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December 2020 Volume 14 / Number 12 Start CRC screening INSIDE GI ONCOLOGY at age 45, USPSTF Task force report Best practices noted for managing malignant now suggests colorectal polyps. • 16 LIVER DISEASE BY ROXANNE NELSON, that all adults aged 45-75 RN, BSN years be screened for CRC. Semaglutide shows

arnes This is an “A” recom- promise in NASH study B creening for colo- mendation for adults aged Phase 2 data show rectal cancer (CRC) 50-75 and a “B” recom- resolution tephanie s Sshould begin at age mendation for adults aged in 60%. • 27 45 years instead of 50 45-49. Dr. Barry explained

ourtesy IBD AND INTESTINAL C years, as recommended that the reason for this Dr. Edward L. Barnes and his associates noted that disparities in care in the current guideline, difference is that the DISORDERS start with later diagnosis of IBD, followed by issues with continuity. the U.S. Preventive Ser- Tool predicted vices Task Force said in 45- to 49-year age group. vedolizumab a draft recommendation “Butbenefit there’s is smaller not much for the nonresponse that is open for public difference between A and Rising IBD rates in comment. B from a practical stand- Point-based scoring “This is the only change point,” he explained. system uses clinical minorities heighten that was made,” said task For adults aged 76-85, variables. • 30 force member Michael PRACTICE Barry, MD, director of of screening need to be need for awareness the Informed Medical weighedthe benefits against and harmsthe indi- MANAGEMENT Decisions Program in the vidual’s overall health and Delay in Stark reform BY AMY KARON wrote Edward L. Barnes, Health Decision Sciences personal circumstances. stunts value-based care MDedge News MD, MPH, of University of Center at Massachusetts This is a “C” recommenda- CMS dragging North Carolina at Chapel General Hospital, Boston. tion. its feet. • 34 - Hill, with his associates. The recommendation is See USPSTF · page 16 ease (IBD) is rapidly in- However, Blacks with IBD Icreasingnflammatory among bowel racial dis and tend to be diagnosed later ethnic minorities, which than Whites, are less likely makes it important to con- to receive recommended Study IDs microbial signature of sider for patients with com- biologics and immunomod- patible symptoms, experts ulators, and are more likely celiac disease in children wrote in Gastroenterology. to receive care at an emer- Crohn’s disease and ul- gency department, to expe- BY AMY KARON healthy children, accord- regardless of whether cerative colitis are “chronic rience delays in colectomy, MDedge News ing to the findings of a children were newly diag- diseases with intermittent and to miss regular visits to study published in Gastro- nosed or had already mod- - IBD specialists because of leven operational tax- enterology. sion, so access to specialists, Eonomic units (OTUs) This microbial signa- Konstantina Zafeiropoulou periodsappropriate of flare therapies, and remis and barriers, they added. of fecal bacteria were andified Ben their Nichols, diet, reported PhD, of frequent follow-up visits financialThese disparities and transportation are less abundant in children approximately four out of - are vital to good outcomes,” See Minorities · page 28 with celiac disease than in ture correctly identified See Celiac · page 9 the Glasgow Royal Infir five cases of celiac disease,

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01_09_to_17_28_31_GIH20_12.indd 1 11/20/2020 3:42:15 PM Not an injection, not an infusion2 • XELJANZ is available in 5 mg or 10 mg twice-daily doses I 2 ORAL • XELJANZ XR is available in 11 mg or 22 mg once-daily doses THE FIRST AND ONLY FDA-APPROVED ORAL JAK INHIBITOR See dosage adjustments in XELJANZ/XELJANZ XR full prescribing information. FOR MODERATELY TO SEVERELY ACTIVE UC1,2 XELJANZ/XELJANZ XR 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) A MARK OF b 1,2 • OCTAVE 2: 17% of patients taking XELJANZ 10 mg twice daily achieved remission vs I RAPID 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) RAPID, POWERFUL, AND SUSTAINED RESULTS IN UC1,2 In a 52-week maintenance study1,2,c I POWERFUL • 41% on XELJANZ 10 mg twice daily and 34% on XELJANZ 5 mg twice daily achieved remissionb AND (primary endpoint) vs 11% on placebo; P<0.0001d SUSTAINED1,2 • 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 Not an actual patient. Pill not to scale.

INDICATION In the UC population, XELJANZ 10 mg twice daily was associated 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, • XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment with greater risk of serious infections compared to 5 mg twice double-blind, placebo-controlled clinical trials. In OCTAVE 1 and 2, two identical, 8-week induction studies, 1139 patients with moderately to severely active of adult patients with moderately to severely active ulcerative daily. Opportunistic herpes zoster infections (including 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 meningoencephalitis, ophthalmologic, and disseminated 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 colitis (UC), who have had an inadequate response or who are permitted to use stable doses of oral aminosalicylates and corticosteroids (prednisone daily dose up to 25 mg equivalent). Concomitant immunosuppressants intolerant to TNF blockers. cutaneous) were seen in patients who were treated with b XELJANZ 10 mg twice daily. (immunomodulators or biological therapies) were not permitted. The primary endpoint was remission. In OCTAVE Sustain, a 52-week maintenance study, • Limitations of Use: Use of XELJANZ/XELJANZ XR in 593 patients who had completed the induction studies and achieved clinical response were rerandomized to XELJANZ 10 mg twice daily, XELJANZ 5 mg twice combination with biological therapies for UC or with potent The risks and benefi ts of treatment with XELJANZ/XELJANZ XR 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 immunosuppressants such as azathioprine and cyclosporine is should be carefully considered prior to initiating therapy in patients entrance into this study for patients who were receiving corticosteroids at baseline. Concomitant immunosuppressants (immunomodulators or biological not recommended. with chronic or recurrent infection, or those who have lived or therapies) were not permitted. The primary endpoint was remission.b Sustained corticosteroid-free remissione was a key secondary endpoint. XELJANZ 5 mg traveled in areas of endemic TB or mycoses. Viral reactivation twice daily is the recommended dosage for maintenance therapy. For patients with loss of response during maintenance treatment, a dosage of 10 mg IMPORTANT SAFETY INFORMATION including herpes virus and hepatitis B reactivation have been twice daily may be considered and limited to the shortest duration. SERIOUS INFECTIONS reported. Screening for viral hepatitis should be performed in Patients treated with XELJANZ/XELJANZ XR are at increased risk accordance with clinical guidelines before starting therapy. IMPORTANT SAFETY INFORMATION (cont’d) pancreatic cancer. NMSCs have been reported in patients for developing serious infections that may lead to hospitalization Patients should be closely monitored for the development of MALIGNANCIES treated with XELJANZ. In the UC population, treatment with or death. Most patients who developed these infections were signs and symptoms of infection during and after treatment Lymphoma and other malignancies have been observed in XELJANZ 10 mg twice daily was associated with greater risk of taking concomitant immunosuppressants, such as methotrexate with XELJANZ/XELJANZ XR, including the possible development patients treated with XELJANZ. Epstein Barr Virus-associated NMSC. Periodic skin examination is recommended for patients or corticosteroids. of tuberculosis in patients who tested negative for latent post-transplant lymphoproliferative disorder has been observed who are at increased risk for skin cancer. If a serious infection develops, interrupt XELJANZ/XELJANZ XR tuberculosis infection prior to initiating therapy. at an increased rate in renal transplant patients treated with THROMBOSIS until the infection is controlled. Caution is also recommended in patients with a history of chronic XELJANZ and concomitant immunosuppressive medications. Thrombosis, including pulmonary embolism, deep venous Reported infections include: lung disease, or in those who develop interstitial lung disease, as Consider the risks and benefi ts of XELJANZ/XELJANZ XR thrombosis, and arterial thrombosis, have occurred in patients they may be more prone to infection. treated with XELJANZ and other Janus kinase inhibitors used to • Active tuberculosis, which may present with pulmonary or treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma treat infl ammatory conditions. RA patients who were 50 years extrapulmonary disease. Patients should be tested for latent MORTALITY of age and older with at least one CV risk factor treated with tuberculosis before XELJANZ/XELJANZ XR use and during skin cancer (NMSC) or when considering continuing XELJANZ/ Rheumatoid arthritis (RA)* patients 50 years of age and older XELJANZ XR in patients who develop a malignancy. XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice therapy. Treatment for latent infection should be initiated prior with at least one cardiovascular (CV) risk factor treated with daily or TNF blockers in a large, ongoing postmarketing safety to XELJANZ/XELJANZ XR use. XELJANZ 10 mg twice a day had a higher rate of all-cause Malignancies (including solid cancers and lymphomas) were study had an observed increase in incidence of these events. • Invasive fungal infections, including cryptococcosis and mortality, including sudden CV death, compared to those treated observed more often in patients treated with XELJANZ 10 mg Many of these events were serious and some resulted in death. pneumocystosis. Patients with invasive fungal infections may with XELJANZ 5 mg given twice daily or TNF blockers in a large, twice daily dosing in the UC long-term extension study. Avoid XELJANZ/XELJANZ XR in patients at risk. Discontinue present with disseminated, rather than localized, disease. ongoing, postmarketing safety study. Other malignancies were observed in clinical studies and the XELJANZ/XELJANZ XR and promptly evaluate patients with • Bacterial, viral, including herpes zoster, and other infections XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is post-marketing setting including, but not limited to, lung symptoms of thrombosis. For patients with UC, use XELJANZ at due to opportunistic pathogens. not recommended for the treatment of RA or PsA†. For UC, use cancer, breast cancer, melanoma, prostate cancer, and the lowest e¢ ective dose and for the shortest duration needed to achieve/maintain therapeutic response. The most common serious infections reported with XELJANZ XELJANZ at the lowest e£ ective dose and for the shortest duration included pneumonia, cellulitis, herpes zoster, urinary tract needed to achieve/maintain therapeutic response. infection, diverticulitis, and appendicitis. Avoid use of XELJANZ/ aXELJANZ 10 mg twice daily (n=905); placebo (n=234).1 XELJANZ XR in patients with an active, serious infection, including * RA=rheumatoid arthritis. XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely bRemission was stringently defi ned as a total Mayo score ≤2, with no individual subscore >1 and a rectal active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as bleeding subscore of 0.2 localized infections, or with chronic or recurrent infection. monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). cUse the lowest effective dose to maintain response.2 Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants dXELJANZ 10 mg twice daily (n=197); XELJANZ 5 mg twice daily (n=198); placebo (n=198).2 FDA=US Food and Drug Administration; JAK=Janus kinase; UC=ulcerative colitis; XR=extended release. such as azathioprine and cyclosporine is not recommended. XELJANZ 10 mg twice daily is not approved for use in RA. e † Sustained corticosteroid-free remission was defi ned as remission (a total Mayo score ≤2, with no individual PsA=psoriatic arthritis. XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis subscore >1 and a rectal bleeding subscore of 0) and not taking corticosteroids for at least 4 weeks prior to Please see additional Important Safety Information and who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic the visit at both Week 24 and Week 52 among patients in remission at baseline.2 drugs (DMARDs). Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent fXELJANZ 10 mg twice daily (n=55); XELJANZ 5 mg twice daily (n=65); placebo (n=59).2 Brief Summary of full Prescribing Information, including immunosuppressants such as azathioprine and cyclosporine is not recommended. XELJANZ 10 mg twice daily is not BOXED WARNING, on the following pages. approved for use in PsA. 6-MP=6-mercaptopurine; TNF=tumor necrosis factor; UC=ulcerative colitis; XR=extended release.

GIHEP_2_3.indd 2 5/12/2020 2:27:26 PM

Cosmos Communications 1 Q1 Q2 C M Y K ej 42476a 02.26.20 133 1 Not an injection, not an infusion2 • XELJANZ is available in 5 mg or 10 mg twice-daily doses I 2 ORAL • XELJANZ XR is available in 11 mg or 22 mg once-daily doses THE FIRST AND ONLY FDA-APPROVED ORAL JAK INHIBITOR See dosage adjustments in XELJANZ/XELJANZ XR full prescribing information. FOR MODERATELY TO SEVERELY ACTIVE UC1,2 XELJANZ/XELJANZ XR 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) A MARK OF b 1,2 • OCTAVE 2: 17% of patients taking XELJANZ 10 mg twice daily achieved remission vs I RAPID 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) RAPID, POWERFUL, AND SUSTAINED RESULTS IN UC1,2 In a 52-week maintenance study1,2,c I POWERFUL • 41% on XELJANZ 10 mg twice daily and 34% on XELJANZ 5 mg twice daily achieved remissionb AND (primary endpoint) vs 11% on placebo; P<0.0001d SUSTAINED1,2 • 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 Not an actual patient. Pill not to scale.

INDICATION In the UC population, XELJANZ 10 mg twice daily was associated 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, • XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment with greater risk of serious infections compared to 5 mg twice double-blind, placebo-controlled clinical trials. In OCTAVE 1 and 2, two identical, 8-week induction studies, 1139 patients with moderately to severely active of adult patients with moderately to severely active ulcerative daily. Opportunistic herpes zoster infections (including 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 meningoencephalitis, ophthalmologic, and disseminated 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 colitis (UC), who have had an inadequate response or who are permitted to use stable doses of oral aminosalicylates and corticosteroids (prednisone daily dose up to 25 mg equivalent). Concomitant immunosuppressants intolerant to TNF blockers. cutaneous) were seen in patients who were treated with b XELJANZ 10 mg twice daily. (immunomodulators or biological therapies) were not permitted. The primary endpoint was remission. In OCTAVE Sustain, a 52-week maintenance study, • Limitations of Use: Use of XELJANZ/XELJANZ XR in 593 patients who had completed the induction studies and achieved clinical response were rerandomized to XELJANZ 10 mg twice daily, XELJANZ 5 mg twice combination with biological therapies for UC or with potent The risks and benefits of treatment with XELJANZ/XELJANZ XR 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 immunosuppressants such as azathioprine and cyclosporine is should be carefully considered prior to initiating therapy in patients entrance into this study for patients who were receiving corticosteroids at baseline. Concomitant immunosuppressants (immunomodulators or biological not recommended. with chronic or recurrent infection, or those who have lived or therapies) were not permitted. The primary endpoint was remission.b Sustained corticosteroid-free remissione was a key secondary endpoint. XELJANZ 5 mg traveled in areas of endemic TB or mycoses. Viral reactivation twice daily is the recommended dosage for maintenance therapy. For patients with loss of response during maintenance treatment, a dosage of 10 mg IMPORTANT SAFETY INFORMATION including herpes virus and hepatitis B reactivation have been twice daily may be considered and limited to the shortest duration. SERIOUS INFECTIONS reported. Screening for viral hepatitis should be performed in Patients treated with XELJANZ/XELJANZ XR are at increased risk accordance with clinical guidelines before starting therapy. IMPORTANT SAFETY INFORMATION (cont’d) pancreatic cancer. NMSCs have been reported in patients for developing serious infections that may lead to hospitalization Patients should be closely monitored for the development of MALIGNANCIES treated with XELJANZ. In the UC population, treatment with or death. Most patients who developed these infections were signs and symptoms of infection during and after treatment Lymphoma and other malignancies have been observed in XELJANZ 10 mg twice daily was associated with greater risk of taking concomitant immunosuppressants, such as methotrexate with XELJANZ/XELJANZ XR, including the possible development patients treated with XELJANZ. Epstein Barr Virus-associated NMSC. Periodic skin examination is recommended for patients or corticosteroids. of tuberculosis in patients who tested negative for latent post-transplant lymphoproliferative disorder has been observed who are at increased risk for skin cancer. If a serious infection develops, interrupt XELJANZ/XELJANZ XR tuberculosis infection prior to initiating therapy. at an increased rate in renal transplant patients treated with THROMBOSIS until the infection is controlled. Caution is also recommended in patients with a history of chronic XELJANZ and concomitant immunosuppressive medications. Thrombosis, including pulmonary embolism, deep venous Reported infections include: lung disease, or in those who develop interstitial lung disease, as Consider the risks and benefi ts of XELJANZ/XELJANZ XR thrombosis, and arterial thrombosis, have occurred in patients they may be more prone to infection. treated with XELJANZ and other Janus kinase inhibitors used to • Active tuberculosis, which may present with pulmonary or treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma treat infl ammatory conditions. RA patients who were 50 years extrapulmonary disease. Patients should be tested for latent MORTALITY of age and older with at least one CV risk factor treated with tuberculosis before XELJANZ/XELJANZ XR use and during skin cancer (NMSC) or when considering continuing XELJANZ/ Rheumatoid arthritis (RA)* patients 50 years of age and older XELJANZ XR in patients who develop a malignancy. XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice therapy. Treatment for latent infection should be initiated prior with at least one cardiovascular (CV) risk factor treated with daily or TNF blockers in a large, ongoing postmarketing safety to XELJANZ/XELJANZ XR use. XELJANZ 10 mg twice a day had a higher rate of all-cause Malignancies (including solid cancers and lymphomas) were study had an observed increase in incidence of these events. • Invasive fungal infections, including cryptococcosis and mortality, including sudden CV death, compared to those treated observed more often in patients treated with XELJANZ 10 mg Many of these events were serious and some resulted in death. pneumocystosis. Patients with invasive fungal infections may with XELJANZ 5 mg given twice daily or TNF blockers in a large, twice daily dosing in the UC long-term extension study. Avoid XELJANZ/XELJANZ XR in patients at risk. Discontinue present with disseminated, rather than localized, disease. ongoing, postmarketing safety study. Other malignancies were observed in clinical studies and the XELJANZ/XELJANZ XR and promptly evaluate patients with • Bacterial, viral, including herpes zoster, and other infections XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is post-marketing setting including, but not limited to, lung symptoms of thrombosis. For patients with UC, use XELJANZ at due to opportunistic pathogens. not recommended for the treatment of RA or PsA†. For UC, use cancer, breast cancer, melanoma, prostate cancer, and the lowest e¢ ective dose and for the shortest duration needed to achieve/maintain therapeutic response. The most common serious infections reported with XELJANZ XELJANZ at the lowest e£ective dose and for the shortest duration included pneumonia, cellulitis, herpes zoster, urinary tract needed to achieve/maintain therapeutic response. infection, diverticulitis, and appendicitis. Avoid use of XELJANZ/ aXELJANZ 10 mg twice daily (n=905); placebo (n=234).1 XELJANZ XR in patients with an active, serious infection, including * RA=rheumatoid arthritis. XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely bRemission was stringently defi ned as a total Mayo score ≤2, with no individual subscore >1 and a rectal active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as bleeding subscore of 0.2 localized infections, or with chronic or recurrent infection. monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). cUse the lowest effective dose to maintain response.2 Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants dXELJANZ 10 mg twice daily (n=197); XELJANZ 5 mg twice daily (n=198); placebo (n=198).2 FDA=US Food and Drug Administration; JAK=Janus kinase; UC=ulcerative colitis; XR=extended release. such as azathioprine and cyclosporine is not recommended. XELJANZ 10 mg twice daily is not approved for use in RA. e † Sustained corticosteroid-free remission was defi ned as remission (a total Mayo score ≤2, with no individual PsA=psoriatic arthritis. XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis subscore >1 and a rectal bleeding subscore of 0) and not taking corticosteroids for at least 4 weeks prior to Please see additional Important Safety Information and who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic the visit at both Week 24 and Week 52 among patients in remission at baseline.2 drugs (DMARDs). Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent fXELJANZ 10 mg twice daily (n=55); XELJANZ 5 mg twice daily (n=65); placebo (n=59).2 Brief Summary of full Prescribing Information, including immunosuppressants such as azathioprine and cyclosporine is not recommended. XELJANZ 10 mg twice daily is not BOXED WARNING, on the following pages. approved for use in PsA. 6-MP=6-mercaptopurine; TNF=tumor necrosis factor; UC=ulcerative colitis; XR=extended release.

