital): Decreased sofosbuvir and velpatasvir concentrations leading to reduced EPCLUSA effect. Coadministration is not recommended. • Antimycobacterials (rifabutin; rifampin; rifapentine): Decreased sofosbuvir and velpatasvir concentrations leading to reduced EPCLUSA effect. Coadministration is not recommended. • HIV Antiretrovirals (efavirenz; regimens containing tenofovir disoproxil fumarate (TDF); tipranavir/ritonavir): • Efavirenz: Decreased concentration of velpatasvir. Coadministration of EPCLUSA with efavirenz-containing regimens is not recommended. • Regimens containing TDF: Due to increased tenofovir concentrations, monitor for tenofovir-associated adverse reactions. Refer to the prescribing information of the TDF-containing product for renal monitoring recommendations. • Tipranavir/ritonavir: Decreased sofosbuvir and velpatasvir concentrations leading to reduced EPCLUSA effect. Coadministration is not recommended. • Herbal Supplements (St. John’s wort): Decreased sofosbuvir and velpatasvir concentrations. Coadministration is not recommended. • HMG-CoA Reductase Inhibitors (rosuvastatin; atorvastatin): Rosuvastatin: Significant increase in rosuvastatin concentrations and risk of rosuvastatin associated myopathy, including rhabdomyolysis. Rosuvastatin may be administered with EPCLUSA at a dose that does not exceed 10 mg. Atorvastatin: May be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis Drugs without Clinically Significant Interactions with EPCLUSA: Based on drug interaction studies conducted with the components of EPCLUSA (sofosbuvir or velpatasvir) or EPCLUSA, no clinically significant drug interactions have been observed with the following drugs. EPCLUSA: atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, raltegravir, or rilpivirine; Sofosbuvir: ethinyl estradiol/norgestimate, methadone, or tacrolimus; Velpatasvir: ethinyl estradiol/norgestimate, ketoconazole, or pravastatin. See use of EPCLUSA with certain HIV antiretroviral regimens

USE IN SPECIFIC POPULATIONS Pregnancy: If EPCLUSA is administered with RBV, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the RBV prescribing information. No adequate human data are available to establish whether or not EPCLUSA poses a risk to pregnancy outcomes. Lactation: It is not known whether the components of EPCLUSA and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed child. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for EPCLUSA and any potential adverse effects on the breastfed child from EPCLUSA or from the underlying maternal condition. If EPCLUSA is administered with RBV, the nursing mother’s information for RBV also applies to this combination regimen. Refer to the RBV prescribing information. Pediatric Use: Safety and effectiveness of EPCLUSA have not been established in pediatric patients. Geriatric Use: Clinical trials of EPCLUSA included 156 subjects aged 65 and over (12% of total number of subjects in the Phase 3 clinical studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of EPCLUSA is warranted in geriatric patients. Renal Impairment: No dosage adjustment of EPCLUSA is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis [see Dosage and Administration, Adverse Reactions, Clinical Pharmacology, and Clinical Studies]. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including ESRD requiring dialysis. Refer to ribavirin tablet prescribing information regarding use of ribavirin in patients with renal impairment. Hepatic Impairment: No dosage adjustment of EPCLUSA is recommended for patients with mild, moderate, or severe hepatic impairment (ChildPugh Class A, B, or C). 208341-GS-024 September 2019 EPCLUSA, the EPCLUSA logo, HARVONI, GILEAD and the GILEAD logo are trademarks of Gilead Sciences, Inc., or its related companies. © 2020 Gilead Sciences, Inc. All rights reserved. EPCP0516 01/20

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Hep Vaccines Lacking Among Liver Patients

hile guidelines call for patients with chronic liver disease to receive vaccinations against the hepatitis A and B viruses, many candidates for liver transplants are not receiving the inoculations, a new study has found. In light of the results, researchers from the University of Cincinnati, who conducted the study, urged hepatologists to obtain comprehensive vaccine histories for all patients scheduled for liver transplantation, and to ensure that their vaccine series are completed before the procedure.

rate Dr. Farooq called “quite low.” This finding was associated with race, as white transplant recipients had significantly lower rates of hepatitis B virus surface antibodies than other groups (P=0.0005), according to the researchers. Moreover, hepatitis B virus core antibodies were present in 17 of 183 patients who did not have surface antibodies to the virus, which indicate evidence of prior infection. Roughly three-fourths of patients in the study had received at least one dose of the hepatitis B vaccine. But only 27% had received the full series of doses.