GIHEP_3.indd 3 5/12/2020 2:28:00 PM

Cosmos Communications 1 Q1 Q2 C M Y K ej 42476a 02.26.20 133 1 IMPORTANT SAFETY INFORMATION (cont’d) causes of liver enzyme elevations is recommended to identify THROMBOSIS (cont’d) potential cases of drug-induced liver injury. XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is Lipid Elevations: Treatment with XELJANZ was associated not recommended for the treatment of RA or PsA. In a long-term with dose-dependent increases in lipid parameters, including extension study in UC, four cases of pulmonary embolism were total cholesterol, low-density lipoprotein (LDL) cholesterol, and reported in patients taking XELJANZ 10 mg twice daily, including high-density lipoprotein (HDL) cholesterol. Maximum eŒ ects one death in a patient with advanced cancer. were generally observed within 6 weeks. There were no clinically GASTROINTESTINAL PERFORATIONS relevant changes in LDL/HDL cholesterol ratios. Manage patients Gastrointestinal perforations have been reported in XELJANZ with hyperlipidemia according to clinical guidelines. Assessment clinical trials, although the role of JAK inhibition is not known. of lipid parameters should be performed approximately 4-8 weeks In these studies, many patients with rheumatoid arthritis were following initiation of XELJANZ/XELJANZ XR therapy. receiving background therapy with Nonsteroidal Anti-Infl ammatory VACCINATIONS Drugs (NSAIDs). There was no discernable diŒ erence in frequency Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. of gastrointestinal perforation between the placebo and the The interval between live vaccinations and initiation of tofacitinib XELJANZ arms in clinical trials of patients with UC, and many therapy should be in accordance with current vaccination guidelines of them were receiving background corticosteroids. XELJANZ/ regarding immunosuppressive agents. Update immunizations in XELJANZ XR should be used with caution in patients who may be agreement with current immunization guidelines prior to initiating at increased risk for gastrointestinal perforation (e.g., patients with XELJANZ/XELJANZ XR therapy. a history of diverticulitis or taking NSAIDs). PATIENTS WITH GASTROINTESTINAL NARROWING HYPERSENSITIVITY Caution should be used when administering XELJANZ XR to Angioedema and urticaria that may refl ect drug hypersensitivity patients with pre-existing severe gastrointestinal narrowing. have been observed in patients receiving XELJANZ/XELJANZ XR There have been rare reports of obstructive symptoms in patients and some events were serious. If a serious hypersensitivity reaction with known strictures in association with the ingestion of other occurs, promptly discontinue tofacitinib while evaluating the drugs utilizing a non-deformable extended release formulation. potential cause or causes of the reaction. HEPATIC and RENAL IMPAIRMENT LABORATORY ABNORMALITIES Use of XELJANZ/XELJANZ XR in patients with severe hepatic Lymphocyte Abnormalities: Treatment with XELJANZ impairment is not recommended. was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte For patients with moderate hepatic impairment or with moderate counts. Avoid initiation of XELJANZ/XELJANZ XR treatment or severe renal impairment taking XELJANZ 5 mg twice daily, in patients with a count less than 500 cells/mm 3. In patients reduce to XELJANZ 5 mg once daily. who develop a confi rmed absolute lymphocyte count less than For UC patients with moderate hepatic impairment or with 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not moderate or severe renal impairment taking XELJANZ 10 mg recommended. Risk of infection may be higher with increasing twice daily, reduce to XELJANZ 5 mg twice daily. degrees of lymphopenia and consideration should be given to ADVERSE REACTIONS lymphocyte counts when assessing individual patient risk of The most common serious adverse reactions were serious infection. Monitor lymphocyte counts at baseline and every infections. The most commonly reported adverse reactions during 3 months thereafter. the fi rst 3 months in controlled clinical trials in patients with Neutropenia: Treatment with XELJANZ was associated with an RA with XELJANZ 5 mg twice daily and placebo, respectively, increased incidence of neutropenia (less than 2000 cells/mm3) (occurring in greater than or equal to 2% of patients treated with compared to placebo. Avoid initiation of XELJANZ/XELJANZ XR XELJANZ with or without DMARDs) were upper respiratory tract treatment in patients with an ANC less than 1000 cells/mm3. For infection, nasopharyngitis, diarrhea, headache, and hypertension. patients who develop a persistent ANC of 500-1000 cells/mm3, The safety profi le observed in patients with active PsA treated interrupt XELJANZ/XELJANZ XR dosing until ANC is greater than with XELJANZ was consistent with the safety profi le observed in or equal to 1000 cells/mm3. In patients who develop an ANC less RA patients. than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not Adverse reactions reported in ≥5% of patients treated with either recommended. Monitor neutrophil counts at baseline and after 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than 4-8 weeks of treatment and every 3 months thereafter. reported in patients receiving placebo in either the induction or Anemia: Avoid initiation of XELJANZ/XELJANZ XR treatment maintenance clinical trials for UC were: nasopharyngitis, elevated in patients with a hemoglobin level less than 9 g/dL. Treatment cholesterol levels, headache, upper respiratory tract infection, with XELJANZ/XELJANZ XR should be interrupted in patients increased blood creatine phosphokinase, rash, diarrhea, and who develop hemoglobin levels less than 8 g/dL or whose herpes zoster. hemoglobin level drops greater than 2 g/dL on treatment. USE IN PREGNANCY Monitor hemoglobin at baseline and after 4-8 weeks of Available data with XELJANZ/XELJANZ XR use in pregnant women treatment and every 3 months thereafter. are insu£ cient to establish a drug associated risk of major birth Liver Enzyme Elevations: Treatment with XELJANZ was defects, miscarriage or adverse maternal or fetal outcomes. There associated with an increased incidence of liver enzyme are risks to the mother and the fetus associated with rheumatoid elevation compared to placebo. Most of these abnormalities arthritis and UC in pregnancy. In animal studies, tofacitinib at occurred in studies with background DMARD (primarily 6.3 times the maximum recommended dose of 10 mg twice daily methotrexate) therapy. If drug-induced liver injury is suspected, demonstrated adverse embryo-fetal fi ndings. The relevance of the administration of XELJANZ/XELJANZ XR should be these fi ndings to women of childbearing potential is uncertain. interrupted until this diagnosis has been excluded. Routine Consider pregnancy planning and prevention for females of monitoring of liver tests and prompt investigation of the reproductive potential.

References: 1. Data on fi le. Pfi zer Inc., New York, NY. 2. XELJANZ [prescribing information]. New York, NY, Pfi zer Inc., December 2019. Please see Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages.

PP-XUC-USA-1289-02 © 2020 Pfi zer Inc. All rights reserved. Printed in USA/February 2020

GIHEP_4.indd 1 5/12/2020 2:31:02 PM Cosmos Communications 1 Q1 Q2 C M Y K ej 42476a 02.26.20 133 1 XELJANZ® (tofacitinib)/XELJANZ® XR (tofacitinib) BRIEF SUMMARY OF PRESCRIBING INFORMATION. potent immunosuppressants such as azathioprine and Malignancy and Lymphoproliferative Disorders SEE PACKAGE INSERT FOR FULL PRESCRIBING cyclosporine is not recommended. Consider the risks and benefits of XELJANZ/XELJANZ XR INFORMATION. CONTRAINDICATIONS treatment prior to initiating therapy in patients with a known None. malignancy other than a successfully treated WARNING: SERIOUS INFECTIONS, MORTALITY, non-melanoma skin cancer (NMSC) or when considering MALIGNANCY, AND THROMBOSIS WARNINGS AND PRECAUTIONS continuing XELJANZ/XELJANZ XR in patients who develop Serious Infections Serious and sometimes fatal infections SERIOUS INFECTIONS Patients treated with a malignancy. Malignancies were observed in clinical due to bacterial, mycobacterial, invasive fungal, viral, or other studies of XELJANZ. XELJANZ/XELJANZ XR are at increased risk for opportunistic pathogens have been reported in patients developing serious infections that may lead to In the seven controlled rheumatoid arthritis clinical studies, receiving XELJANZ. The most common serious infections 11 solid cancers and one lymphoma were diagnosed in hospitalization or death. Most patients who reported with XELJANZ included pneumonia, cellulitis, developed these infections were taking 3328 patients receiving XELJANZ with or without DMARD, herpes zoster, urinary tract infection, diverticulitis, and compared to 0 solid cancers and 0 lymphomas in concomitant immunosuppressants such as appendicitis. Among opportunistic infections, tuberculosis methotrexate or corticosteroids. 809 patients in the placebo with or without DMARD group and other mycobacterial infections, cryptococcosis, during the first 12 months of exposure. Lymphomas and If a serious infection develops, interrupt XELJANZ/ histoplasmosis, esophageal candidiasis, pneumocystosis, XELJANZ XR until the infection is controlled. solid cancers have also been observed in the long-term multidermatomal herpes zoster, cytomegalovirus infections, extension studies in rheumatoid arthritis patients treated Reported infections include: BK virus infection, and listeriosis were reported with with XELJANZ. • Active tuberculosis, which may present with XELJANZ. Some patients have presented with disseminated pulmonary or extrapulmonary disease. Patients rather than localized disease, and were often taking During the 2 PsA controlled clinical studies there were should be tested for latent tuberculosis before concomitant immunomodulating agents such as 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ/XELJANZ XR use and during therapy. methotrexate or corticosteroids. XELJANZ plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in Treatment for latent infection should be initiated In the UC population, XELJANZ treatment with 10 mg twice prior to XELJANZ/XELJANZ XR use. the placebo plus nonbiologic DMARD group (3 months daily was associated with greater risk of serious infections exposure) and 0 malignancies in 106 patients in the • Invasive fungal infections, including compared to 5 mg twice daily. Additionally, opportunistic adalimumab plus nonbiologic DMARD group (12 months cryptococcosis and pneumocystosis. Patients herpes zoster infections (including meningoencephalitis, exposure). No lymphomas were reported. Malignancies with invasive fungal infections may present with ophthalmologic, and disseminated cutaneous) were seen in have also been observed in the long-term extension study disseminated, rather than localized, disease. patients who were treated with XELJANZ 10 mg twice daily. in psoriatic arthritis patients treated with XELJANZ. • Bacterial, viral, including herpes zoster, and other Other serious infections that were not reported in clinical During the UC controlled clinical studies (8-week induction infections due to opportunistic pathogens. studies may also occur (e.g., coccidioidomycosis). and 52-week maintenance studies), which included The risks and benefits of treatment with XELJANZ/ Avoid use of XELJANZ/XELJANZ XR in patients with an 1220 patients, 0 cases of solid cancer or lymphoma were XELJANZ XR should be carefully considered prior active, serious infection, including localized infections. The observed in XELJANZ-treated patients. In the long-term to initiating therapy in patients with chronic or risks and benefits of treatment should be considered prior to extension study, malignancies (including solid cancers and recurrent infection. initiating XELJANZ/XELJANZ XR in patients: lymphomas) were observed more often in patients treated Patients should be closely monitored for the • with chronic or recurrent infection with XELJANZ 10 mg twice daily. development of signs and symptoms of infection • who have been exposed to tuberculosis In Phase 2B, controlled dose-ranging trials in de-novo renal during and after treatment with XELJANZ/ • with a history of a serious or an opportunistic infection transplant patients, all of whom received induction therapy XELJANZ XR, including the possible development • who have resided or traveled in areas of endemic with basiliximab, high-dose corticosteroids, and of tuberculosis in patients who tested negative for tuberculosis or endemic mycoses; or mycophenolic acid products, Epstein Barr Virus-associated latent tuberculosis infection prior to initiating post-transplant lymphoproliferative disorder was observed therapy. • with underlying conditions that may predispose them to infection. in 5 out of 218 patients treated with XELJANZ (2.3%) MORTALITY Rheumatoid arthritis patients 50 years compared to 0 out of 111 patients treated with cyclosporine. of age and older with at least one cardiovascular Patients should be closely monitored for the development of signs and symptoms of infection during and after Other malignancies were observed in clinical studies and (CV) risk factor treated with XELJANZ 10 mg twice the post-marketing setting, including, but not limited to, a day had a higher rate of all-cause mortality, treatment with XELJANZ/XELJANZ XR. XELJANZ/ XELJANZ XR should be interrupted if a patient develops a lung cancer, breast cancer, melanoma, prostate cancer, and including sudden CV death, compared to those pancreatic cancer. treated with XELJANZ 5 mg given twice daily or serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with Non-Melanoma Skin Cancer Non-melanoma skin TNF blockers in a large, ongoing, postmarketing cancers (NMSCs) have been reported in patients treated safety study. XELJANZ/XELJANZ XR should undergo prompt and complete diagnostic testing appropriate for an with XELJANZ. Periodic skin examination is recommended MALIGNANCIES Lymphoma and other immunocompromised patient; appropriate antimicrobial for patients who are at increased risk for skin cancer. In the malignancies have been observed in patients therapy should be initiated, and the patient should be UC population, treatment with XELJANZ 10 mg twice daily treated with XELJANZ. Epstein Barr Virus- closely monitored. was associated with greater risk of NMSC. associated post-transplant lymphoproliferative Caution is also recommended in patients with a history of Thrombosis Thrombosis, including pulmonary embolism, disorder has been observed at an increased rate in chronic lung disease, or in those who develop interstitial lung deep venous thrombosis, and arterial thrombosis, have renal transplant patients treated with XELJANZ disease, as they may be more prone to infections. occurred in patients treated with XELJANZ and other Janus and concomitant immunosuppressive kinase (JAK) inhibitors used to treat inflammatory conditions. medications. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to Patients with rheumatoid arthritis 50 years of age and older THROMBOSIS Thrombosis, including pulmonary lymphocyte counts when assessing individual patient risk of with at least one CV risk factor treated with XELJANZ 10 mg embolism, deep venous thrombosis, and arterial infection. Discontinuation and monitoring criteria for twice daily compared to XELJANZ 5 mg twice daily or TNF thrombosis have occurred in patients treated with lymphopenia are recommended. blockers in a large, ongoing postmarketing study had an XELJANZ and other Janus kinase inhibitors used to observed increase in incidence of these events. Many of treat inflammatory conditions. Rheumatoid Tuberculosis Patients should be evaluated and tested for latent or active infection prior to and per applicable these events were serious and some resulted in death. arthritis patients who were 50 years of age and A dosage of XELJANZ 10 mg twice daily or older with at least one CV risk factor treated with guidelines during administration of XELJANZ/XELJANZ XR. Anti-tuberculosis therapy should also be considered prior to XELJANZ XR 22 mg once daily is not recommended XELJANZ 10 mg twice daily compared to for the treatment of RA or PsA. XELJANZ 5 mg twice daily or TNF blockers in a administration of XELJANZ/XELJANZ XR in patients with a large, ongoing postmarketing safety study had an past history of latent or active tuberculosis in whom an In a long-term extension study in patients with UC, four observed increase in incidence of these events. adequate course of treatment cannot be confirmed, and for cases of pulmonary embolism were reported in patients Many of these events were serious and some patients with a negative test for latent tuberculosis but who taking XELJANZ 10 mg twice daily, including one death in a resulted in death. Avoid XELJANZ/XELJANZ XR in have risk factors for tuberculosis infection. Consultation patient with advanced cancer. patients at risk. Discontinue XELJANZ/XELJANZ XR with a physician with expertise in the treatment of Promptly evaluate patients with symptoms of thrombosis and promptly evaluate patients with symptoms tuberculosis is recommended to aid in the decision about and discontinue XELJANZ/XELJANZ XR in patients with of thrombosis. whether initiating anti-tuberculosis therapy is appropriate for symptoms of thrombosis. For patients with ulcerative colitis, use XELJANZ an individual patient. Avoid XELJANZ/XELJANZ XR in patients that may be at at the lowest effective dose and for the shortest Patients should be closely monitored for the development of increased risk of thrombosis. For the treatment of UC, use duration needed to achieve/maintain therapeutic signs and symptoms of tuberculosis, including patients who XELJANZ at the lowest effective dose and for the shortest response. tested negative for latent tuberculosis infection prior to duration needed to achieve/maintain therapeutic response. initiating therapy. Gastrointestinal Perforations Events of gastrointestinal INDICATIONS AND USAGE Patients with latent tuberculosis should be treated with perforation have been reported in clinical studies with Rheumatoid Arthritis XELJANZ/XELJANZ XR (tofacitinib) standard antimycobacterial therapy before administering XELJANZ, although the role of JAK inhibition in these is indicated for the treatment of adult patients with XELJANZ/XELJANZ XR. events is not known. In these studies, many patients with moderately to severely active rheumatoid arthritis who Viral Reactivation Viral reactivation, including cases of rheumatoid arthritis were receiving background therapy have had an inadequate response or intolerance to herpes virus reactivation (e.g., herpes zoster), were observed with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). methotrexate. It may be used as monotherapy or in in clinical studies with XELJANZ. Postmarketing cases of There was no discernable difference in frequency of combination with methotrexate or other nonbiologic hepatitis B reactivation have been reported in patients treated gastrointestinal perforation between the placebo and the disease-modifying antirheumatic drugs (DMARDs). with XELJANZ. The impact of XELJANZ/XELJANZ XR on XELJANZ arms in clinical trials of patients with UC, and • Limitations of Use: Use of XELJANZ/XELJANZ XR in chronic viral hepatitis reactivation is unknown. Patients who many of them were receiving background corticosteroids. combination with biologic DMARDs or with potent screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed XELJANZ/XELJANZ XR should be used with caution in immunosuppressants such as azathioprine and patients who may be at increased risk for gastrointestinal cyclosporine is not recommended. in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is perforation (e.g., patients with a history of diverticulitis or Psoriatic Arthritis XELJANZ/XELJANZ XR is indicated increased in patients treated with XELJANZ/XELJANZ XR taking NSAIDs). Patients presenting with new onset for the treatment of adult patients with active psoriatic and appears to be higher in patients treated with XELJANZ in abdominal symptoms should be evaluated promptly for arthritis who have had an inadequate response or Japan and Korea. early identification of gastrointestinal perforation. intolerance to methotrexate or other disease-modifying Hypersensitivity Reactions such as angioedema and antirheumatic drugs (DMARDs). Mortality Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated urticaria that may reflect drug hypersensitivity have been • Limitations of Use: Use of XELJANZ/XELJANZ XR in with XELJANZ 10 mg twice a day had a higher rate of observed in patients receiving XELJANZ/XELJANZ XR. combination with biologic DMARDs or with potent all-cause mortality, including sudden CV death, compared to Some events were serious. If a serious hypersensitivity immunosuppressants such as azathioprine and those treated with XELJANZ 5 mg given twice daily or TNF reaction occurs, promptly discontinue tofacitinib while cyclosporine is not recommended. blockers in a large, ongoing, postmarketing safety study. evaluating the potential cause or causes of the reaction. Ulcerative Colitis XELJANZ/XELJANZ XR is indicated for A dosage of XELJANZ 10 mg twice daily or ADVERSE REACTIONS the treatment of adult patients with moderately to severely XELJANZ XR 22 mg once daily is not recommended The following clinically significant adverse reactions are active ulcerative colitis (UC), who have had an inadequate for the treatment of RA or PsA. described elsewhere in the labeling: response or who are intolerant to TNF blockers. For the treatment of UC, use XELJANZ at the lowest • Serious Infections • Limitations of Use: Use of XELJANZ/XELJANZ XR in effective dose and for the shortest duration needed to • Mortality combination with biological therapies for UC or with achieve/maintain therapeutic response. • Malignancy and Lymphoproliferative Disorders

GIHEP_5.indd 1 5/12/2020 2:33:32 PM • Thrombosis 100 patient-years) who received 10 mg twice daily of creatinine was <0.1 mg/dL in the 12-month pooled safety • Gastrointestinal Perforations XELJANZ. The rate difference between XELJANZ doses analysis; however with increasing duration of exposure in • Hypersensitivity (and the corresponding 95% confidence interval) was the long-term extensions, up to 2% of patients were • Laboratory Abnormalities 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily discontinued from XELJANZ treatment due to the Clinical Trials Experience Because clinical studies are XELJANZ minus 5 mg twice daily XELJANZ. protocol-specified discontinuation criterion of an increase in conducted under widely varying conditions, adverse The median XELJANZ exposure prior to diagnosis of an creatinine by more than 50% of baseline. The clinical reaction rates observed in the clinical studies of a drug opportunistic infection was 8 months (range from 41 to significance of the observed serum creatinine elevations is cannot be directly compared to rates in the clinical studies 698 days). unknown. of another drug and may not predict the rates observed in a Malignancy In the seven controlled trials, during the 0 to Other Adverse Reactions Adverse reactions occurring in broader patient population in clinical practice. 3 months exposure, malignancies excluding NMSC were 2% or more of patients on 5 mg twice daily or 10 mg twice Rheumatoid Arthritis The clinical studies described in the reported in 0 patients who received placebo and 2 patients daily XELJANZ and at least 1% greater than that observed following sections were conducted using XELJANZ. (0.3 events per 100 patient years) who received either in patients on placebo with or without DMARD are Although other doses of XELJANZ have been studied, the XELJANZ 5 mg or 10 mg twice daily. The rate difference summarized in the table below. recommended dose of XELJANZ is 5 mg twice daily. between treatment groups (and the corresponding 95% Common Adverse Reactions* in Clinical Trials of confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient- XELJANZ for the Treatment of Rheumatoid Arthritis The recommended dose for XELJANZ XR is 11 mg once With or Without Concomitant DMARDs (0-3 Months) daily. A dosage of XELJANZ 10 mg twice daily or years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo. XELJANZ XR 22 mg once daily is not a recommended XELJANZ XELJANZ regimen for the treatment of rheumatoid arthritis. In the seven controlled trials, during the 0 to 12 months 5 mg 10 mg Twice Placebo The following data includes two Phase 2 and five Phase 3 exposure, malignancies excluding NMSC were reported in Twice Daily Daily** double-blind, controlled, multicenter trials. In these trials, 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per N = 1336 N = 1349 N = 809 patients were randomized to doses of XELJANZ 5 mg Preferred Term (%) (%) (%) twice daily (292 patients) and 10 mg twice daily 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and Upper respiratory 4 4 3 (306 patients) monotherapy, XELJANZ 5 mg twice daily tract infection (1044 patients) and 10 mg twice daily (1043 patients) in the corresponding 95% confidence interval) was combination with DMARDs (including methotrexate) and 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily Nasopharyngitis 4 3 3 XELJANZ minus 5 mg twice daily XELJANZ. One of these placebo (809 patients). All seven protocols included Diarrhea 4 3 2 provisions for patients taking placebo to receive treatment malignancies was a case of lymphoma that occurred during with XELJANZ at Month 3 or Month 6 either by patient the 0 to 12 month period in a patient treated with Headache 4 3 2 XELJANZ 10 mg twice daily. response (based on uncontrolled disease activity) or by Hypertension 2 2 1 design, so that adverse events cannot always be The most common types of malignancy, including unambiguously attributed to a given treatment. Therefore, malignancies observed during the long-term extension, N reflects randomized and treated patients from the seven some analyses that follow include patients who changed were lung and breast cancer, followed by gastric, colorectal, clinical trials. treatment by design or by patient response from placebo to renal cell, prostate cancer, lymphoma, and malignant melanoma. * reported in ≥2% of patients treated with either dose of XELJANZ in both the placebo and XELJANZ group of a XELJANZ and ≥1% greater than that reported for given interval. Comparisons between placebo and Laboratory Abnormalities placebo. XELJANZ were based on the first 3 months of exposure, Lymphopenia In the controlled clinical trials, confirmed and comparisons between XELJANZ 5 mg twice daily and ** the recommended dose of XELJANZ for the treatment decreases in absolute lymphocyte counts below of rheumatoid arthritis is 5 mg twice daily. XELJANZ 10 mg twice daily were based on the first 500 cells/mm3 occurred in 0.04% of patients for the 12 months of exposure. 5 mg twice daily and 10 mg twice daily XELJANZ groups Other adverse reactions occurring in controlled and The long-term safety population includes all patients who combined during the first 3 months of exposure. open-label extension studies included: participated in a double-blind, controlled trial (including earlier Confirmed lymphocyte counts less than 500 cells/mm3 were Blood and lymphatic system disorders: Anemia development phase studies) and then participated in one of associated with an increased incidence of treated and Infections and infestations: Diverticulitis two long-term safety studies. The design of the long-term serious infections. Metabolism and nutrition disorders: Dehydration safety studies allowed for modification of XELJANZ doses Neutropenia In the controlled clinical trials, confirmed Psychiatric disorders: Insomnia according to clinical judgment. This limits the interpretation of decreases in ANC below 1000 cells/mm3 occurred in 0.07% the long-term safety data with respect to dose. Nervous system disorders: Paresthesia of patients for the 5 mg twice daily and 10 mg twice daily Respiratory, thoracic and mediastinal disorders: The most common serious adverse reactions were serious XELJANZ groups combined during the first 3 months of infections. Dyspnea, cough, sinus congestion, interstitial lung disease exposure. (cases were limited to patients with rheumatoid arthritis The proportion of patients who discontinued treatment due There were no confirmed decreases in ANC below and some were fatal) to any adverse reaction during the 0 to 3 months exposure 500 cells/mm3 observed in any treatment group. in the double-blind, placebo-controlled trials was 4% for Gastrointestinal disorders: Abdominal pain, dyspepsia, There was no clear relationship between neutropenia vomiting, gastritis, nausea patients taking XELJANZ and 3% for placebo-treated and the occurrence of serious infections. patients. Hepatobiliary disorders: Hepatic steatosis In the long-term safety population, the pattern and incidence Overall Infections In the seven controlled trials, during the Skin and subcutaneous tissue disorders: Rash, of confirmed decreases in ANC remained consistent with erythema, pruritus 0 to 3 months exposure, the overall frequency of infections what was seen in the controlled clinical trials. was 20% and 22% in the 5 mg twice daily and 10 mg twice Musculoskeletal, connective tissue and bone disorders: daily groups, respectively, and 18% in the placebo group. Liver Enzyme Elevations Confirmed increases in liver Musculoskeletal pain, arthralgia, tendonitis, joint swelling enzymes greater than 3 times the upper limit of normal The most commonly reported infections with XELJANZ (3x ULN) were observed in patients treated with XELJANZ. Neoplasms benign, malignant and unspecified were upper respiratory tract infections, nasopharyngitis, In patients experiencing liver enzyme elevation, modification (including cysts and polyps): Non-melanoma skin and urinary tract infections (4%, 3%, and 2% of patients, of treatment regimen, such as reduction in the dose of cancers respectively). concomitant DMARD, interruption of XELJANZ, or reduction General disorders and administration site conditions: Serious Infections In the seven controlled trials, during the in XELJANZ dose, resulted in decrease or normalization of Pyrexia, fatigue, peripheral edema 0 to 3 months exposure, serious infections were reported liver enzymes. Clinical Experience in Methotrexate-Naïve Patients in 1 patient (0.5 events per 100 patient-years) who received In the controlled monotherapy trials (0-3 months), no Study RA-VI was an active-controlled clinical trial in placebo and 11 patients (1.7 events per 100 patient-years) differences in the incidence of ALT or AST elevations were methotrexate-naïve patients. The safety experience in who received XELJANZ 5 mg or 10 mg twice daily. The rate observed between the placebo, and XELJANZ 5 mg, and these patients was consistent with Studies RA-I through V. difference between treatment groups (and the corresponding 10 mg twice daily groups. 95% confidence interval) was 1.1 (-0.4, 2.5) events Psoriatic Arthritis XELJANZ 5 mg twice daily and 10 mg per 100 patient-years for the combined 5 mg twice daily In the controlled background DMARD trials (0-3 months), twice daily were studied in 2 double-blind Phase 3 clinical and 10 mg twice daily XELJANZ group minus placebo. ALT elevations greater than 3x ULN were observed in 1.0%, trials in patients with active psoriatic arthritis (PsA). 1.3% and 1.2% of patients receiving placebo, 5 mg, and Although other doses of XELJANZ have been studied, the In the seven controlled trials, during the 0 to 12 months 10 mg twice daily, respectively. In these trials, AST elevations recommended dose of XELJANZ is 5 mg twice daily. The exposure, serious infections were reported in 34 patients greater than 3x ULN were observed in 0.6%, 0.5% and recommended dose for XELJANZ XR is 11 mg once daily. (2.7 events per 100 patient-years) who received 5 mg twice 0.4% of patients receiving placebo, 5 mg, and 10 mg twice A dosage of XELJANZ 10 mg twice daily or daily of XELJANZ and 33 patients (2.7 events per 100 patient- daily, respectively. XELJANZ XR 22 mg once daily is not recommended years) who received 10 mg twice daily of XELJANZ. for the treatment of PsA. The rate difference between XELJANZ doses (and the One case of drug-induced liver injury was reported in a corresponding 95% confidence interval) was patient treated with XELJANZ 10 mg twice daily for Study PsA-I (NCT01877668) had a duration of 12 months -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice approximately 2.5 months. The patient developed and enrolled patients who had an inadequate response to a daily XELJANZ minus 5 mg twice daily XELJANZ. symptomatic elevations of AST and ALT greater than 3x ULN nonbiologic DMARD and who were naïve to treatment and bilirubin elevations greater than 2x ULN, which required with a TNF blocker. Study PsA-I included a 3-month The most common serious infections included pneumonia, hospitalizations and a liver biopsy. placebo-controlled period and also included adalimumab cellulitis, herpes zoster, and urinary tract infection. Lipid Elevations In the controlled clinical trials, 40 mg subcutaneously once every 2 weeks for 12 months. Tuberculosis In the seven controlled trials, during the 0 to dose-related elevations in lipid parameters (total cholesterol, Study PsA-II (NCT01882439) had a duration of 6 months 3 months exposure, tuberculosis was not reported in LDL cholesterol, HDL cholesterol, triglycerides) were and enrolled patients who had an inadequate response to patients who received placebo, 5 mg twice daily of observed at one month of exposure and remained stable at least one approved TNF blocker. This clinical trial included XELJANZ, or 10 mg twice daily of XELJANZ. thereafter. Changes in lipid parameters during the first a 3-month placebo controlled period. In the seven controlled trials, during the 0 to 12 months 3 months of exposure in the controlled clinical trials are In these combined Phase 3 clinical trials, 238 patients were exposure, tuberculosis was reported in 0 patients who summarized below: randomized and treated with XELJANZ 5 mg twice daily received 5 mg twice daily of XELJANZ and 6 patients • Mean LDL cholesterol increased by 15% in the and 236 patients were randomized and treated with (0.5 events per 100 patient-years) who received 10 mg twice XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily. All patients in the clinical trials daily of XELJANZ. The rate difference between XELJANZ XELJANZ 10 mg twice daily arm. were required to receive treatment with a stable dose of a doses (and the corresponding 95% confidence interval) • Mean HDL cholesterol increased by 10% in the nonbiologic DMARD [the majority (79%) received was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg XELJANZ 5 mg twice daily arm and 12% in the methotrexate]. The study population randomized and twice daily XELJANZ minus 5 mg twice daily XELJANZ. XELJANZ 10 mg twice daily arm. treated with XELJANZ (474 patients) included 45 (9.5%) Cases of disseminated tuberculosis were also reported. • Mean LDL/HDL ratios were essentially unchanged in patients aged 65 years or older and 66 (13.9%) patients The median XELJANZ exposure prior to diagnosis of XELJANZ-treated patients. with diabetes at baseline. tuberculosis was 10 months (range from 152 to 960 days). In a controlled clinical trial, elevations in LDL cholesterol and The safety profile observed in patients with active psoriatic Opportunistic Infections (excluding tuberculosis) In the ApoB decreased to pretreatment levels in response to arthritis treated with XELJANZ was consistent with the seven controlled trials, during the 0 to 3 months exposure, statin therapy. safety profile observed in rheumatoid arthritis patients. opportunistic infections were not reported in patients who In the long-term safety population, elevations in lipid Ulcerative Colitis XELJANZ has been studied in patients received placebo, 5 mg twice daily of XELJANZ, or 10 mg with moderately to severely active UC in 4 randomized, twice daily of XELJANZ. parameters remained consistent with what was seen in the controlled clinical trials. double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose ranging UC-V) and an open-label long term In the seven controlled trials, during the 0 to 12 months Serum Creatinine Elevations In the controlled clinical trials, exposure, opportunistic infections were reported in extension study (UC-IV). Adverse reactions reported in dose-related elevations in serum creatinine were observed ≥5% of patients treated with either 5 mg or 10 mg twice 4 patients (0.3 events per 100 patient-years) who received with XELJANZ treatment. The mean increase in serum 5 mg twice daily of XELJANZ and 4 patients (0.3 events per daily of XELJANZ and ≥1% greater than reported in