that health care providers who manage these patients ensure that their vaccine series are completed. “The CDC recommends that patients found to have hepatitis C, as well as those with chronic liver disease, be screened for antibodies for hepatitis A and B, and be vaccinated if needed,” Kenneth E. Sherman, MD, PhD, the division director and the Gould Professor of Medicine at the University of Cincinnati, said. “That’s something that can begin with primary care physicians and community gastroenterologists.” Robert S. Brown Jr., MD, MPH, the clinical chief

‘What this highlights is that for these very important vaccines, we need a different strategy. Either primary care providers have to pick up the slack or these vaccines have to be more widely available, in much the same way we get flu vaccine.’ —Robert S. Brown Jr., MD, MPH, Weill Cornell Medicine

“Patients with cirrhosis and advanced liver disease are generally at higher risk for viral hepatitis infections, and tend to have a more severe course if they are infected,” Priya Farooq, MD, a hepatology fellow at the University of Cincinnati, said. “These individuals also respond more poorly to vaccination, so we wanted to explore this further.” Dr. Farooq and her colleagues reviewed the electronic medical records of all patients with advanced liver disease who had received either cadaveric liver or liver/kidney transplants at Cincinnati between January 2016 and September 2018. Documentation of vaccine history was obtained from both institutional records and county health departments. In an abstract submitted to the 2020 Digestive Disease Week (Sa1518), the researchers reported on data from 286 liver transplant recipients. Of these, only 34.7% had hepatitis B virus surface antibodies—a

Medical records failed to provide data regarding vaccine dosage in 28.3% of cases. When recorded, however, most patients (62/132) received only a single 10- or 20-mcg recombinant hepatitis B virus vaccine. Dr. Farooq’s group found that only 65 patients received the full vaccine series against hepatitis A. However, 73% demonstrated antibodies against hepatitis A immunoglobulin G (IgG). “It was interesting that fewer than 25% of patients had completed a full hepatitis A series, but almost three-quarters of the cohort demonstrated IgG positivity,” Dr. Farooq said. Although the hepatitis A virus antibody was observed twice as frequently as its counterpart to hepatitis B, the researchers noted that this finding likely reflects higher rates of prior infection rather than higher rates of vaccination. In light of the findings, the researchers recommended

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of gastroenterology and hepatology at Weill Cornell Medicine, in New York City, said the findings were unsurprising—but not insignificant. “What this highlights is that for these very important vaccines, we need a different strategy,” Dr. Brown said. “Either primary care providers have to pick up the slack or these vaccines have to be more widely available, in much the same way we get flu vaccine. Pharmacies already have systems in place to remind patients about refills and to get them back for doses 2 and 3.” The study also underscores the advantage of a twodose vaccination strategy for hepatitis A and B, which likely improves compliance, he added. —Michael Vlessides Dr. Sherman reported financial relationships with AbbVie, Gilead, Inovio, Intercept, Medpace and UniQure. Drs. Farooq and Brown reported no relevant financial conflicts of interest. The abstract was named a Poster of Distinction at the meeting.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Checkpoint Inhibitors Appear to Threaten Liver Grafts

iver transplant patients who receive checkpoint inhibitors for the treatment of cancer may be at increased risk for injury or loss of the donor organ, new research shows. In patients who have undergone a liver transplant, a systematic review of the literature suggests there is a risk for graft injury and graft loss in liver transplant recipients who are treated with immune checkpoint inhibitors. A systematic review of the literature found as many as one-third of transplant patients exposed to checkpoint inhibitors rejected their new livers, generally early in the course of their chemotherapy, according to Faisal S. Ali, MD, a clinical resident in the Department of Internal Medicine at Amita Health Saint Joseph Hospital Chicago, who helped conduct the study. Although the data are considered only hypothesisgenerating, a similar signal has been reported in patients exposed to checkpoint inhibitors after kidney transplantation, Dr. Ali said. “In the liver transplant population, the odds of malignancy are more than twice as great as that of the general population, so this could be a growing issue for patients and physicians,” Dr. Ali said. However, he added that, for the moment, it would be premature for clinicians to raise the potential risk with their patients. “The body of evidence is still very weak, and there might be worse consequences for a transplant patient forgoing treatment with a checkpoint inhibitor when this therapy is indicated,” Dr. Ali said. For the analysis, which Dr. Ali submitted to the 2020 Digestive Disease Week (abstract 211), the researchers looked at studies and case reports of patients with liver transplant exposed to checkpoint inhibitors. Twenty-one patients were identified from case reports and case series. The average time from transplant to malignancy and treatment with a checkpoint inhibitor was more than three years. This interval did not differ for those who did or did not experience rejection. Once the checkpoint inhibitor was initiated, the median time to graft