GIHEP_6.indd 1 5/12/2020 2:35:38 PM patients receiving placebo in either the induction or exposure registry that monitors pregnancy outcomes in Data maintenance clinical trials were: nasopharyngitis, elevated women exposed to XELJANZ/XELJANZ XR during Following administration of tofacitinib to lactating rats, cholesterol levels, headache, upper respiratory tract pregnancy. Patients should be encouraged to enroll in the concentrations of tofacitinib in milk over time paralleled infection, increased blood creatine phosphokinase, rash, XELJANZ/XELJANZ XR pregnancy registry if they become those in serum, and were approximately 2 times diarrhea, and herpes zoster. pregnant. To enroll or obtain information from the registry, higher in milk relative to maternal serum at all time Induction Trials (Study UC-I, UC-II, and UC-V): patients can call the toll free number 1-877-311-8972. points measured. Common adverse reactions reported in ≥2% of patients Risk Summary Available data with XELJANZ/XELJANZ XR Females and Males of Reproductive Potential treated with XELJANZ 10 mg twice daily and ≥1% greater use in pregnant women are insufficient to establish a drug Contraception Females In an animal reproduction than that reported in patients receiving placebo in the associated risk of major birth defects, miscarriage or adverse study, tofacitinib at AUC multiples of 13 times the 3 induction trials were: headache, nasopharyngitis, maternal or fetal outcomes. There are risks to the mother and recommended dose of 5 mg twice daily and 6.3 times elevated cholesterol levels, acne, increased blood creatine the fetus associated with rheumatoid arthritis and UC in the maximum recommended dose of 10 mg twice daily phosphokinase, and pyrexia. pregnancy (see Clinical Considerations). In animal demonstrated adverse embryo-fetal findings. However, Maintenance Trial (Study UC-III): reproduction studies, fetocidal and teratogenic effects were there is uncertainty as to how these animal findings relate noted when pregnant rats and rabbits received tofacitinib to females of reproductive potential treated with the Common adverse reactions reported in ≥4% of patients during the period of organogenesis at exposures multiples of treated with either dose of XELJANZ and ≥1% greater than recommended clinical dose. Consider pregnancy planning 73-times and 6.3-times the maximum recommended dose and prevention for females of reproductive potential. reported in patients receiving placebo are shown in the of 10 mg twice daily, respectively. Further, in a peri- and table below. Infertility Females Based on findings in rats, treatment post-natal study in rats, tofacitinib resulted in reductions in with XELJANZ/XELJANZ XR may result in reduced fertility Common Adverse Reactions* in UC Patients during the live litter size, postnatal survival, and pup body weights at Maintenance Trial (Study UC-III) in females of reproductive potential. It is not known if this exposure multiples of approximately 73-times the effect is reversible. recommended dose of 5 mg twice daily and approximately XELJANZ XELJANZ 36 times the maximum recommended dose of 10 mg twice Pediatric Use The safety and effectiveness of XELJANZ/ 5 mg 10 mg Placebo XELJANZ XR in pediatric patients have not been established. Twice Daily Twice Daily daily, respectively (see Data). The estimated background risks of major birth defects and Geriatric Use Of the 3315 patients who enrolled in N = 198 N = 196 N = 198 miscarriage for the indicated populations are unknown. All rheumatoid arthritis Studies I to V, a total of 505 rheumatoid Preferred Term (%) (%) (%) pregnancies have a background risk of birth defect, loss, or arthritis patients were 65 years of age and older, including Nasopharyngitis 10 14 6 other adverse outcomes. The background risks in the U.S. 71 patients 75 years and older. The frequency of serious general population of major birth defects and miscarriages infection among XELJANZ-treated subjects 65 years of age Elevated cholesterol 5 9 1 and older was higher than among those under the age of 65. levels** are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively. Of the 1156 XELJANZ-treated patients in the UC program, a Headache 9 3 6 Clinical Considerations total of 77 patients (7%) were 65 years of age or older. The number of patients aged 65 years and older was not Upper respiratory 7 6 4 Disease-Associated Maternal and/or Embryo/Fetal Risk tract infection sufficient to determine whether they responded differently Published data suggest that increased disease activity is from younger patients. Increased blood 3 7 2 associated with the risk of developing adverse pregnancy creatine phosphokinase As there is a higher incidence of infections in the elderly outcomes in women with rheumatoid arthritis or ulcerative population in general, caution should be used when Rash 3 6 4 colitis. Adverse pregnancy outcomes include preterm treating the elderly. delivery (before 37 weeks of gestation), low birth weight (less Diarrhea 2 5 3 than 2500 g) infants, and small for gestational age at birth. Use in Diabetics Herpes zoster 1 5 1 Data As there is a higher incidence of infection in diabetic population in general, caution should be used when Gastroenteritis 3 4 3 Animal Data In a rat embryofetal developmental study, in treating patients with diabetes. which pregnant rats received tofacitinib during Anemia 4 2 2 organogenesis, tofacitinib was teratogenic at exposure Renal Impairment Nausea 1 4 3 levels approximately 146 times the recommended dose of Moderate and Severe Impairment 5 mg twice daily, and approximately 73 times the maximum XELJANZ-treated patients with moderate or severe renal * reported in ≥4% of patients treated with either dose of recommended dose of 10 mg twice daily (on an AUC basis at impairment had greater tofacitinib blood concentrations XELJANZ and ≥1% greater than reported for placebo. oral doses of 100 mg/kg/day in rats). Teratogenic effects than XELJANZ-treated patients with normal renal function. ** includes hypercholesterolemia, hyperlipidemia, blood consisted of external and soft tissue malformations of Therefore, dosage adjustment of XELJANZ/XELJANZ XR is cholesterol increased, dyslipidemia, blood triglycerides anasarca and membranous ventricular septal defects, recommended in patients with moderate or severe renal increased, low density lipoprotein increased, low respectively; and skeletal malformations or variations impairment (including but not limited to those with severe density lipoprotein abnormal, or lipids increased. (absent cervical arch; bent femur, fibula, humerus, radius, insufficiency who are undergoing hemodialysis). In the long-term extension study, malignancies (including scapula, tibia, and ulna; sternoschisis; absent rib; misshapen • Rheumatoid arthritis and psoriatic arthritis patients solid cancers, lymphomas and NMSC) were observed femur; branched rib; fused rib; fused sternebra; and with moderate or severe renal impairment receiving more often in patients treated with XELJANZ 10 mg twice hemicentric thoracic centrum). In addition, there was an XELJANZ XR should switch to XELJANZ and adjust daily. Four cases of pulmonary embolism were reported in increase in post-implantation loss, consisting of early and the dosage. patients taking XELJANZ 10 mg twice daily, including one late resorptions, resulting in a reduced number of viable Mild impairment fatality in a patient with advanced cancer. fetuses. Mean fetal body weight was reduced. No No dosage adjustment is required in patients with mild Dose-dependent adverse reactions seen in patients treated developmental toxicity was observed in rats at exposure renal impairment. levels approximately 58 times the recommended dose of with XELJANZ 10 mg twice daily, in comparison to 5 mg Hepatic Impairment twice daily, include the following: herpes zoster infections, 5 mg twice daily, and approximately 29 times the maximum serious infections, and NMSC. recommended dose of 10 mg twice daily (on an AUC basis at Severe Impairment Postmarketing Experience Immune system disorders: oral doses of 30 mg/kg/day in pregnant rats). XELJANZ/XELJANZ XR has not been studied in patients Drug hypersensitivity (events such as angioedema and In a rabbit embryofetal developmental study in which with severe hepatic impairment; therefore, use of urticaria have been observed). pregnant rabbits received tofacitinib during the period of XELJANZ/XELJANZ XR in patients with severe hepatic DRUG INTERACTIONS organogenesis, tofacitinib was teratogenic at exposure impairment is not recommended. The table below includes drugs with clinically important levels approximately 13 times the recommended dose of Moderate Impairment drug interactions when administered concomitantly with 5 mg twice daily, and approximately 6.3 times the maximum XELJANZ-treated patients with moderate hepatic XELJANZ/XELJANZ XR and instructions for preventing or recommended dose of 10 mg twice daily (on an AUC basis at impairment had greater tofacitinib blood concentration than managing them. oral doses of 30 mg/kg/day in rabbits) in the absence of signs XELJANZ-treated patients with normal hepatic function. Clinical Relevant Interactions Affecting XELJANZ and of maternal toxicity. Teratogenic effects included Higher blood concentrations may increase the risk of some XELJANZ XR When Coadministered with Other Drugs thoracogastroschisis, omphalocele, membranous ventricular adverse reactions. Therefore, dosage adjustment of septal defects, and cranial/skeletal malformations XELJANZ/XELJANZ XR is recommended in patients with Strong CYP3A4 Inhibitors (e.g., ketoconazole) (microstomia, microphthalmia), mid-line and tail defects. In moderate hepatic impairment. addition, there was an increase in post-implantation loss Increased exposure to tofacitinib • Rheumatoid arthritis and psoriatic arthritis patients Clinical Impact associated with late resorptions. No developmental toxicity receiving XELJANZ XR should switch to XELJANZ and Intervention Dosage adjustment of XELJANZ/ was observed in rabbits at exposure levels approximately adjust the dosage. XELJANZ XR is recommended 3 times the recommended dose of 5 mg twice daily, and Mild Impairment approximately 1.5 times the maximum recommended dose Moderate CYP3A4 Inhibitors Coadministered with No dosage adjustment of XELJANZ/XELJANZ XR is Strong CYP2C19 Inhibitors (e.g., fluconazole) of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits). required in patients with mild hepatic impairment. Clinical Impact Increased exposure to tofacitinib In a peri- and postnatal development study in pregnant rats Hepatitis B or C Serology Intervention Dosage adjustment of XELJANZ/ that received tofacitinib from gestation day 6 through day 20 The safety and efficacy of XELJANZ/XELJANZ XR have not XELJANZ XR is recommended of lactation, there were reductions in live litter size, postnatal been studied in patients with positive hepatitis B virus or Strong CYP3A4 Inducers (e.g., rifampin) survival, and pup body weights at exposure levels hepatitis C virus serology. approximately 73 times the recommended dose of 5 mg Clinical Impact Decreased exposure to tofacitinib and twice daily, and approximately 36 times the maximum OVERDOSAGE may result in loss of or reduced clinical recommended dose of 10 mg twice daily (on an AUC basis at There is no specific antidote for overdose with XELJANZ/ response oral doses of 50 mg/kg/day in rats). There was no effect on XELJANZ XR. In case of an overdose, it is recommended Intervention Coadministration with XELJANZ/ behavioral and learning assessments, sexual maturation or that the patient be monitored for signs and symptoms of XELJANZ XR is not recommended the ability of the F1 generation rats to mate and produce adverse reactions. In a study in subjects with end stage renal disease (ESRD) Immunosuppressive Drugs (e.g., azathioprine, viable F2 generation fetuses in rats at exposure levels tacrolimus, cyclosporine) approximately 17 times the recommended dose of 5 mg undergoing hemodialysis, plasma tofacitinib concentrations twice daily, and approximately 8.3 times the maximum declined more rapidly during the period of hemodialysis and Clinical Impact Risk of added immunosuppression; recommended dose of 10 mg twice daily (on an AUC basis at dialyzer efficiency, calculated as dialyzer clearance/blood flow coadministration with biologic DMARDs or oral doses of 10 mg/kg/day in rats). entering the dialyzer, was high [mean (SD) = 0.73 (0.15)]. potent immunosuppressants has not However, due to the significant non-renal clearance of been studied in patients with rheumatoid Lactation arthritis, psoriatic arthritis, or UC. Risk Summary There are no data on the presence of tofacitinib, the fraction of total elimination occurring by tofacitinib in human milk, the effects on a breastfed infant, or hemodialysis was small, and thus limits the value of Intervention Coadministration with XELJANZ/ hemodialysis for treatment of overdose with XELJANZ/ XELJANZ XR is not recommended the effects on milk production. Tofacitinib is present in the milk of lactating rats (see Data). When a drug is present in XELJANZ XR. This brief summary is based on XELJANZ®/XELJANZ® XR USE IN SPECIFIC POPULATIONS animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in adults (tofacitinib) Prescribing Information LAB-0445-19.0 Issued: All information provided in this section is applicable to December 2019 XELJANZ and XELJANZ XR as they contain the same treated with XELJANZ/XELJANZ XR, such as increased risk active ingredient (tofacitinib). of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours Pregnancy after the last dose of XELJANZ or 36 hours after the last dose © 2020 Pfizer Inc. All rights reserved. January 2020 Pregnancy Exposure Registry There is a pregnancy of XELJANZ XR (approximately 6 elimination half-lives).

GIHEP_7.indd 1 1 Q1 Q2 5/12/2020 2:37:37 PM †NEWS LETTER FROM THE EDITOR Top AGA Community Scientific firepower will save us COVID-19 numbers again are increasing patient cases dramatically. Community infection rates have have next month’s editorial in mind, and I - nearly doubled, and hospitals and health care lookwe publish for useful its officialphrases, newspaper. quotes, ideas, I always and ularly bring their questions to the AGA Com- workers are stretched beyond their limits. It opinions. If you are interested in becoming Pmunityhysicians (https://community.gastro.org) with difficult patient scenarios to reg seek EIC, please email [email protected] for advice from colleagues about therapy and disease this pandemic was managed (mismanaged) more information. management options, is difficult not to feel anger about how poorly best practices, and di- charge and by a large agnoses. The upgraded segmentby so many of ourofficials popu- in As EIC, you will choose the next editorial networking platform lation who still refuse now features a news- protective actions to limit board and forge professional friendships spread. While politics and that are gratifying. You will assume scenarios and regularly scheduled Roundtable dis- ideology continue to cost responsibility for the content, where you feed for difficult patient must balance your own views with those In case you missed it, here are some clinical discus- cussionssions and with Roundtables experts in in the the field. newsfeed this month: ourAmerican saving lives, grace. scientific of both the AGA and our readership. • Practice update: Small intestinal bacteria over- firepowerMy editorial will emergeboard and as Dr. Allen growth (SIBO) (https://community.gastro.org/ posts/22838) year at the helm of GI & Hepatology News. I would be remiss not to acknowledge the • Case: Polypectomy with low neutrophils (https:// AGAI are issuedentering a search our final for the next Editor in contribution that Lora T. McGlade, MS, has community.gastro.org/posts/22844) Chief (EIC), who will take over October 2021. made to GI & Hepatology News. She has been • Case: Esophagus adenocarcinoma after sleeve I urge anyone interested to apply (https:// my partner, as the Frontline Medical Commu- gastrectomy (https://community.gastro.org/ gastro.org/news/prestigious-aga-publica- nications Editor in charge of GI & Hepatology posts/22868) tions-seek-new-editors-in-chief/). As EIC, News. Next month, she will move on to assume • Case: you will choose the next editorial board and a new role. I cannot thank her enough for help- when is it safe? (https://community.gastro.org/ forge professional friendships that are grati- ing make this newspaper work. As the months posts/22890) Restarting infliximab after shingles – fying. You will assume responsibility for the go on, I will highlight the contributions of oth- • Case: Flatulence in Colorado (https://community. content, where you must balance your own ers from the AGA, our Board, and Frontline. gastro.org/posts/22901) views with those of both the AGA and our Please stay safe and do not let your guard • Case: Serrated epithelial change (SEC) in IBD readership. down. COVID-19 is merciless and relentless. (https://community.gastro.org/posts/22948) As EIC, each month I am given space for “If you think research is expensive, try dis- • Case: Multiloculated pancreatic cyst (https:// 300 words to communicate interesting ideas ease.” – Mary Lasker. community.gastro.org/posts/22935) and opinions. The AGA gives the newspaper great editorial freedom, and I hope we have John I. Allen, MD, MBA, AGA View all upcoming Roundtables in the community at supported AGA’s mission and values when Editor in Chief https://community.gastro.org/discussions.

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Editor in ChiEf, Gi & hEpatoloGy nEws Gi & hEpatoloGy nEws is the official newspaper of the American frontlinE mEdiCal CommuniCations soCiEty partnErs John I. Allen, MD, MBA, AGAF Gastroenterological Association (AGA) Institute and provides the Executive Editor Kathy Scarbeck, MA Editor in ChiEf, thE nEw GastroEntEroloGist gastroenterologist with timely and relevant news and commentary about Editor Lora T. McGlade, MS Vijaya L. Rao, MD clinical developments and about the impact of health care policy. Content for Creative Director Louise A. Koenig assoCiatE Editors Gi & hEpatoloGy nEws is developed through a partnership of the newspaper’s Megan A. Adams, MD, JD, MSc medical board of editors (Editor in Chief and Associate Editors), Frontline Director, Production/Manufacturing Rebecca Slebodnik Ziad Gellad, MD, MPH, AGAF Medical Communications Inc. and the AGA Institute Staff. “News from the Kim L. Isaacs, MD, PhD, AGAF AGA” is provided exclusively by the AGA, AGA Institute, and AGA Research Charles J. Kahi, MD, MS, AGAF Foundation. All content is reviewed by the medical board of editors for National Account Manager Joshua Norton 512-375-8202, [email protected] Gyanprakash A. Ketwaroo, MD, MSc accuracy, timeliness, and pertinence. To add clarity and context to important Larry R. Kosinski, MD, MBA, AGAF developments in the field, select content is reviewed by and commented on by Senior Director of Classified Sales Tim LaPella, 484-921-5001, Sonia S. Kupfer, MD external experts selected by the board of editors. [email protected] Wajahat Mehal, MD, PhD The ideas and opinions expressed in Gi & hEpatoloGy nEws do not Advertising Offices 7 Century Drive, Suite 302, Parsippany, NJ 07054-4609 973-206-3434, fax 973-206-9378 Editors EmEritus, Gi & hEpatoloGy nEws necessarily reflect those of the AGA Institute or the Publisher. The AGA Colin W. Howden, MD, AGAF Institute and Frontline Medical Communications Inc. will not assume Editorial Offices 2275 Research Blvd, Suite 400, Rockville, MD 20850, Charles J. Lightdale, MD, AGAF responsibility for damages, loss, or claims of any kind arising from or related 240-221-2400, fax 240-221-2548 Editor EmEritus, thE nEw GastroEntEroloGist to the information contained in this publication, including any claims related Bryson Katona, MD, PhD to the products, drugs, or services mentioned herein. Advertisements do aGa institutE staff not constitute endorsement of products on the part of the AGA Institute or Managing Editor, GI & HepatoloGy News, Jillian L. Schweitzer Frontline Medical Communications Inc. Managing Editor, tHe New GastroeNteroloGIst, Ryan A. Farrell POSTMASTER Send changes of address (with old mailing label) to GI & Senior Publications Manager, Brook A. Simpson Hepatology News, Subscription Service, 10255 W Higgins Road, Suite 280, Director of Publications Lindsey M. Brounstein Rosemont, IL 60018-9914. FRONTLINE MEDICAL COMMUNICATIONS RECIPIENT To change your address, contact Subscription Services at 1-800-430- Vice President of Publications Erin C. Landis Corporate 5450. For paid subscriptions, single issue purchases, and missing issue claims, offiCErs of thE aGa institutE VP, Sales Mike Guire call Customer Service at 1-833-836-2705 or e-mail custsvc.gihep@ President M. Bishr Omary, MD, PhD, AGAF VP, Member Marketing & Digital Production Amy Pfeiffer fulcoinc.com President-Elect John M. Inadomi, MD, AGAF The AGA Institute headquarters is located at 4930 Del Ray Avenue, President, Custom Solutions JoAnn Wahl Vice President John M. Carethers, MD, AGAF Bethesda, MD 20814, [email protected]. Circulation Director Jared Sonners Secretary/Treasurer Lawrence S. Kim, MD, AGAF Gi & hEpatoloGy nEws (ISSN 1934-3450) is published monthly for Director, Custom Programs Patrick Finnegan ©2020 by the AGA Institute. All rights reserved. No part of this publication may be $230.00 per year by Frontline Medical Communications Inc., 7 Century Scan this QR In affiliation with Global Academy for Medical Education, LLC reproduced or transmitted in any form or by any means, electronic or mechanical, Drive, Suite 302, Parsippany, NJ 07054-4609. Code to visit including photocopy, recording, or any information storage and retrieval system, without mdedge.com/ Vice President, Proprietary Conferences, MedscapeLive David J. Small, MBA permission in writing from the publisher. Phone 973-206-3434, fax 973-206-9378 gihepnews

8 December 2020 / GI & Hepatology News

08_18_19_GIH20_12.indd 8 11/20/2020 3:44:21 PM †FROM THE AGA JOURNALS Link between gastroparesis symptoms, constipation?

BY AMY KARON MDedge News constipation (a score of 4 or 5 on a 5-point emptying). In the multivariable analysis, severe medications,ceptor antagonists, and it isor unclearcannabinoids. if these However, induced evere constipation affected 34% of adults constipationmany patients or were if patients taking had combinations primary dis- of with gastroparesis symptoms and showed scale) correlated significantly with a higher S score on the Gastroparesis Cardinal Symptoms anorectal dysfunction, said Adil E. Bharucha, symptom severity in a multicenter prospective patientsIndex (GCSI), with withgastroparesis an odds ratio symptoms of 1.85 were (95% sig- orders, such as abnormal colonic motility or study.a significant positive correlation with confidence interval, 1.30-2.67). In addition, - the gastroenterology and hepatology division Henry P. Parkman, MD, of Temple University MBBS, MD, AGAF, a professor of medicine in in Philadelphia and his associates used a modi- nificantly more likely to report pain in the low - er abdomen (OR, 1.34; 95% CI, 1.06-1.69) and and a medical director in the office of clinical ing scintigraphy, and wireless motility capsule to use medications to manage constipation (OR, withtrials gastroparesis at Mayo Clinic, and Rochester, constipation, Minn., clinicians who fied GI symptoms questionnaire, gastric-empty- and5.09; Hepatology. 95% CI, 2.75-9.41). The findings were shouldwas not consider involved withdrawing in the study. constipatingFor patients published online in Clinical Gastroenterology medications, performing anorectal testing, and enrollsstudies individualsof 338 participants with gastroparesis in the National symp- In the use of individual drug classes, including tomsstitutes (whether of Health or Gastroparesisnot they have Registry,delayed gastric which opiates,Constipation tricyclic was antidepressants, not significantly 5HT3 linked re- with Continued on page 14 referring patients for pelvic floor biofeedback

untreated children, who were test- Question cause or consequence that, after patients started a gluten- Celiac from page 1 said. Gas chromatography showed ed at baseline and then after 6 and and ammonia decreased. of disease processes such as nutri- disease12 months showed on a gluten-freeno evidence diet. of free“Even diet, though fecal levels we identified of butyrate - Children with new-onset celiac mary. “It is not clear whether the celiacmicrobes disease identified or are [in the this result study] of it. resultsent malabsorption, from a gluten-free or whether diet. dys dysbiosis, while a gluten-free diet withdifferences untreated in the celiac abundance disease ofand contribute to the pathogenesis of biosis is present at disease onset or explained up to 2.8% of variation healthya few species controls, between the profound patients mi- performed gas chromatography and ain measure microbiota of species-level between patients diver- and Future research should explore the For the study, the researchers sity,controls. was generallyMicrobial similaralpha diversity, among role of the disease-specific species - crobial dysbiosis noted in Crohn’s identified here,” the researchers 16S ribosomal RNA sequencing of- thedisease investigators was not observed, commented. at least “Al- wrote in Gastroenterology. - fecal samples from 141 children, in groups, but between 3% and 5%- thoughusing crude several diversity alterations indices,” in the neticallyCeliac diseasepredisposed, is multifactorial. only a small cluding 20 with newly biopsy-con of all taxa differed. Irrespective of - proportionWhile up to develop 40% of peopleit, suggesting are ge diagnosedfirmed, previously and on a untreated gluten-free celiac tictreatment, for celiac the disease decreased with abunan error - that environmental factors are key disease; 45 children previously dance of the 11P OTUs was diagnos intestinal microbiota of children with established celiac disease ap have linked celiac disease with ondiet; regular 19 unaffected medications siblings; and hadand no rate of 21.5% ( < .001 vs. random pear to be effects of a gluten-free - to pathogenesis. Recent studies history57 healthy of chronic children gastrointestinal who were not associatedclassification). with Notably, nutrient most or food- of diet, there are specific bacteria symptoms. A single fecal sample these 11 discrepant OTUs were that are distinct biomarkers of ce isalterations pathogenic in orthe a gut secondary microbiome, effect of gluten ingestion, the researchers performingliac disease.” in vitro tests of “can- but it is unclear whether dysbiosis group intake and with biomarkers Future research might involve was tested for all but the previously - t is well known that gluten ingestion in genetically munedidate” cells, bacteria, and studying coculturing whether I - thesedietar bacteriay interventions with human alter theim ac disease, and research over the past decade has that this unique signature is present at diagnosis and- - susceptible individuals does not guarantee celi identifies taxa for further investigation. - A significantly different microbial profile and me researchersrelative abundance said. of these bac natesearched immunity, for environmental which leads totriggers. the adaptive Gut gluten-freetabolites were diet identified are an important in subjects consid- on teria in the gut microbiome, the microbiota play a role in activation of in erationgluten-free when diets. committing The consequences a patient to of this the the Biotechnology and Biological damage that is characteristic of celiac dis- Nutricia Research Foundation, ease.immune The response authors ofand this the study small-bowel sought to may play a role in persistent symptoms identify whether there is a distinct micro- andlife-long the increased therapy. The health microbiome conditions changes we see providedSciences Researchfunding. ThreeCouncil, coinves- and in treated celiac disease. Those on a glu- tigatorsThe Catherine disclosed McEwan ties to Foundation Nutricia, - - ease,bial pattern in comparison among celiac with healthydisease controlspatients, Janssen, Takeda, and several other both those with treated and untreated dis Dr. Adams ten-free diet have other micronutrient defi 4D Pharma, AbbVie, Celltrion, understood.ciencies in addition A gluten-free to microbiome diet focused changes on coinvestigator reported chairing and healthy siblings. - and the health sequelae of this are not fully pharmaceutical companies. One- The authors identified three groups of - - rope. The remaining investigators bacterial taxa: 1) unique to celiac disease indepen restoring the normal gut flora through probiotic or the working group for ISLI Eu dent of treatment, 2) new-onset disease and treat gluten-free prebiotic or fiber supplementation in celi interest. ment responsive, and 3) reflective of diet changes Dawnac disease Wiese patients Adams, could MD, MS, prove is assistant beneficial. professor and reported having no [email protected] of highlyand not predict unique celiac to disease. disease Within regardless the first of treatment. group, 11 medical director, Center for Human Nutrition, depart- distinct operational taxonomic units (OTUs) could- ment of gastroenterology, hepatology, and nutrition, SOURCE: Zafeiropoulou K et al. Gas- - Vanderbilt University Medical Center, Nashville, Tenn. troenterology. 2020 Aug 10;S0016- From these results, we cannot determine if the mi She has no conflicts of interest. 5085(20)35023-X. doi: 10.1053/j. crobial signature is a result of disease or a contrib gastro.2020.08.007. utor to disease development; however, it reinforces MDedge.com/gihepnews / December 2020 9

01_09_to_17_28_31_GIH20_12.indd 9 11/20/2020 3:42:16 PM For the treatment of Helicobacter pylori infection in adults Outsmart Resistance. Eradicate H. pylori. High rates of H. pylori eradication • 84% eradication overall • 90% eradication in patients with confi rmed blood levels of any Talicia component at day 131 Zero to minimal H. pylori resistance • In vitro testing of 345 H. pylori isolates collected at baseline from patients enrolled in the Talicia pivotal trial demonstrated 0% resistance to rifabutin and 6.4% resistance to amoxicillin, the antibiotics in Talicia Favorable safety and tolerability • Treatment discontinuation due to an adverse event occurred in only 1% of patients receiving Talicia Therapy designed with patients in mind • All-in-one capsule • Four capsules q8h with food for 14 days • One Rx and copay Eradication starts here

Please see Brief Summary of Prescribing Information on adjacent pages.

IMPORTANT SAFETY INFORMATION Talicia contains omeprazole, a proton pump inhibitor (PPI), amoxicillin, a penicillin-class Talicia may reduce the efficacy of hormonal contraceptives. An additional non-hormonal method antibacterial, and rifabutin, a rifamycin antibacterial. It is contraindicated in patients with known of contraception is recommended when taking Talicia. hypersensitivity to any of these medications, any other components of the formulation, any Talicia should not be used in patients with hepatic impairment or severe renal impairment. other beta-lactams or any other rifamycin. Acute Interstitial Nephritis has been observed in patients taking PPIs and penicillins. Talicia is contraindicated in patients receiving rilpivirine-containing products. Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been Talicia is contraindicated in patients receiving delavirdine or voriconazole. reported in patients taking PPIs. These events have occurred as both new onset and exacerbation Serious and occasionally fatal hypersensitivity reactions have been reported with omeprazole, of existing autoimmune disease. amoxicillin and rifabutin. The most common adverse reactions (≥1%) were diarrhea, headache, nausea, abdominal pain, Clostridioides diffi cile-associated diarrhea (CDAD) has been reported with use of nearly all chromaturia, rash, dyspepsia, oropharyngeal pain, vomiting, and vulvovaginal candidiasis.

antibacterial agents and may range from mild diarrhea to fatal colitis. REFERENCE: Graham DY, Canaan Y, Maher J, Wiener G, Hulten KG, Kalfus IN. Rifabutin-based triple therapy (RHB-105) for Helicobacter pylori Talicia may cause fetal harm. Talicia is not recommended for use in pregnancy. eradication: a double-blind, randomized, controlled trial. Ann Intern Med. 2020;172(12):795-802. ©2020 RedHill Biopharma Ltd. All rights reserved. US-TAL-049 09/2020

GIHEP_10.indd 1 9/25/2020 10:58:07 AM 9/24/20 2:41 PM For the treatment of Helicobacter pylori infection in adults Outsmart Resistance. Eradicate H. pylori. High rates of H. pylori eradication • 84% eradication overall • 90% eradication in patients with confirmed blood levels of any Talicia component at day 131 Zero to minimal H. pylori resistance • In vitro testing of 345 H. pylori isolates collected at baseline from patients enrolled in the Talicia pivotal trial demonstrated 0% resistance to rifabutin and 6.4% resistance to amoxicillin, the antibiotics in Talicia Favorable safety and tolerability • Treatment discontinuation due to an adverse event occurred in only 1% of patients receiving Talicia Therapy designed with patients in mind • All-in-one capsule • Four capsules q8h with food for 14 days • One Rx and copay Eradication starts here

Please see Brief Summary of Prescribing Information on adjacent pages.

IMPORTANT SAFETY INFORMATION Talicia contains omeprazole, a proton pump inhibitor (PPI), amoxicillin, a penicillin-class Talicia may reduce the effi cacy of hormonal contraceptives. An additional non-hormonal method antibacterial, and rifabutin, a rifamycin antibacterial. It is contraindicated in patients with known of contraception is recommended when taking Talicia. hypersensitivity to any of these medications, any other components of the formulation, any Talicia should not be used in patients with hepatic impairment or severe renal impairment. other beta-lactams or any other rifamycin. Acute Interstitial Nephritis has been observed in patients taking PPIs and penicillins. Talicia is contraindicated in patients receiving rilpivirine-containing products. Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been Talicia is contraindicated in patients receiving delavirdine or voriconazole. reported in patients taking PPIs. These events have occurred as both new onset and exacerbation Serious and occasionally fatal hypersensitivity reactions have been reported with omeprazole, of existing autoimmune disease. amoxicillin and rifabutin. The most common adverse reactions (≥1%) were diarrhea, headache, nausea, abdominal pain, Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all chromaturia, rash, dyspepsia, oropharyngeal pain, vomiting, and vulvovaginal candidiasis. antibacterial agents and may range from mild diarrhea to fatal colitis. REFERENCE: Graham DY, Canaan Y, Maher J, Wiener G, Hulten KG, Kalfus IN. Rifabutin-based triple therapy (RHB-105) for Helicobacter pylori Talicia may cause fetal harm. Talicia is not recommended for use in pregnancy. eradication: a double-blind, randomized, controlled trial. Ann Intern Med. 2020;172(12):795-802. ©2020 RedHill Biopharma Ltd. All rights reserved. US-TAL-049 09/2020