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rejection in those who experienced the complication was 10 days, he reported. No risk factors have been clearly identified from this small series of patients, but features in these data deserve study as more cases are collected, according to Dr. Ali. For example, only one of 10 patients receiving a tacrolimus-based immunosuppressive regimen experienced graft rejection versus three of eight receiv-

ing mycophenolate mofetil and three of four receiving sirolimus. In addition, only 23% of the patients in the systematic review were female, he noted. In this series, graft rejection occurred in patients taking the programmed death-1 inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) or pembrolizumab (Keytruda, Merck) as well as the cytotoxic T-lymphocyte–associated antigen 4 inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb). Nivolumab was the most commonly used checkpoint inhibitor in those with or without rejection. Nearly 60% of cases collected in this series were being treated with checkpoint inhibitors for hepatocellular cancer, which was also the most common indication for liver transplantation. The indication for checkpoint inhibitor treatment in the remaining cases,

with the exception of one case of colorectal cancer, was melanoma. The apparent increased risk for rejection from checkpoint inhibitors might be related directly to their therapeutic role, which is characterized as taking the brakes off lymphocyte activity. Although Dr. Ali said an off-target effect is more likely, he said this needs further evaluation. “It might be helpful for clinicians to be aware of this risk, but we do not know the best way to monitor for this complication or what adjustments to make,” Dr. Ali said. No evidence supports withholding checkpoint inhibitors, which may have curative potential in advanced cancers, and even in patients who have undergone a liver transplant. Numerous other case series have been published showing an association between checkpoint inhibitors and rejection of solid-organ transplants, including liver grafts, said Stefan Munker, MD, who is completing his training in gastrointestinal oncology at the University of Munich. Dr. Munker led a study of 14 cases published two years ago (United European Gastroenterol J 2018;6[7]:970-973), which also found that rejection after exposure to a checkpoint inhibitor occurred relatively rapidly. Of the four (29%) with rejection, all of which were observed within three weeks, three were fatal. However, Dr. Munker agreed that the risk for rejection does not necessarily preclude treatment with a checkpoint inhibitor. The decision should be made “on an individual basis” in consideration of potential benefits for the treatment of cancer, he said. “At the present state of knowledge, the decision to treat transplant patients with checkpoint inhibitors is to be considered” as a last resort, he said. Despite the substantial risk for graft failure, he said treatment might be justified in the absence of acceptable alternatives. —Ted Bosworth Drs. Ali and Munker reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

On the Horizon: Noninvasive Test May Predict Outcomes in Liver Patients

he use of a noninvasive test for liver function can accurately predict decompensation, death, or the need for liver transplantation in patients with cirrhosis, new research shows.

“We wanted to see whether it can help predict decompensation, death or liver transplant in cirrhotic patients in the long term,” Dr. Fallahzadeh said. As part of the test, patients with cirrhosis receive a fixed dose of cholate substrate. Blood levels are then measured to document hepatic clearance. The output of the test is a comprehensive disease

severity index (DSI), which the researchers said is a comprehensive measure of global hepatic function and physiology. “The DSI tells us globally how healthy or sick the liver is,” Dr. Fallahzadeh said. “The higher the DSI, the seeker the liver.” To help determine the test’s efficacy, the investigators examined the records

of patients with cirrhosis who underwent the dual cholate test at Baylor University between 2011 and 2018; median follow-up was roughly four years. After adjusting for possible confounding variables, the researchers examined the independent association between increased DSI and decompensation.

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Articles from the current month’s issue Predicting decompensation in patients with cirrhosis is challenged by the lack of a test that captures functional decline. Biopsy and elastography provide information about the extent of liver fibrosis, but not how well the organ is working, according to Mohammad Amin Fallahzadeh, MD, a medical resident at Baylor University Medical Center, in Dallas. The dual cholate test (HepQuant Shunt)—which measures hepatic clearance of oral and IV cholate—may help bridge this gap. The test assesses hepatocyte function, hepatic blood flow, portal blood flow and portosystemic shunting.

Articles ahead of print Web-exclusive content

see Predict, page 44

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Older With IBD: Long-Term Outcomes After IPAA n this month’s installment, Kian Keyashian, MD, a clinical assistant professor of medicine in the Division of Gastroenterology and Hepatology at Stanford University in Redwood City, Calif., discusses the significance of a recent paper examining long-term functional outcomes and quality of life (QOL) in older people with ulcerative colitis who have undergone ileal pouch–anal anastomosis (IPAA).