RHTC320 2 Page Spread Launch Journal Ad REVISED GI and Hep News V1 FINAL 092420.indd 1 GIHEP_11.indd 3 9/25/20209/24/20 10:58:09 2:41 AM PM BRIEF SUMMARY OF PRESCRIBING INFORMATION patient and increases the risk of the development of drug-resistant bacteria. Liver: hepatic dysfunction, cholestatic jaundice, cholestasis, acute cytolytic hepatitis Mycophenolate mofetil (MMF): Use TALICIA with caution in transplant patients TALICIA® (omeprazole magnesium, amoxicillin and rifabutin) delayed-release capsules, for oral use 6 ADVERSE REACTIONS Renal: crystalluria Prevention or Management receiving MMF. See the prescribing information of other drugs dependent on 1 INDICATIONS AND USAGE The following serious adverse reactions are described below and elsewhere in labeling: Hemic and Lymphatic Systems: anemia, hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, gastric pH for absorption. 1.1 Helicobacter pylori Infection TALICIA is indicated for the treatment of Helicobacter pylori infection • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] eosinophilia, leukopenia, and agranulocytosis Tacrolimus • Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.2)] in adults. Central Nervous System: hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral Potential for increased tacrolimus blood levels, especially in patients who are To reduce the development of drug-resistant bacteria and maintain the effectiveness of TALICIA • Acute Interstitial Nephritis [see Warnings and Precautions (5.4)] changes, and/or dizziness Clinical Impact 1.2 Usage • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6)] intermediate or poor metabolizers of CYP2C19. and other antibacterial drugs, TALICIA should be used only to treat or prevent infections that are proven or Rifabutin strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are • Rash in Patients with Mononucleosis [see Warnings and Precautions (5.7)] Prevention or Monitor tacrolimus whole blood levels and adjust dose as per the prescribing • Uveitis [see Warnings and Precautions (5.8)] Blood and lymphatic system disorders: agranulocytosis, lymphopenia Management information for tacrolimus. available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such 7 DRUG INTERACTIONS data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 6.1 Clinical Trials Experience with TALICIA Because clinical trials are conducted under widely varying Drugs Metabolized via the CYP450 Enzymes (e.g., cyclosporine, disulfiram) conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to 7.1 Interactions with Other Drugs and Diagnostics Drug interaction studies with TALICIA have not 2 DOSAGE AND ADMINISTRATION rates in the clinical trials of another drug and may not reflect the rates observed in practice. been conducted. The drug interaction information described here is based on the prescribing information Clinical Impact Interactions are reported with omeprazole and other drugs metabolized via the Administer four (4) TALICIA capsules every 8 hours for 14 days with food. Instruct patients to swallow the of individual TALICIA components: omeprazole, amoxicillin, and rifabutin. CYP450 enzymes. TALICIA capsules whole, with a full glass of water (8 ounces). Each dose (4 capsules) of TALICIA includes The safety of TALICIA was assessed in adult patients who were screened and found to be positive for rifabutin 50 mg, amoxicillin 1,000 mg and omeprazole 40 mg. Do not crush or chew TALICIA capsules. Do H. pylori infection in one active-controlled (Study 1) and one placebo-controlled (Study 2) clinical trial. Rifabutin is a substrate and inducer of cytochrome P450 (CYP) 3A enzymes. Omeprazole is a substrate and Prevention or Monitor patients to determine if it is necessary to adjust the dosage of these other not take TALICIA with alcohol. Patients received TALICIA, amoxicillin and omeprazole, or placebo every eight hours for 14 consecutive an inhibitor of CYP2C19, and a substrate of CYP3A4. Co-administration of TALICIA and other drugs that are Management drugs when taken concomitantly with TALICIA. days taken with food. A total of 305 patients received TALICIA in Studies 1 and 2, 227 patients received substrates, inhibitors, or inducers of these enzymes may alter concentrations of rifabutin/omeprazole or Oral Contraceptives If a dose is missed, patients should continue the normal dosing schedule until the medication is completed. other co-administered drugs [See Table 2 below]. Do not take two doses at one time to make up for a missed dose. 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% Omeprazole magnesium is a PPI. Refer to the prescribing information of the drugs used concomitantly with Concomitant use of amoxicillin and rifabutin with hormonal contraceptives may 4 CONTRAINDICATIONS were white with 64.2% Hispanic or Latino. TALICIA for further information on their interactions with PPIs. lead to loss of its efficacy due to lower estrogen reabsorption and decreased Clinical Impact ethinylestradiol and norethindrone concentrations, respectively [see Warnings and 4.1 Hypersensitivity Reactions TALICIA is contraindicated in patients with known hypersensitivity Adverse Reactions Leading to Discontinuation Table 2: Interactions with TALICIA When Co-Administered with Other Drugs and Diagnostics to the components of TALICIA: amoxicillin [or other ß-lactam antibacterial drugs (e.g., penicillins Precautions (5.3)]. Treatment discontinuation due to an adverse reaction occurred in 1% (4/305) of patients receiving TALICIA, and cephalosporins)], omeprazole (or other benzimidazoles [e.g. proton pump inhibitors (PPIs) and CYP2C19 or CYP3A4 Inducers Prevention or Patients should be advised to use additional or alternative non-hormonal methods anthelmintics]), rifabutin (or any other rifamycins), or to any other component of TALICIA. Hypersensitivity <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 Clinical Impact Decreased exposure of omeprazole when used concomitantly with strong inducers. Management of contraception. reactions may include anaphylaxis or Stevens Johnson Syndrome, anaphylactic shock, angioedema, Diagnostic Investigations for Neuroendocrine Tumors bronchospasm, interstitial nephritis, rash and urticaria [see Warnings and Precautions (5.1), Adverse congestion, and nasopharyngitis, in one patient each. St. John’s Wort, rifampin: Avoid concomitant use with TALICIA [see Warnings and Most Common Adverse Reactions Prevention or Reactions (6.1)]. Management Precautions (5.5)]. PPI-induced decrease in gastric acidity may lead to increased serum chromogranin 4.2 Rilpivirine-containing Products Proton pump inhibitors (PPIs), including omeprazole (a component Selected adverse reactions occurring in ≥1% of patients receiving TALICIA in Study 1 and 2 are described Ritonavir-containing products: See prescribing information for specific drugs. Clinical Impact A (CgA) levels, which may cause false positive results in diagnostics for of TALICIA), are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions in Table 1. CYP2C19 or CYP3A4 Inhibitors neuroendocrine tumors [see Warnings and Precautions (5.9)]. (7.1)]. Table 1: Selected Adverse Reactions Occurring in 1% or Greater of Patients Receiving TALICIA in Clinical Impact Increased blood levels of omeprazole and rifabutin. Assess CgA levels at least 14 days after stopping TALICIA treatment and consider 4.3 Delavirdine The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving Studies 1 and 2 Prevention or repeating the test if initial CgA levels are high. If serial tests are performed (e.g., Voriconazole: Concomitant use with TALICIA is contraindicated [see Management for monitoring), the same commercial laboratory should be used for testing, as delavirdine [see Drug Interactions (7.1)]. Study 1 Study 2 Contraindications (4)]. 4.4 Voriconazole The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving Prevention or reference ranges between tests may vary. Amoxicillin Management Fluconazole, posaconazole, and itraconazole: Avoid concomitant use with TALICIA. voriconazole [see Drug Interactions (7.1)]. If coadministration cannot be avoided, monitor patients for rifabutin associated Urine Glucose Test Adverse Reaction TALICIA and TALICIA Placebo 5 WARNINGS AND PRECAUTIONS (N=228) Omeprazole (N=77) (N=41) adverse events, and lack of anti-fungal efficacy. High urine concentrations of ampicillin or amoxicillin may result in false-positive 5.1 Hypersensitivity Reactions Serious and fatal hypersensitivity reactions, e.g. anaphylaxis, angioedema, n (%) (N=227) n (%) n (%) CYP2C19 Substrates (e.g., Clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clinical Impact reactions when using glucose tests based on the Benedict’s copper reduction erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute n (%) reaction that determines the amount of reducing substances like glucose in generalized exanthematous pustulosis, hypersensitivity vasculitis, interstitial nephritis, and serum sickness Clinical Impact Increased plasma concentrations of CYP2C19 substrate drugs or decreased/ the urine. have been reported with the components of TALICIA: omeprazole, amoxicillin and rifabutin. Diarrhea 23 (10.1) 18 (7.9) 11 (14.3) 4 (9.8) increased plasma concentrations of its active metabolite(s). a Prevention or Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute Headache 17 (7.5) 16 (7.0) 12 (15.6) 4 (9.8) Prevention or Clopidogrel: Consider use of alternative anti-platelet therapy [see Warnings and Management Glucose tests based on enzymatic glucose oxidase reactions should be used. Management Precautions (5.5)]. Avoid concomitant use with TALICIA. bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, Nausea 11 (4.8) 12 (5.3) 3 (3.9) 1 (2.4) Interaction with Secretin Stimulation Test muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of Abdominal painb 8 (3.5) 11 (4.8) 3 (3.9) 2 (4.9) Antiretrovirals/Protease Inhibitors breath, chest pain, cough, syncope, palpitations). Hyper-response in gastrin secretion in response to secretin stimulation test may c Antiretrovirals/protease inhibitors may increase rifabutin blood levels. Clinical Impact There have been reports of individuals with a history of penicillin hypersensitivity who have experienced Chromaturia 0 0 10 (13.0) 1 (2.4) falsely suggest gastrinoma. d The effect of PPIs (such as omeprazole in TALICIA) on antiretroviral drugs is variable. severe reactions when treated with cephalosporins. Rash 6 (2.6) 2 (0.9) 4 (5.2) 0 The clinical importance and the mechanisms behind these interactions are not Prevention or Test should be performed at least 14 days after stopping TALICIA treatment to allow Before initiating therapy with TALICIA, inquire about history of hypersensitivity reactions to penicillins, Dyspepsiae 5 (2.2) 3 (1.3) 1 (1.3) 0 always known. Management gastrin levels to return to baseline. cephalosporins, rifamycins, or PPIs. Discontinue TALICIA and institute immediate therapy, if hypersensitivity Vomiting 5 (2.2) 5 (2.2) 1 (1.3) 2 (4.9) • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and False Positive Urine Tests for Tetrahydrocannabinol (THC) reactions occur. Clinical Impact nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect Oropharyngeal pain 2 (0.9) 2 (0.9) 3 (3.9) 0 There have been reports of false positive urine screening tests for THC in patients 5.2 Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has and promote the development of drug resistance. Clinical Impact receiving PPIs. been reported with use of omeprazole, a component of TALICIA and nearly all antibacterial agents, including Vulvovaginal candidiasisf 5 (2.2) 5 (2.2) 0 0 • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used Prevention or amoxicillin and rifabutin, which are components of TALICIA and may range in severity from mild diarrhea to a concomitantly with omeprazole may increase toxicity. Headache includes: headache and migraine. Management An alternative confirmatory method should be considered to verify positive results. fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth b Abdominal pain includes: abdominal pain, abdominal pain upper, and abdominal pain lower. There are other antiretroviral drugs which do not result in clinically relevant of C. difficile. c Riboflavin was administered in Study 1 to prevent unintentional unblinding and may have contributed to interactions with omeprazole. Other Laboratory Tests CDAD must be considered in all patients who present with diarrhea following proton pump inhibitor and under-reporting of chromaturia. Delavirdine: Combination treatment with TALICIA and delavirdine is contraindicated Following administration of ampicillin or amoxicillin to pregnant women, a transient or antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two d Rash includes: rash, rash maculo-papular, rash morbilliform, and urticaria. [see Contraindications (4)]. Clinical Impact decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, months after the administration of antibacterial agents. e Dyspepsia includes: dyspepsia and epigastric discomfort. Rilpivirine-containing products: Concomitant use with TALICIA is contraindicated conjugated estrone, and estradiol has been noted. If CDAD is confirmed, TALICIA should be discontinued. Appropriate fluid and electrolyte management, f Vulvovaginal candidiasis includes: vulvovaginal candidiasis, vulvovaginal mycotic infection, fungal Prevention or [see Contraindications (4)]. protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be infection, and vaginal discharge + vulvovaginal burning sensation + vulvovaginal pruritus. Management Avoid concomitant use of TALICIA with amprenavir, indinavir, lopinavir/ritonavir, 8 USE IN SPECIFIC POPULATIONS instituted as clinically indicated. 6.2 Other Important Adverse Reactions from the Labeling of the Individual Components of TALICIA saquinavir/ritonavir, ritonavir, tipranavir/ritonavir, fosamprenavir/ritonavir, or nelfinavir 8.1 Pregnancy 5.3 Reduced Efficacy of Hormonal Contraceptives TALICIA may reduce the efficacy of hormonal Additional adverse reactions that occurred in 1% or greater of patients treated with omeprazole or rifabutin [see Warnings and Precautions (5.5)]. Risk Summary contraceptives. Therefore, an additional non-hormonal highly effective method of contraception should be alone in clinical trials were as follows: Other antiretrovirals: See prescribing information for specific antiretroviral drugs. Based on animal reproduction studies, TALICIA may cause fetal harm when administered to pregnant used while taking TALICIA [see Drug Interactions (7.1)]. Omeprazole Flatulence, acid regurgitation, upper respiratory infection, constipation, dizziness, asthenia, back Probenecid women. There are no adequate and well controlled studies of amoxicillin, omeprazole, or rifabutin (used 5.4 Acute Interstitial Nephritis Acute interstitial nephritis (AIN) has been observed in patients taking pain, and cough. Clinical Impact Increased and prolonged blood levels of amoxicillin. separately or together) in pregnant women. Use of TALICIA is generally not recommended for use in PPIs including omeprazole as well as in patients taking penicillins such as amoxicillin, a component of pregnancy. If TALICIA is used during pregnancy, advise pregnant women of the potential risk to a fetus. Rifabutin Flatulence, asthenia, chest pain, fever, pain, leucopenia, anemia, anorexia, eructation, myalgia, Allopurinol TALICIA. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to insomnia, and taste perversion. 8.2 Lactation an idiopathic hypersensitivity reaction. Discontinue TALICIA if AIN develops [see Contraindications (4.1)]. The following selected adverse reactions occurred in less than 1% of patients treated with rifabutin alone: Increase in the incidence of rashes is reported in patients receiving both allopurinol Risk Summary 5.5 Risk of Adverse Reactions or Loss of Efficacy Due to Drug Interactions Components of flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, dyspnea, skin discoloration, thrombocytopenia, Clinical Impact and amoxicillin together compared to patients receiving amoxicillin alone. It is not Data from a published clinical lactation study reports that amoxicillin is present in human milk. Published TALICIA have the potential for clinically important drug interactions [see Contraindications (4) and Drug pancytopenia, and jaundice. known whether this potentiation of amoxicillin rashes is due to allopurinol or the adverse effects with amoxicillin exposure in the breast-fed infant include diarrhea. hyperuricemia present in these patients. Interactions (7)]. 6.3 Post-Marketing Experience with Components of TALICIA Because these reactions are voluntarily The developmental and health benefits of breastfeeding should be considered along with the mother’s Avoid concomitant use of TALICIA with other CYP2C19 or CYP3A4 inducers (e.g. St. John’s Wort, rifampin) reported from a population of uncertain size, it is not always possible to reliably estimate their actual Prevention or Discontinue allopurinol at the first appearance of skin rash. Assess benefit-risk of clinical need for TALICIA and any potential adverse effects on the breast-fed child from TALICIA or from the as they can substantially decrease omeprazole concentrations. Avoid concomitant use of TALICIA with frequency or establish a causal relationship to drug exposure. Management continuing TALICIA treatment. underlying condition. CYP2C19 and/or CYP3A4 inhibitors (e.g. fluconazole, itraconazole) as it may significantly increase the Omeprazole Warfarin, and Other Oral Anticoagulants 8.3 Females and Males of Reproductive Potential plasma concentration of component (s) of TALICIA. Depending on the protease inhibitor, the concomitant Cardiovascular: angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema Abnormal prolongation of prothrombin time (increased international normalized ratio Contraception use of TALICIA should be avoided (e.g. amprenavir, indinavir) or dose adjustments for a concomitantly Both rifabutin and amoxicillin components of TALICIA interact with hormonal contraceptives resulting in administered protease inhibitor(s) may be required. Concomitant use of PPIs with methotrexate (primarily Endocrine: gynecomastia [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants Gastrointestinal: pancreatitis including fatal pancreatitis, anorexia, irritable colon, fecal discoloration, Clinical Impact and in patients receiving PPIs, including omeprazole, and warfarin concomitantly. lower levels of these contraceptives. Therefore, female patients taking hormonal contraceptives should use at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading an additional non-hormonal highly effective method of contraception while taking TALICIA. to methotrexate toxicities. Avoid TALICIA in patients on high-dose methotrexate. Concomitant use of mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis, fundic gland Increases in INR and prothrombin time may lead to abnormal bleeding and even clopidogrel and omeprazole reduces the pharmacological activity of clopidogrel. Avoid TALICIA in patients polyps, gastroduodenal carcinoids in patients with Zollinger-Ellison syndrome on long-term treatment as a death. 8.5 Geriatric Use Clinical studies of TALICIA did not include sufficient numbers of subjects aged 65 on clopidogrel. When using TALICIA, consider alternative anti-platelet therapy [see Drug Interactions (7)]. manifestation of the underlying condition associated with such tumors Prevention or Monitor INR and prothrombin time and adjust the dose of warfarin or other oral 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. 5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic Hepatic: fatal hepatic failure or necrosis, hepatic encephalopathy, hepatocellular disease, cholestatic Management anticoagulants to maintain the desired level of anticoagulation. 8.6 Renal Impairment It is recommended to avoid the use of TALICIA in patients with severe renal lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events disease, mixed hepatitis, jaundice Methotrexate have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of Metabolism and Nutritional disorders: hypoglycemia, hypomagnesemia, with or without hypocalcemia impairment (GFR < 30 mL/min). Amoxicillin is primarily eliminated by the kidney. PPI-induced lupus erythematosus cases were CLE. If signs or symptoms consistent with CLE or SLE and/or hypokalemia, hyponatremia, weight gain Concomitant use of omeprazole with methotrexate (primarily at high doses) 8.7 Hepatic Impairment It is recommended to avoid the use of TALICIA in patients with hepatic may elevate and prolong serum levels of methotrexate and/or its metabolite develop in patients receiving TALICIA, discontinue the drug and evaluate as appropriate. Musculoskeletal: muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture. Clinical Impact impairment. In patients with hepatic impairment (Child-Pugh Class A, B, or C) exposure to omeprazole hydroxymethotrexate, possibly leading to methotrexate toxicities [see Warnings and substantially increased compared to healthy subjects. 5.7 Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who Nervous System/Psychiatric: depression, agitation, aggression, hallucinations, confusion, insomnia, Precautions (5.5)]. receive amoxicillin develop an erythematous skin rash. Avoid TALICIA in patients with mononucleosis. nervousness, apathy, somnolence, anxiety, dream abnormalities, tremors, paresthesia, vertigo 10 OVERDOSAGE Prevention or No information is available on accidental overdosage of TALICIA in humans. 5.8 Uveitis Due to the possible occurrence of uveitis, patients should be carefully monitored when Respiratory: epistaxis Avoid concomitant use of TALICIA in patients receiving high-dose methotrexate. Management In case of an overdose, patients should contact a physician, poison control center, or emergency room. rifabutin, a component of TALICIA, is given in combination with clarithromycin (or other macrolides) and/or Skin: photosensitivity, urticaria, pruritus, petechiae, purpura, alopecia, dry skin, hyperhidrosis fluconazole and related compounds. If uveitis is suspected, refer for an ophthalmologic evaluation and, if Digoxin Special Senses: tinnitus, taste perversion considered necessary, suspend treatment with rifabutin [see Adverse Reactions (6.2)]. Clinical Impact Potential for increased digoxin blood levels. 5.9 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A Ocular: optic atrophy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision TALICIA is distributed by RedHill Biopharma Inc. Raleigh, NC Urogenital: hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, Prevention or Monitor digoxin concentrations. Dose adjustment may be needed to maintain TALICIA is manufactured in Sweden for RedHill Biopharma Ltd. Tel Aviv, Israel (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may Management therapeutic drug concentrations. See digoxin prescribing information. cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at glycosuria, urinary frequency, testicular pain TALICIA is a trademark registered with the U.S. Patent and Trademark Office and used under license by least 14 days after TALICIA treatment and consider repeating the test if initial CgA levels are high [see Drug Hematologic: Agranulocytosis, hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, RedHill Biopharma Inc. Interactions (7)]. leukopenia, leukocytosis mycophenolate mofetil, ketoconazole/itraconazole) ©2020 RedHill Biopharma Ltd. All rights reserved. TAL/0050 04/2020 Amoxicillin 5.10 Development of Drug-Resistant Bacteria Prescribing TALICIA either in the absence of a proven Clinical Impact Omeprazole can alter the absorption of other drugs due to its effect of reducing or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the Gastrointestinal: black hairy tongue intragastric acidity thereby increasing gastric pH.

GIHEP_1RHTC3202.indd Talicia 1 PI Brief Summary GI and Hep News V1 FINAL 092420.indd 1 10/20/2020 11:10:46 AM 9/24/20 9:42 AM BRIEF SUMMARY OF PRESCRIBING INFORMATION patient and increases the risk of the development of drug-resistant bacteria. Liver: hepatic dysfunction, cholestatic jaundice, cholestasis, acute cytolytic hepatitis Mycophenolate mofetil (MMF): Use TALICIA with caution in transplant patients TALICIA® (omeprazole magnesium, amoxicillin and rifabutin) delayed-release capsules, for oral use 6 ADVERSE REACTIONS Renal: crystalluria Prevention or Management receiving MMF. See the prescribing information of other drugs dependent on 1 INDICATIONS AND USAGE The following serious adverse reactions are described below and elsewhere in labeling: Hemic and Lymphatic Systems: anemia, hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, gastric pH for absorption. 1.1 Helicobacter pylori Infection TALICIA is indicated for the treatment of Helicobacter pylori infection • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] eosinophilia, leukopenia, and agranulocytosis Tacrolimus • Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.2)] in adults. Central Nervous System: hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral Potential for increased tacrolimus blood levels, especially in patients who are To reduce the development of drug-resistant bacteria and maintain the effectiveness of TALICIA • Acute Interstitial Nephritis [see Warnings and Precautions (5.4)] changes, and/or dizziness Clinical Impact 1.2 Usage • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6)] intermediate or poor metabolizers of CYP2C19. and other antibacterial drugs, TALICIA should be used only to treat or prevent infections that are proven or Rifabutin strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are • Rash in Patients with Mononucleosis [see Warnings and Precautions (5.7)] Prevention or Monitor tacrolimus whole blood levels and adjust dose as per the prescribing • Uveitis [see Warnings and Precautions (5.8)] Blood and lymphatic system disorders: agranulocytosis, lymphopenia Management information for tacrolimus. available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such 7 DRUG INTERACTIONS data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 6.1 Clinical Trials Experience with TALICIA Because clinical trials are conducted under widely varying Drugs Metabolized via the CYP450 Enzymes (e.g., cyclosporine, disulfiram) conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to 7.1 Interactions with Other Drugs and Diagnostics Drug interaction studies with TALICIA have not 2 DOSAGE AND ADMINISTRATION rates in the clinical trials of another drug and may not reflect the rates observed in practice. been conducted. The drug interaction information described here is based on the prescribing information Clinical Impact Interactions are reported with omeprazole and other drugs metabolized via the Administer four (4) TALICIA capsules every 8 hours for 14 days with food. Instruct patients to swallow the of individual TALICIA components: omeprazole, amoxicillin, and rifabutin. CYP450 enzymes. TALICIA capsules whole, with a full glass of water (8 ounces). Each dose (4 capsules) of TALICIA includes The safety of TALICIA was assessed in adult patients who were screened and found to be positive for rifabutin 50 mg, amoxicillin 1,000 mg and omeprazole 40 mg. Do not crush or chew TALICIA capsules. Do H. pylori infection in one active-controlled (Study 1) and one placebo-controlled (Study 2) clinical trial. Rifabutin is a substrate and inducer of cytochrome P450 (CYP) 3A enzymes. Omeprazole is a substrate and Prevention or Monitor patients to determine if it is necessary to adjust the dosage of these other not take TALICIA with alcohol. Patients received TALICIA, amoxicillin and omeprazole, or placebo every eight hours for 14 consecutive an inhibitor of CYP2C19, and a substrate of CYP3A4. Co-administration of TALICIA and other drugs that are Management drugs when taken concomitantly with TALICIA. days taken with food. A total of 305 patients received TALICIA in Studies 1 and 2, 227 patients received substrates, inhibitors, or inducers of these enzymes may alter concentrations of rifabutin/omeprazole or Oral Contraceptives If a dose is missed, patients should continue the normal dosing schedule until the medication is completed. other co-administered drugs [See Table 2 below]. Do not take two doses at one time to make up for a missed dose. 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% Omeprazole magnesium is a PPI. Refer to the prescribing information of the drugs used concomitantly with Concomitant use of amoxicillin and rifabutin with hormonal contraceptives may 4 CONTRAINDICATIONS were white with 64.2% Hispanic or Latino. TALICIA for further information on their interactions with PPIs. lead to loss of its efficacy due to lower estrogen reabsorption and decreased Clinical Impact ethinylestradiol and norethindrone concentrations, respectively [see Warnings and 4.1 Hypersensitivity Reactions TALICIA is contraindicated in patients with known hypersensitivity Adverse Reactions Leading to Discontinuation Table 2: Interactions with TALICIA When Co-Administered with Other Drugs and Diagnostics to the components of TALICIA: amoxicillin [or other ß-lactam antibacterial drugs (e.g., penicillins Precautions (5.3)]. Treatment discontinuation due to an adverse reaction occurred in 1% (4/305) of patients receiving TALICIA, and cephalosporins)], omeprazole (or other benzimidazoles [e.g. proton pump inhibitors (PPIs) and CYP2C19 or CYP3A4 Inducers Prevention or Patients should be advised to use additional or alternative non-hormonal methods anthelmintics]), rifabutin (or any other rifamycins), or to any other component of TALICIA. Hypersensitivity <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 Clinical Impact Decreased exposure of omeprazole when used concomitantly with strong inducers. Management of contraception. reactions may include anaphylaxis or Stevens Johnson Syndrome, anaphylactic shock, angioedema, Diagnostic Investigations for Neuroendocrine Tumors bronchospasm, interstitial nephritis, rash and urticaria [see Warnings and Precautions (5.1), Adverse congestion, and nasopharyngitis, in one patient each. St. John’s Wort, rifampin: Avoid concomitant use with TALICIA [see Warnings and Most Common Adverse Reactions Prevention or Reactions (6.1)]. Management Precautions (5.5)]. PPI-induced decrease in gastric acidity may lead to increased serum chromogranin 4.2 Rilpivirine-containing Products Proton pump inhibitors (PPIs), including omeprazole (a component Selected adverse reactions occurring in ≥1% of patients receiving TALICIA in Study 1 and 2 are described Ritonavir-containing products: See prescribing information for specific drugs. Clinical Impact A (CgA) levels, which may cause false positive results in diagnostics for of TALICIA), are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions in Table 1. CYP2C19 or CYP3A4 Inhibitors neuroendocrine tumors [see Warnings and Precautions (5.9)]. (7.1)]. Table 1: Selected Adverse Reactions Occurring in 1% or Greater of Patients Receiving TALICIA in Clinical Impact Increased blood levels of omeprazole and rifabutin. Assess CgA levels at least 14 days after stopping TALICIA treatment and consider 4.3 Delavirdine The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving Studies 1 and 2 Prevention or repeating the test if initial CgA levels are high. If serial tests are performed (e.g., Voriconazole: Concomitant use with TALICIA is contraindicated [see Management for monitoring), the same commercial laboratory should be used for testing, as delavirdine [see Drug Interactions (7.1)]. Study 1 Study 2 Contraindications (4)]. 4.4 Voriconazole The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving Prevention or reference ranges between tests may vary. Amoxicillin Management Fluconazole, posaconazole, and itraconazole: Avoid concomitant use with TALICIA. voriconazole [see Drug Interactions (7.1)]. If coadministration cannot be avoided, monitor patients for rifabutin associated Urine Glucose Test Adverse Reaction TALICIA and TALICIA Placebo 5 WARNINGS AND PRECAUTIONS (N=228) Omeprazole (N=77) (N=41) adverse events, and lack of anti-fungal efficacy. High urine concentrations of ampicillin or amoxicillin may result in false-positive 5.1 Hypersensitivity Reactions Serious and fatal hypersensitivity reactions, e.g. anaphylaxis, angioedema, n (%) (N=227) n (%) n (%) CYP2C19 Substrates (e.g., Clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clinical Impact reactions when using glucose tests based on the Benedict’s copper reduction erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute n (%) reaction that determines the amount of reducing substances like glucose in generalized exanthematous pustulosis, hypersensitivity vasculitis, interstitial nephritis, and serum sickness Clinical Impact Increased plasma concentrations of CYP2C19 substrate drugs or decreased/ the urine. have been reported with the components of TALICIA: omeprazole, amoxicillin and rifabutin. Diarrhea 23 (10.1) 18 (7.9) 11 (14.3) 4 (9.8) increased plasma concentrations of its active metabolite(s). a Prevention or Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute Headache 17 (7.5) 16 (7.0) 12 (15.6) 4 (9.8) Prevention or Clopidogrel: Consider use of alternative anti-platelet therapy [see Warnings and Management Glucose tests based on enzymatic glucose oxidase reactions should be used. Management Precautions (5.5)]. Avoid concomitant use with TALICIA. bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, Nausea 11 (4.8) 12 (5.3) 3 (3.9) 1 (2.4) Interaction with Secretin Stimulation Test muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of Abdominal painb 8 (3.5) 11 (4.8) 3 (3.9) 2 (4.9) Antiretrovirals/Protease Inhibitors breath, chest pain, cough, syncope, palpitations). Hyper-response in gastrin secretion in response to secretin stimulation test may c Antiretrovirals/protease inhibitors may increase rifabutin blood levels. Clinical Impact There have been reports of individuals with a history of penicillin hypersensitivity who have experienced Chromaturia 0 0 10 (13.0) 1 (2.4) falsely suggest gastrinoma. d The effect of PPIs (such as omeprazole in TALICIA) on antiretroviral drugs is variable. severe reactions when treated with cephalosporins. Rash 6 (2.6) 2 (0.9) 4 (5.2) 0 The clinical importance and the mechanisms behind these interactions are not Prevention or Test should be performed at least 14 days after stopping TALICIA treatment to allow Before initiating therapy with TALICIA, inquire about history of hypersensitivity reactions to penicillins, Dyspepsiae 5 (2.2) 3 (1.3) 1 (1.3) 0 always known. Management gastrin levels to return to baseline. cephalosporins, rifamycins, or PPIs. Discontinue TALICIA and institute immediate therapy, if hypersensitivity Vomiting 5 (2.2) 5 (2.2) 1 (1.3) 2 (4.9) • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and False Positive Urine Tests for Tetrahydrocannabinol (THC) reactions occur. Clinical Impact nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect Oropharyngeal pain 2 (0.9) 2 (0.9) 3 (3.9) 0 There have been reports of false positive urine screening tests for THC in patients 5.2 Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has and promote the development of drug resistance. Clinical Impact receiving PPIs. been reported with use of omeprazole, a component of TALICIA and nearly all antibacterial agents, including Vulvovaginal candidiasisf 5 (2.2) 5 (2.2) 0 0 • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used Prevention or amoxicillin and rifabutin, which are components of TALICIA and may range in severity from mild diarrhea to a concomitantly with omeprazole may increase toxicity. Headache includes: headache and migraine. Management An alternative confirmatory method should be considered to verify positive results. fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth b Abdominal pain includes: abdominal pain, abdominal pain upper, and abdominal pain lower. There are other antiretroviral drugs which do not result in clinically relevant of C. difficile. c Riboflavin was administered in Study 1 to prevent unintentional unblinding and may have contributed to interactions with omeprazole. Other Laboratory Tests CDAD must be considered in all patients who present with diarrhea following proton pump inhibitor and under-reporting of chromaturia. Delavirdine: Combination treatment with TALICIA and delavirdine is contraindicated Following administration of ampicillin or amoxicillin to pregnant women, a transient or antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two d Rash includes: rash, rash maculo-papular, rash morbilliform, and urticaria. [see Contraindications (4)]. Clinical Impact decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, months after the administration of antibacterial agents. e Dyspepsia includes: dyspepsia and epigastric discomfort. Rilpivirine-containing products: Concomitant use with TALICIA is contraindicated conjugated estrone, and estradiol has been noted. If CDAD is confirmed, TALICIA should be discontinued. Appropriate fluid and electrolyte management, f Vulvovaginal candidiasis includes: vulvovaginal candidiasis, vulvovaginal mycotic infection, fungal Prevention or [see Contraindications (4)]. protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be infection, and vaginal discharge + vulvovaginal burning sensation + vulvovaginal pruritus. Management Avoid concomitant use of TALICIA with amprenavir, indinavir, lopinavir/ritonavir, 8 USE IN SPECIFIC POPULATIONS instituted as clinically indicated. 6.2 Other Important Adverse Reactions from the Labeling of the Individual Components of TALICIA saquinavir/ritonavir, ritonavir, tipranavir/ritonavir, fosamprenavir/ritonavir, or nelfinavir 8.1 Pregnancy 5.3 Reduced Efficacy of Hormonal Contraceptives TALICIA may reduce the efficacy of hormonal Additional adverse reactions that occurred in 1% or greater of patients treated with omeprazole or rifabutin [see Warnings and Precautions (5.5)]. Risk Summary contraceptives. Therefore, an additional non-hormonal highly effective method of contraception should be alone in clinical trials were as follows: Other antiretrovirals: See prescribing information for specific antiretroviral drugs. Based on animal reproduction studies, TALICIA may cause fetal harm when administered to pregnant used while taking TALICIA [see Drug Interactions (7.1)]. Omeprazole Flatulence, acid regurgitation, upper respiratory infection, constipation, dizziness, asthenia, back Probenecid women. There are no adequate and well controlled studies of amoxicillin, omeprazole, or rifabutin (used 5.4 Acute Interstitial Nephritis Acute interstitial nephritis (AIN) has been observed in patients taking pain, and cough. Clinical Impact Increased and prolonged blood levels of amoxicillin. separately or together) in pregnant women. Use of TALICIA is generally not recommended for use in PPIs including omeprazole as well as in patients taking penicillins such as amoxicillin, a component of pregnancy. If TALICIA is used during pregnancy, advise pregnant women of the potential risk to a fetus. Rifabutin Flatulence, asthenia, chest pain, fever, pain, leucopenia, anemia, anorexia, eructation, myalgia, Allopurinol TALICIA. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to insomnia, and taste perversion. 8.2 Lactation an idiopathic hypersensitivity reaction. Discontinue TALICIA if AIN develops [see Contraindications (4.1)]. The following selected adverse reactions occurred in less than 1% of patients treated with rifabutin alone: Increase in the incidence of rashes is reported in patients receiving both allopurinol Risk Summary 5.5 Risk of Adverse Reactions or Loss of Efficacy Due to Drug Interactions Components of flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, dyspnea, skin discoloration, thrombocytopenia, Clinical Impact and amoxicillin together compared to patients receiving amoxicillin alone. It is not Data from a published clinical lactation study reports that amoxicillin is present in human milk. Published TALICIA have the potential for clinically important drug interactions [see Contraindications (4) and Drug pancytopenia, and jaundice. known whether this potentiation of amoxicillin rashes is due to allopurinol or the adverse effects with amoxicillin exposure in the breast-fed infant include diarrhea. hyperuricemia present in these patients. Interactions (7)]. 6.3 Post-Marketing Experience with Components of TALICIA Because these reactions are voluntarily The developmental and health benefits of breastfeeding should be considered along with the mother’s Avoid concomitant use of TALICIA with other CYP2C19 or CYP3A4 inducers (e.g. St. John’s Wort, rifampin) reported from a population of uncertain size, it is not always possible to reliably estimate their actual Prevention or Discontinue allopurinol at the first appearance of skin rash. Assess benefit-risk of clinical need for TALICIA and any potential adverse effects on the breast-fed child from TALICIA or from the as they can substantially decrease omeprazole concentrations. Avoid concomitant use of TALICIA with frequency or establish a causal relationship to drug exposure. Management continuing TALICIA treatment. underlying condition. CYP2C19 and/or CYP3A4 inhibitors (e.g. fluconazole, itraconazole) as it may significantly increase the Omeprazole Warfarin, and Other Oral Anticoagulants 8.3 Females and Males of Reproductive Potential plasma concentration of component (s) of TALICIA. Depending on the protease inhibitor, the concomitant Cardiovascular: angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema Abnormal prolongation of prothrombin time (increased international normalized ratio Contraception use of TALICIA should be avoided (e.g. amprenavir, indinavir) or dose adjustments for a concomitantly Both rifabutin and amoxicillin components of TALICIA interact with hormonal contraceptives resulting in administered protease inhibitor(s) may be required. Concomitant use of PPIs with methotrexate (primarily Endocrine: gynecomastia [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants Gastrointestinal: pancreatitis including fatal pancreatitis, anorexia, irritable colon, fecal discoloration, Clinical Impact and in patients receiving PPIs, including omeprazole, and warfarin concomitantly. lower levels of these contraceptives. Therefore, female patients taking hormonal contraceptives should use at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading an additional non-hormonal highly effective method of contraception while taking TALICIA. to methotrexate toxicities. Avoid TALICIA in patients on high-dose methotrexate. Concomitant use of mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis, fundic gland Increases in INR and prothrombin time may lead to abnormal bleeding and even clopidogrel and omeprazole reduces the pharmacological activity of clopidogrel. Avoid TALICIA in patients polyps, gastroduodenal carcinoids in patients with Zollinger-Ellison syndrome on long-term treatment as a death. 8.5 Geriatric Use Clinical studies of TALICIA did not include sufficient numbers of subjects aged 65 on clopidogrel. When using TALICIA, consider alternative anti-platelet therapy [see Drug Interactions (7)]. manifestation of the underlying condition associated with such tumors Prevention or Monitor INR and prothrombin time and adjust the dose of warfarin or other oral 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. 5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic Hepatic: fatal hepatic failure or necrosis, hepatic encephalopathy, hepatocellular disease, cholestatic Management anticoagulants to maintain the desired level of anticoagulation. 8.6 Renal Impairment It is recommended to avoid the use of TALICIA in patients with severe renal lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events disease, mixed hepatitis, jaundice Methotrexate have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of Metabolism and Nutritional disorders: hypoglycemia, hypomagnesemia, with or without hypocalcemia impairment (GFR < 30 mL/min). Amoxicillin is primarily eliminated by the kidney. PPI-induced lupus erythematosus cases were CLE. If signs or symptoms consistent with CLE or SLE and/or hypokalemia, hyponatremia, weight gain Concomitant use of omeprazole with methotrexate (primarily at high doses) 8.7 Hepatic Impairment It is recommended to avoid the use of TALICIA in patients with hepatic may elevate and prolong serum levels of methotrexate and/or its metabolite develop in patients receiving TALICIA, discontinue the drug and evaluate as appropriate. Musculoskeletal: muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture. Clinical Impact impairment. In patients with hepatic impairment (Child-Pugh Class A, B, or C) exposure to omeprazole hydroxymethotrexate, possibly leading to methotrexate toxicities [see Warnings and substantially increased compared to healthy subjects. 5.7 Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who Nervous System/Psychiatric: depression, agitation, aggression, hallucinations, confusion, insomnia, Precautions (5.5)]. receive amoxicillin develop an erythematous skin rash. Avoid TALICIA in patients with mononucleosis. nervousness, apathy, somnolence, anxiety, dream abnormalities, tremors, paresthesia, vertigo 10 OVERDOSAGE Prevention or No information is available on accidental overdosage of TALICIA in humans. 5.8 Uveitis Due to the possible occurrence of uveitis, patients should be carefully monitored when Respiratory: epistaxis Avoid concomitant use of TALICIA in patients receiving high-dose methotrexate. Management In case of an overdose, patients should contact a physician, poison control center, or emergency room. rifabutin, a component of TALICIA, is given in combination with clarithromycin (or other macrolides) and/or Skin: photosensitivity, urticaria, pruritus, petechiae, purpura, alopecia, dry skin, hyperhidrosis fluconazole and related compounds. If uveitis is suspected, refer for an ophthalmologic evaluation and, if Digoxin Special Senses: tinnitus, taste perversion considered necessary, suspend treatment with rifabutin [see Adverse Reactions (6.2)]. Clinical Impact Potential for increased digoxin blood levels. 5.9 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A Ocular: optic atrophy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision TALICIA is distributed by RedHill Biopharma Inc. Raleigh, NC Urogenital: hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, Prevention or Monitor digoxin concentrations. Dose adjustment may be needed to maintain TALICIA is manufactured in Sweden for RedHill Biopharma Ltd. Tel Aviv, Israel (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may Management therapeutic drug concentrations. See digoxin prescribing information. cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at glycosuria, urinary frequency, testicular pain TALICIA is a trademark registered with the U.S. Patent and Trademark Office and used under license by least 14 days after TALICIA treatment and consider repeating the test if initial CgA levels are high [see Drug Hematologic: Agranulocytosis, hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, RedHill Biopharma Inc. Interactions (7)]. leukopenia, leukocytosis mycophenolate mofetil, ketoconazole/itraconazole) ©2020 RedHill Biopharma Ltd. All rights reserved. TAL/0050 04/2020 Amoxicillin 5.10 Development of Drug-Resistant Bacteria Prescribing TALICIA either in the absence of a proven Clinical Impact Omeprazole can alter the absorption of other drugs due to its effect of reducing or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the Gastrointestinal: black hairy tongue intragastric acidity thereby increasing gastric pH.