I Study

Outcomes

Minagawa T, Ikeuchi H, Kuwahara R, et al. Functional outcomes and quality of life in elderly patients after restorative proctocolectomy for ulcerative colitis. Digestion. 2019 Feb 5. [Epub ahead of print]. doi: 10.1159/000502286 Researchers at Hyogo College of Medicine, in Nishinomiya, Japan, asked 224 older patients with UC who had undergone IPAA at their institution between 1987 and 2015 to complete a questionnaire about their QOL and functional outcomes after the procedure. Those between 65 and 69 years of age were considered elderly, while individuals over 70 were classified as “super-elderly.” The participants had undergone IPAA at least two years before the survey. The median duration of postoperative follow-up was 9.5 years for elderly patients and 15.9 years in the super-elderly group. Seventy elderly and 66 super-elderly patients completed the questionnaire. The median age at the time of surgery among elderly patients was 57 years, compared with 60 years among super-elderly patients. Rates of elective or emergency surgery and use of staples or hand-sewn sutures were similar for both age groups.

Patients in both age groups reported an average of eight bowel movements per day. Rates of soiling, which the researchers defined as three or more incidents of leaking per week, did not differ significantly during daytime (53% vs. 56% for elderly vs. super-elderly) and nighttime (65.7% vs. 53%; P=0.16). Also, the researchers didn’t observe significant differences in the percentage of elderly and super-elderly patients who said their daytime or nighttime soiling had worsened compared with the first postoperative year (5.7% vs. 12.1% of elderly and super-elderly reporting worsened daytime soiling; P=0.23 and 7.1% vs. 9.1% for worsened nighttime soiling; P=0.76). In the group of super-elderly patients, more women than men reported nighttime soiling (n=16 vs. 19; P=0.048). A statistically similar number of patients in both age groups had given birth vaginally, which is a risk factor for incontinence, according to the researchers. Rates of pouchitis (18.6% vs. 7.6% for elderly vs. super-elderly, respectively) and anastomotic leakage (4.3% vs. 10.6%, respectively) were statistically similar between groups. No significant differences were reported between the elderly and superelderly groups in QOL scores, as measured using the validated Modified Fecal Incontinence QOL scale (27 vs. 31 points for elderly vs. super-elderly).

Dr. Keyashian: D IPAA is often considered a alternative to ileostomy an i patients with UC who in u undergo colectomy. While c conditions such as pouc chitis or Crohn’s disease of t pouch can occur after the s surgery, the long-term funct of the pouch—particution l larly regarding incontinence with longer duration after pouch creation—can be a concern and is largely unknown. For an older patient who is contemplating different

surgical options after colectomy for UC, a risk–benefit discussion can highlight the short-term outcomes. But, with limited long-term data, one may not be able to elucidate long-term functional outcomes with these options. Given the higher risk for incontinence in older patients with reduced sphincter strength, such individuals are not offered IPAA to prevent incontinence and reduced QOL (Ann Surg 2003;238[2]:221; Am J Surg 2003;185[4]:333-338). This interesting study from a Japanese center performing high volumes of IPAA for UC showed that, despite 10 to 15 years since pouch creation, older patients had good functional outcomes with generally good QOL. This finding is in contrast to previous studies showing worsened QOL in older patients

undergoing low anterior resection of the colon for rectal cancer (Cancer Chemother 2016;43[12]:1526-1528). The strengths of this study include a large sample size with a high survey response rate of over 60% and use of a previously developed incontinence QOL scale developed for surgical management of rectal cancer. Studies like this are essential to expand our discussion of long-term QOL and risk for incontinence, particularly in the older patient population. Additional research is necessary to identify clinical predictors of soiling/incontinence and lower QOL in older patients with UC considering IPAA. With such studies, the patient can make more informed decisions regarding surgical treatment. —Compiled by David Wild

Predict continued from page 43

Categories of Model for End-Stage Liver Disease (MELD) and DSI were stratified as either high risk (high DSI/high MELD); intermediate risk (high DSI/ low MELD or low DSI/high MELD); or low risk (low DSI/low MELD). In a study submitted to the Digestive Disease Week 2020 (abstract 476), the investigators reported that 85 patients (age, 57 years; 73% men) underwent testing. Of these, the median MELD score was 8.1±6.2, while DSI was 26±15.5. A total of 23 patients (27.1%) experienced the study’s primary composite outcome of decompensation,

death or liver transplantation. At baseline, DSI was significantly lower in patients with compensated cirrhosis (22.4) than in their counterparts with decompensated cirrhosis (31.1; P<0.001). The cumulative incidence of composite outcome was significantly higher in patients with DSI greater than 26 than among those whose DSI levels were 26 or lower (P=0.002). After stratifying by MELD-DSI category, the study also found that the cumulative incidence of the composite outcome was significantly higher in high-risk patients compared with

those in the intermediate- and lowrisk groups (P<0.001). Multivariate analysis demonstrated that DSI above 26 was independently associated with increased risk for composite outcome (hazard ratio, 3.48; 95% CI, 1.42-8.53). “We think the biggest benefit of the test is in early cirrhosis,” Dr. Fallahzadeh said. “In those patients, MELD doesn’t really help stratify them as low or high risk. But DSI does.” K. Rajender Reddy, MD, the director of hepatology at the University of Pennsylvania, in Philadelphia, said the dual cholate test, which is not yet FDA

approved, “certainly has applicability in assessing liver function, and could potentially be used in various scenarios.” However, Dr. Reddy questioned its convenience. “Patients have to go to a facility and concurrently receive a liquid formulation and an intravenous form of cholate, then have blood drawn at periodic intervals up to 90 minutes,” he said. “If it can be transformed to an outpatient home device, that would obviously be the best fit.” —Michael Vlessides Drs. Fallahzadeh and Reddy reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

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AUGUST 2020

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Strategy continued from page 1

Steroids Increase Risk For Poor Outcomes IBD researchers around the world have been working around the clock gathering and analyzing data, publishing their results, and issuing guidance for clinicians. One such initiative is SECURE-IBD, an international physician-driven open-access registry of IBD patients with COVID-19. As of this writing, more than 1,500 patients are in the system. In a published analysis of the first 525 patients with IBD in the registry, project co-founder Ryan Ungaro MD, MS, an assistant professor at the Susan and Leonard Feinstein IBD Clinical Center at Icahn School of Medicine at Mount Sinai, in New York City, reported a 3% fatality rate and a 7% rate of a composite outcome of ICU admission, ventilator support and death (Gastroenterology 2020 May 18. [Epub ahead of print]. www.gastrojournal.org/article/ S0016-5085[20]30655-7/pdf ). “Older patients and those with multiple comorbidities appear to be at the highest risk, as in the general population, but corticosteroid use also worsens outcomes,” Dr. Ungaro said. A small Italian study confirmed that conclusion, finding a sixfold increased risk for death and a fivefold higher risk for pneumonia with systemic corticosteroid use among IBD patients with COVID-19 (Gut 2020;69[7]:1213-1217). “The best thing to do for your IBD patients is to maintain their disease in remission and avoid use of corticosteroids,” Dr. Ungaro said, noting the SECUREIBD population may have more severe COVID-19, as these patients are most likely to be reported by clinicians.

Expert Guidance In a separate international effort, 66 leading gastroenterologists published an extensive guidance document in June covering topics from whether certain IBD medications increase the risk for COVID-19 to the wisdom of performing elective endoscopies during the pandemic (www.gastrojournal.org/article/ S0016-5085[20]30465-0/pdf ). One of the recommendations that received widespread support from the panel was that IBD therapies should be paused during a COVID-19 infection and

Micro continued from page 35

the 21 randomized controlled trials that met inclusion criteria (RR, 0.98; 95% CI, 0.90-1.08; P=0.72). Parenterally administered selenium also did not have any demonstrable effect in a subgroup analysis of patients with infections. There was no positive or negative effect on length of stay in the ICU or hospital, renal function, or ventilatordays (RR, 0.95; 95% CI, 0.88-1.02; P=0.15), the researchers found. These results are surprising, given

throughout the recovery period, David Rubin, MD, a professor of medicine and the chief of the Section of Gastroenterology at the University of Chicago Medicine, said. “The general suggestion right now is to hold therapies for two weeks to see if the patient clears the virus without having noticeable problems,” Dr. Rubin, who was a member of the International Organization for the Study of Inflammatory Bowel Disease that wrote the 76 statements, said. “If they develop the disease and then recover, they should restart treatments after that period.”

‘Intestinal COVID-19’ Some community clinicians in COVID-19 hot spots have become experts through a trial by fire during the pandemic. James George, MD, a gastroenterologist in private practice in New York City, who said he has treated between 50 and 60 IBD patients with COVID-19, began seeing what he calls symptoms of “intestinal COVID-19” well before New York City’s surge of cases. “I had some IBD patients coming in late in January with diarrhea and abdominal cramps, and many of them didn’t have the respiratory symptoms typical of COVID-19,” Dr. George recalled. In his experience, the gastrointestinal symptoms of COVID-19 typically resolve within seven to 10 days. “Since then,

that selenium enhances the body’s most powerful antioxidant and antiinflammatory response mechanisms, Dr. Stoppe said. “Yet clearly, clinical data in general ICU patients could not demonstrate significant benefits, and nutrition guidelines don’t recommend its general use” (Clin Nutr 2019;38[1]:48-79; Crit Care Med 2016;44[2]:390-438). Despite the negative findings, data suggest there may be specific populations that may benefit from selenium supplementation. For example, Dr. Stoppe is researching the effects of selenium supplementation in high-risk

I’ve been telling my IBD patients to sit tight through these symptoms and see if they disappear on their own,” he said. Dr. George said teasing apart the symptoms of an IBD flare from “intestinal COVID-19,” which 20% to 30% of infected individuals experience, can be a challenge. But the good news is that COVID-19 does not seem to aggravate the course of IBD. While IBD flares can generally be managed as usual during the pandemic, Dr. George said he avoids prescribing corticosteroids, given that use of these agents worsens outcomes of the infection. “Unfortunately, some patients still need these drugs, and in those cases I try to use intestinal release corticosteroids like budesonide, if I can,” he said. “That’s really the one change in treatment that I’ve been trying to make.” Dr. Axelrad advised clinicians to send email blasts to IBD patients with reminders to continue using their current medications, to maintain remission and avoid requiring corticosteroids for a relapse. “Equally important is taking their mental health into consideration,” he added. “Patients may feel increasingly depressed and anxious during this time, so I would also advise clinicians to have a good referral system for virtual mental health and nutrition services.”

patients undergoing cardiac surgery in the SUSTAIN CSX trial (Trials 2014;15:339. doi.org/10.1186/17456215-15-339). He said he anticipates data from the trial by the end of the year. “We may just have to focus on the sickest patients,” Dr. Stoppe said. “It’s a point that comes out more and more in clinical trials.” —Lynne Peeples Dr. Rice reported consulting for Baxter and Nestlé. Dr. Miller reported serving as a faculty member on an educational clinical nutrition fellowship sponsored by Nestlé. Drs. Stoppe and Ayers reported no relevant financial conflicts of interest.

—David Wild

Gastroenterology & Endoscopy News, the independent monthly newspaper for gastroenterologists, has been providing physicians with comprehensive and objective information since 1978. The newspaper is circulated to more than 19,647 gastroenterologists, colorectal surgeons, and hepatologists, and GI-specific physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of January 2020). Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Please send address changes to Gastroenterology & Endoscopy News, 545 W. 45th Street, 8th Floor, New York, NY 10036. Copyright © 2020 McMahon Publishing.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2020

Legal continued from page 10

Previous studies by her group and others showed an increase in presentations to the emergency department and hospital for cyclic vomiting in the wake of legalization of cannabis (Intern Med J 2019;49[5]:649-655). However, she said, it is possible these cases are due to cyclic vomiting syndrome (CVS), a diagnosis largely unrecognized and misdiagnosed for decades. Several studies have used

CHS to describe someone admitted for CVS who was treated, ceased smoking cannabis in the hospital, and did not have another episode for three or four weeks. “That’s not how the disorder works,” Dr. Venkatesan said. “It’s an episodic disorder, and it is important to follow patients for at least six months to a year to determine if cannabis is truly causing hyperemesis.” Cannabis is stored in fat cells and released into the bloodstream for

months, she said, even in heavy cannabis users. True CHS likely only resolves months after stopping use, Dr. Venkatesan said. The new study may reflect an increase in cyclic vomiting after legalization of marijuana, she said, but because no diagnostic code exists for CHS, and because hospitalists vary in their coding for marijuana abuse, investigators should not presume that patients had true CHS. A recent paper by her group (Neurogastroenterol Motil 2019:31

Strong Cannabis continued from page 10

cannabinoid hyperemesis syndrome and worsening of psychiatric disorders, and can precipitate psychosis.” The researchers called on policymakers and regulatory agencies to develop evidence-based practices for medical cannabis pain relief. “Regulatory bodies have already adopted the practice of overseeing medications deemed safe for over the counter use at low doses but with serious dose-dependent adverse effects,” the study noted. “If the FDA cannot regulate products in medicinal dispensaries, states should develop policies in line with scientific evidence to provide safer products to patients. New policies are needed, and a more constructive dialogue should exist among policymakers, scientists and the cannabis industry,” Dr. Romero-Sandoval said. The FDA has maintained cannabis as a Schedule I therapeutic, and Dr. Franson does not think there will be additional guidance from the agency at this time. “Thus, it is up to the states to implement regulations,” she said. “Patient education is also needed. Knowledgeable clinicians need to assist their patients in the proper use of cannabis.” The current study cites unconfirmed THC and CBD levels as a limitation that requires further investigation. “The THC concentrations we uncovered are the concentrations patients would find online when looking for a product in dispensaries to treat their pain,” Dr. Romero-Sandoval said. “Additional studies are needed to confirm product labels are the same as information online, and that this information is accurate and supported by approved testing methods. We require this for medicines. This should be required for medicinal cannabis.” —Sherree Geyer

BRIEF SUMMARY OF PRESCRIBING INFORMATION This Brief Summary does not include all the information needed to use XIFAXAN safely and effectively. See full prescribing information for XIFAXAN. XIFAXAN® (rifaximin) tablets, for oral use Initial U.S. Approval: 2004 To reduce the development of drug-resistant bacteria and maintain the effectiveness of XIFAXAN and other antibacterial drugs, XIFAXAN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. 1 INDICATIONS AND USAGE 1.3 Irritable Bowel Syndrome with Diarrhea XIFAXAN is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. 2 DOSAGE AND ADMINISTRATION 2.3 Dosage for Irritable Bowel Syndrome with Diarrhea The recommended dose of XIFAXAN is one 550 mg tablet taken orally three times a day for 14 days. Patients who experience a recurrence of symptoms can be retreated up to two times with the same dosage regimen. 2.4 Administration XIFAXAN can be taken with or without food. 4 CONTRAINDICATIONS XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis. 5 WARNINGS AND PRECAUTIONS Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24 to 48 hours and alternative antibiotic therapy should be considered. 5.2 Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. 5.4 Severe (Child-Pugh Class C) Hepatic Impairment There is increased systemic exposure in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh Class C). 5.5 Concomitant Use with P-glycoprotein Inhibitors Concomitant administration of drugs that are P-glycoprotein (P-gp) inhibitors with XIFAXAN can substantially increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of XIFAXAN and a P-gp inhibitor such as cyclosporine is needed. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-gp inhibitors may further increase the systemic exposure to rifaximin. 6 ADVERSE REACTIONS 6.1 Clinical Studies 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. Irritable Bowel Syndrome with Diarrhea The safety of XIFAXAN for the treatment of IBS-D was evaluated in 3 placebo-controlled studies in which 952 patients were randomized to XIFAXAN 550 mg three times a day for 14 days. The adverse reaction that occurred at a frequency ɗ2% in XIFAXAN-treated patients at a higher rate than placebo in Trials 1 and 2 for IBS-D was: • nausea (3% XIFAXAN, 2% placebo) The adverse reactions that occurred at a frequency ɗ2%

in XIFAXAN-treated patients (n=328) at a higher rate than placebo (n=308) in Trial 3 for IBS-D during the double-blind treatment phase were: • ALT increased (XIFAXAN 2%, placebo 1%) • nausea (XIFAXAN 2%, placebo 1%) Less Common Adverse Reactions The following adverse reactions, presented by body system, were reported in less than 2% of patients in clinical trials of TD and IBS-D and in less than 5% of patients in clinical trials of HE: Hepatobiliary disorders: Clostridium colitis Investigations: Increased blood creatine phosphokinase Musculoskeletal and connective tissue disorders: myalgia 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of XIFAXAN. Infections and Infestations Cases of C. difficile-associated colitis have been reported. General Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration. 7 DRUG INTERACTIONS 7.1 P-glycoprotein Inhibitors Concomitant administration of cyclosporine, an inhibitor of P-gp and OATPs significantly increased the systemic exposure of rifaximin. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-gp inhibitors may further increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of XIFAXAN and a P-gp inhibitor such as cyclosporine is needed. 7.2 Warfarin Changes in INR have been reported postmarketing in patients receiving rifaximin and warfarin concomitantly. Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. 7.3 CYP3A4 Substrates An in vitro study has suggested that rifaximin induces CYP3A4. However, in patients with normal liver function, XIFAXAN at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on XIFAXAN use in pregnant women to inform any drug associated risks. Teratogenic effects were observed in animal reproduction studies following administration of rifaximin to pregnant rats and rabbits during organogenesis. Advise pregnant women of the potential risk to a fetus. 8.2 Lactation Risk Summary There is no information regarding the presence of rifaximin in human milk, the effects of rifaximin on the breastfed infant, or the effects of rifaximin on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for XIFAXAN and any potential adverse effects on the breastfed infant from XIFAXAN or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of XIFAXAN has not been established in pediatric patients less than 18 years of age for IBS-D. 8.5 Geriatric Use In the clinical studies of IBS-D, 11% of patients were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied. 8.7 Hepatic Impairment Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUCਰ) of rifaximin was about 10-, 14-, and 21-fold higher in those patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally. Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment.

[suppl 2]:e13606) collated and analyzed case series and case reports on CHS, and proposed criteria to diagnose CHS. “Future research in this area should improve our understanding of the role of cannabis use in cyclic vomiting and help us better understand and manage this disorder,” Dr. Venkatesan and her colleagues wrote. —Karen Blum Drs. Hujoel and Venkatesan reported no relevant financial conflicts of interest.

10 OVERDOSAGE No specific information is available on the treatment of overdosage with XIFAXAN. In the case of overdosage, discontinue XIFAXAN, treat symptomatically, and institute supportive measures as required. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Malignant schwannomas in the heart were significantly increased in male Crl:CD (SD) rats that received rifaximin by oral gavage for two years at 150 to 250 mg/kg per day (doses equivalent to 2.4 to 4 times the recommended dose of 200 mg three times daily for TD, and equivalent to 1.3 to 2.2 times the recommended dose of 550 mg twice daily for HE, based on relative body surface area comparisons). There was no increase in tumors in Tg.rasH2 mice dosed orally with rifaximin for 26 weeks at 150 to 2000 mg/kg per day (doses equivalent to 1.2 to 16 times the recommended daily dose for TD and equivalent to 0.7 to 9 times the recommended daily dose for HE, based on relative body surface area comparisons). Rifaximin was not genotoxic in the bacterial reverse mutation assay, chromosomal aberration assay, rat bone marrow micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay, or the CHO/HGPRT mutation assay. There was no effect on fertility in male or female rats following the administration of rifaximin at doses up to 300 mg/kg (approximately 5 times the clinical dose of 600 mg per day for TD, and approximately 2.6 times the clinical dose of 1100 mg per day for HE, adjusted for body surface area). 17 PATIENT COUNSELING INFORMATION Persistent Diarrhea For those patients being treated for travelers’ diarrhea, discontinue XIFAXAN if diarrhea persists more than 24-48 hours or worsens. Advise the patient to seek medical care for fever and/or blood in the stool. Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibiotics alters the normal flora of the colon which may lead to C. difficile. Patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If diarrhea occurs after therapy or does not improve or worsens during therapy, advise patients to contact a physician as soon as possible. Administration with Food Inform patients that XIFAXAN may be taken with or without food. Antibacterial Resistance Counsel patients that antibacterial drugs including XIFAXAN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When XIFAXAN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by XIFAXAN or other antibacterial drugs in the future. Manufactured for: Salix Pharmaceuticals, a division of Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA Rifaximin for Travelers’ Diarrhea, Hepatic encephalopathy and IBS are protected by US Patent Nos. 7,045,620; 7,612,199; 7,902,206; 7,906,542; 8,158,781; 8,158,644; 8,193,196; 8,518,949; 8,741,904; 8,835,452; 8,853,231; and 9,271,968. Rifaximin for Travelers’ Diarrhea is also protected by US Patent No. 7,928,115. Rifaximin for Hepatic encephalopathy is also protected by US Patent No. 8,642,573; 8,829,017; 8,946,252; 8,969,398; 9,421,195; and 9,629,828. Rifaximin for IBS is also protected by US Patent Nos. 6,861,053; 7,452,857; 7,605,240; 7,718,608; 7,915,275; 7,935,799; and 8,309,569. The Xifaxan 200 mg and 550 mg products and the Xifaxan trademark are licensed by Alfasigma S.p.A. to Salix Pharmaceuticals or its affiliates. All other product/brand names are trademarks of the respective owners. © Valeant Pharmaceuticals North America LLC Website: www.Salix.com Based on 9593702 Rev. 01/2018

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