RHTC320 Talicia PI Brief Summary GI and Hep News V1 FINAL 092420.indd 1 GIHEP_13.indd 1 10/20/20209/24/20 11:14:08 9:42 AM AM †FROM THE AGA JOURNALS

Continued from page 9 [based on] physiological measures, medication Therefore, future studies of patients with therapy if anorectal tests are positive, he said use, and detailed symptom questionnaires,” the gastroparesis and constipation should forgo while acknowledging the need for more data study’s method of grouping patients based on grouping patients based on GI motor patterns on these approaches. For patients without evi- continuous variables could mask relevant clin- and instead validate patient-reported symptom dence of anorectal disorders, he recommended ical nuances, Dr. Levinthal said. He emphasized measures by using novel sensory tests with “simple laxatives or, if necessary, prescription stimuli such as eating, drinking, and balloon dis- tension, Dr. Levinthal said. He also recommend- upper gastrointestinal symptoms.” ed studying cognitive and emotional functioning medications,In this study, some constipation of which alsomay did also not benefit cor- ‘These observations highlight that sensory in this patients, given that conditions such as relate with gastric emptying, which suggests mechanisms are very important factors depression and anxiety are known to affect GI that “motility disturbances in the foregut are that are not interrogated by physiological sensation. separable from those in the hindgut,” said David The National Institute of Diabetes and Diges- Levinthal, MD, PhD, director of the neurogastro- motility tests, but that nonetheless may have tive and Kidney Diseases provided funding. The enterology and motility center at the University an outsized impact on how patients feel.’ of Pittsburgh Medical Center, who also was not - involved in the work. Constipation was only entsinvestigators for anorectal reported devices having jointly no withconflicts Minnesota of marginally linked with colonic transit time (OR, Medicalinterest. Technologies,Dr. Bharucha reportedMedspira, having and Medtronic filed pat 1.04; 95% CI, 1.00-1.07), and delayed gastric that individual physiological tests do not reliably and receiving royalties from Medspira. Dr. Levin- emptying did not predict the severity of dys- predict the presence or severity of GI symptoms: thal reported having served on advisory boards pepsia, he noted. “These observations highlight “What would you make of a 50-hour colonic for Takeda Pharmaceuticals and Alexza Pharma- that sensory mechanisms are very important transit time [CTT]? Or a 60-hour CTT? One could ceuticals. factors that are not interrogated by physiological have either no constipation or severe constipa- [email protected] motility tests, but that nonetheless may have an tion with those values. In clinical practice, it is outsized impact on how patients feel.” SOURCE: Parkman HP et al. Clin Gastroenterol Hepatol. Despite “fairly good phenotyping of patients CTT result [when] formulating a treatment plan.” 2020 Oct 28. doi: 10.1016/j.cgh.2020.10.045. less certain how useful it is to know a specific †GI ONCOLOGY FIT unfit for inpatient, emergency settings

BY MICHAEL VLESSIDES 48% of whom were women, who tation than those without (OR, 3.3; essary indications. underwent at least one FIT test. 95% CI, 1.9-5.5; P < .0001). ost fecal immunochemical Mean age of the study cohort was Of the 117 FIT-positive patients in the inpatient and emergency Mtests (FIT) in the hospital set- 54 years. Only three of the tests, or who underwent a GI consultation, settings,“We feel and that measures FIT is unfit should for usebe ting or the ED are performed for in- 0.5%, were performed to screen for upper endoscopy was a more taken to curb its use,” Dr. Bhatti appropriate indications, according common outcome than colonosco- concluded. “We presented our data to new data. interval, 0.09%-1.52%). py (51.3% vs. 23.1%; P < .0001). to our hospital leadership and a de- “This is the largest study that colorectal cancer (95% confidence cision was made to remove the FIT focuses exclusively on the use of ‘Another option – and this has been done in many settings as an orderable test from the EMR.” FIT in the ED, inpatient wards, and These results are “striking,” said with the fecal occult blood test – is just take FIT off the Jennifer Christie, MD, from Emory misuse,” said investigator Umer units or out of the ER, so providers won’t be tempted University, Atlanta. in the ICU, and it shows significant Bhatti, MD, from Indiana University, to use it as an assessment of these patients.’ “We should be educating our ER Indianapolis. providers and inpatient providers The only “validated indication” about the proper use of FIT,” she for FIT is to screen for colorectal Among the indications docu- Of the 34 patients who underwent said in an interview. “Another op- cancer. However, “99.5% of the FIT mented for FIT were anemia in colonoscopy or sigmoidoscopy, tion – and this has been done in tests done in our study were for 242 (44.0%) patients, suspected GI one was diagnosed with colorectal many settings with the fecal occult inappropriate indications,” he re- bleeding in 225 (40.9%), abdominal cancer and one with advanced ad- blood test – is just take FIT off the ported at the annual meeting of the pain in 31 (5.6%), and change in enoma. units or out of the ER, so provid- American College of Gastroenterol- bowel habits in 19 (3.5%). Overt GI bleeding was a better ers won’t be tempted to use it as ogy, where the study was honored The tests were performed most predictor of a GI consultation than an assessment of these patients. with an ACG Presidential Poster often in the ED (45.3%) and on the a positive FIT result. In fact, use of Because often times, as this study Award. FIT for patients with overt GI bleed- showed, it doesn’t really impact And the inappropriate use of FIT also performed in the ICU (10.5%) ing indicates a poor understanding outcomes.” in these settings had no positive andhospital burn floor unit (42.2%),(2.0%). but were of the test’s utility, the investigators In fact, unnecessary FIT could effect on clinical decision-making, Overall, 297 of the tests, or 54%, reported. put patients at risk for unnecessary he added. were negative, and 253, or 46%, “For patients with overt GI bleed- procedures. “We also know that For their study, Dr. Bhatti and were positive. ing, having a positive FIT made no calling for an inpatient or ER con- colleagues looked at all instances of “GI consults were obtained in difference on how often a bleeding sult from a gastroenterologist may FIT use in their hospital’s electronic 46.2% of the FIT-positive group, - increase both length of stay and medical records from November compared with 13.1% of the py, suggesting that FIT should not costs,” she added. 2017 to October 2019 to assess FIT-negative patients” (odds ratio, besource used was to guide identified decisions on endosco about Dr. Bhatti and Dr. Christie dis- how often FIT was being used, the 5.93; 95% CI, 3.88-9.04, P < .0001), endoscopy or hospitalization,” Dr. - indications for which it was being Dr. Bhatti reported. Bhatti said. tionships. used, and the impact of its use on Among FIT-positive patients, closed no relevant financial rela clinical care. those with overt bleeding were urges their peers to consider mea- A version of this article originally more likely to receive a GI consul- suresIn light to reduce of these FIT findings, tests for the unnec- team appeared on Medscape.com.

14They identified 550 patients, December 2020 / GI & Hepatology News

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GIHEP_15.indd 1 9/17/2020 11:57:15 AM †GI ONCOLOGY Task force: Best practices for malignant CR polyps

BY AMY KARON Moderate-quality evidence links submucosal The MSTFCC recommends that, when reporting on MDedge News invasion with two types of polyp morphology: a malignant colorectal polyp, pathologists follow the structured template of the College of American or patients with malignant colorectal polyps, type) showing a depression or sessile shape and Pathologists and note the lesion’s histologic type, endoscopists should look for features of deep LST-NGLST-G (laterally (laterally spreading spreading tumor, tumor, granular nongranular type) grade of differentiation, extent of tumor exten- Fsubmucosal invasion and should retrieve, that includes a dominant nodule. According to sion or invasion, stalk and mucosal margin, and handle, and submit specimens in ways that sup- low-quality evidence, these lesions should be man- presence or absence of lymphovascular invasion. port thorough and accurate pathologic assessment, Specimen integrity, polyp size and morphology, and according to new recommendations from the U.S. For both pedunculated and nonpedunculated tumor budding are also useful. To reduce miscom- Multi-Society Task Force on Colorectal Cancer. polyps, features denoting a high risk for munication and facilitate appropriate management, “In nonpedunculated lesions with features of pathologists should avoid using the terms carcino- deep submucosal invasion, endoscopic biopsy is residual or recurrent malignancy are poor ma and cancer when describing malignant colorec- followed by surgical resection. In cases without tumor differentiation, lymphovascular invasion, tal polyps, according to the MSTFCC. features of deep submucosal invasion, en bloc re- The decision to recommend adjuvant surgery section and proper specimen handling should be or more than 1 mm of submucosal invasion. “is based on polyp shape, whether there was en considered (if feasible) for lesions with a high risk bloc resection and adequate histologic assessment, Aasma aged with en bloc rather than piecemeal resection. the presence or absence of unfavorable histologic Shaukat, MD, MPH, AGAF, of the Minneapolis Vet- features, the patient’s risk for surgical mortality eransof superficial Affairs Healthsubmucosal Care Systeminvasion,” and wrote her fellow polyps (even if large) and should be considered for - experts. The recommendations were published in LST-GEn bloc lesions resection with is a important dominant fornodule. all pedunculated Resected Gastroenterology. pedunculated polyps should be retrieved through managementand morbidity, can and optimize patient clinicalpreferences,” outcomes the rec for Malignant colorectal polyps invade the submu- the suction channel – if doing so does not require patientsommendations with malignant state. Because polyps, multidisciplinary gastroenterol- cosa but do not extend into the muscularis propria. them to be cut – or with a net or snare during ogists, pathologists, oncologists, and surgeons Pedunculated and nonpedunculated polyps should should identify best ways to communicate with be considered to invade the deep submucosa if suspected submucosal invasion that are removed each other and share decision-making conjointly enscope bloc withdrawal. should be pinned Nonpedunculated peripherally lesions around with the and with patients. “Patient values are important in cases where the risk of residual cancer and the (neoplasticthey are classified and invasive, as NICE with (NBI an International irregular arrange- 10% formalin. This practice helps pathologists ori- Colorectal Endoscopic) type 3, Kudo type VN ententire specimens circumference to correctly to a hard assess surface depth and of invasionfixed in notes. “In these latter cases, shared decision-mak- - and margin involvement. risk of surgical mortality are similar,” the MSTFCC edment), lesions or Kudo with thesetype VI features (an amorphous should be structure, biopsied For both pedunculated and nonpedunculated pol- The authors of the task force recommendations (inwith the a lossarea of of or surface decrease feature in pits). disruption), “Nonpedunculat tattooed yps, features denoting a high risk for residual or re- ing is emphasized.” (unless in or near the cecum), and referred to sur- current malignancy are poor tumor differentiation, since 2016. gery. Pedunculated polyps with features of deep lymphovascular invasion, or more than 1 mm of reported having no relevant [email protected] of interest submucosal invasion should undergo endoscopic submucosal invasion. For nonpedunculated polyps, - additional high-risk features include tumor bud- SOURCE: Shaukat A et al. Gastroenterology. 2020 Nov 4. mendations. ding and tumor involvement of the cautery margin. doi: 10.1053/j.gastro.2020.08.050. polypectomy,” according to the MSTFCC recom

The rest of the new draft recom- Defining populations CRC rates up in younger adults mendation is similar to the 2016 CRC in young adults made the news USPSTF from page 1 guidelines, in which the task force in August 2020 when Chadwick says there is convincing evidence Increasing the pressure for “Right now it is very confusing that CRC screening substantially change reduces disease-related mortality. Boseman,died of colon known cancer. for Diagnosedhis role as Kingin The move comes after mounting ev- Dr. Yee said in an interview at that However, it does not recommend T’Challa in Marvel’s “Black Panther,” idence of an increase in CRC among time.to physicians “The USPSTF and to and the the public,” ACS dif- any one screening approach over “The recent passing of Chadwick younger adults and mounting pres- fer as far as the age to begin screen- 2016, he was only 43 years old. sure to lower the starting age. ing, and insurers may not cover the ‘The risk now for age 45-49 are with his loved ones during this Two years ago, the American Can- cost of colorectal cancer screening is pretty similar to the risk Boseman is tragic, and our thoughts cer Society revised its own screening guidelines and lowered the starting for people in their early 50s. Chadwickdifficult time,” was saidat higher Dr. Barry. risk for“As de- age to 45 years. Soon afterward, a tookbefore notice age 50.” of recent data showing So in some ways, today’s a Black man, the data show that coalition of 22 public health and pa- anDr. increase Barry saidin the that incidence the Task of Force CRC Unfortunately, there is currently tient advocacy groups joined the ACS among younger adults. late 40-year-olds are like notveloping enough colorectal evidence cancer.” that screening in submitting a letter to the USPSTF “The risk now for age 45-49 is yesterday’s 50-year-olds.’ asking that the task force reconsider pretty similar to the risk for people help prevent tragic deaths such as its 2016 guidance (which recom- in their early 50s. So in some ways, another. It recommends both direct Chadwick’s,Black men younger he commented. than 45 could“The mends starting at age 50 years). today’s late 40-year-olds are like visualization, such as colonoscopy, task force is calling for more re- The starting age for screening - as well as noninvasive stool-based search on colorectal cancer screen- is an important issue, commented mented. tests. It does not recommend se- Judy Yee, MD, chair of radiology at yesterday’sThe task force 50-year-olds,” used simulation he com rum tests, urine tests, or capsule - - endoscopy because there is not yet Limitinging in Black screening adults,” he toadded. demiologic data suggested and “that enough evidence about the bene- those at higher risk the Albert Einstein College of Med modelswe could that prevent confirmed some whatadditional the epi In contrast to the USPSTF and ACS theicine Colon and theCancer Montefiore Committee Health of the colorectal cancer deaths by starting “The right test is the one a patient guidelines, which recommend AmericanSystem in CollegeNew York of andRadiology. chair of fits and harms of these tests. Continued on following page

16 screening at age 45,” he said. will do,” Dr. Barry commented.December 2020 / GI & Hepatology News

01_09_to_17_28_31_GIH20_12.indd 16 11/20/2020 3:42:18 PM †GI ONCOLOGY Statins may lower risk of colorectal cancer

BY WILL PASS associated with a 60% CRC risk reduction (pooled MDedge News OR, 0.40; 95% CI, 0.19-0.86; P = .019).

both analyses (I2 greater than 75), most promi- of colorectal cancer (CRC) in patients with nentlyDr. Singh in the noted IBD populations,“significant heterogeneity” which he ascribed in Statin use may significantly lower the risk to “differences in demographic features, ethnic (IBD), based on a meta-analysis and systematic groups, and risk factors for CRC.” review.or without inflammatory bowel disease While publication bias was absent from the In more than 15,000 patients with IBD, statin non-IBD analysis, it was detected in the IBD ock use was associated with a 60% reduced risk of t portion of the study. Dr. Singh said that selection

CRC, reported lead author Kevin N. Singh, MD, of hinks bias due to exclusive use of observational studies NYU Langone Medical Center in New York, and /T may also have been present in the IBD analysis. colleagues. “Statin use has been linked with a risk re- risk reduction of CRC in the IBD population,

duction for cancers including hepatocellular rogerashford including“Prospective whether trials the are effects needed of statinsto confirm differ the carcinoma, breast, gastric, pancreatic, and bil- between ulcerative colitis and Crohn’s disease iary tract cancers, but data supporting the use patients,” Dr. Singh said. of statins for chemoprevention against CRC is Additional analyses are underway, he added, - ‘Prospective trials are needed to confirm including one that will account for the potential- sentation at the annual meeting of the American the risk reduction of CRC in the IBD ly confounding effect of aspirin use. Collegeconflicting,” of Gastroenterology. Dr. Singh said during a virtual pre population, including whether the effects According to David E. Kaplan, MD, AGAF, of He noted a 2014 meta-analysis by Lytras and the University of Pennsylvania, Philadelphia, colleagues that reported a 9% CRC risk reduc- of statins differ between ulcerative - tion in statin users who did not have IBD (World colitis and Crohn’s disease patients.’ duced CRC in IBD provides additional support J Gastroenterol. 2014 Feb 21. doi: 10.3748/ for“The the finding clinical that importance statins are of associated the antineoplastic with re wjg.v20.i7.1858). In patients with IBD, data are effects of statins. This effect has been strongly scarce, according to Dr. Singh. observed in liver cancer, and is pending pro- To further explore the relationship between meta-analysis involving 15,342 patients from spective validation.” statin use and CRC in patients without IBD, the in- Dr. Kaplan also offered some mechanistic in- vestigators analyzed data from 52 studies, includ- an unpublished abstract. In the four published sight into why statins have an anticancer effect, ing 8 randomized clinical trials, 17 cohort studies, studies,five observational 1,161 patients studies, used one statins of which while was 12,145 pointing to “the centrality of cholesterol biosyn- and 27 case-control studies. Of the 11,459,306 did not. thesis for development and/or progression of patients involved, approximately 2 million used In the non-IBD population, statin use was associ- malignancy.” statins and roughly 9 million did not. ated with a 20% reduced risk of CRC (pooled odds The investigators and Dr. Kaplan reported no To evaluate the same relationship in patients P with IBD, the investigators conducted a separate less than .001). In patients with IBD, statin use was [email protected] ratio, 0.80; 95% confidence interval, 0.73-0.88; relevant conflicts of interest.

Continued from previous page PERSPECTIVE screening for CRC for everyone over a certain age, a set of recommenda- Moving the goal posts for colorectal cancer screening tions developed by an international panel of experts suggests screen- linicians and researchers have actively rising incidence curve of EOCRC. And we must ing only for individuals who are at Cdebated the pros and cons of lowering do so without direct evidence to guide us as higher risk for CRC. the screening age to 45 years since 2018, As previously reported, these when the American Cancer Society released this younger group, the best modality to use, guidelines suggest restricting its colorectal cancer (CRC) screening guide- to the magnitude of the benefit of screening screening to adults whose cumu- lines. The most compelling argument in from screening in this group. We must also be lative cancer risk is 3% or more support of lowering the screening age is that carefulor tools not to risk to worsen stratify racial who isand likely geographic to benefit in the next 15 years, the point at recent data from Surveillance Epidemiology disparities in CRC screening, which already and End Results (SEER) show that the CRC exist for African Americans, Native Americans, and harms favors screening. incidence rates in 45- to 50-year-olds are Dr. Shaukat and other minorities and rural residents. Final- whichThe authors,the balance led betweenby Lise Hel- benefits similar to rates seen in 50- to 54-year-olds ly, even though the goal posts are changing, our singen, MD, Clinical Effectiveness - target remains to get to 80% screening rates for all age Research Group, University of tiate screening at age 50 were widely established. groups, and not neglect the currently underscreened Oslo, said “the optimal choice for Termedabout 20 early-onset years ago, whenCRC (EOCRC), the first theguidelines underlying to ini 50- to 75-year-olds, who are at a much higher risk of each person requires shared deci- reasons for this increase are not completely under- CRC than their younger counterparts. sion-making.” stood, and while the absolute numbers of EOCRC Such a risk-based approach is cases are smaller than in older-age groups, modeling Aasma Shaukat, MD, MPH, AGAF, is an investigator, “increasingly regarded as the most studies show that screening this age group is both Center for Care Delivery and Outcomes Research, appropriate way to discuss can- section chief and staff physician, GI section, Minneap- cer screening.” That approach is Over the last 20 years we have made major strides in olis VA Health Care System; staff physician, Fairview already used in prostate and lung efficientreducing andthe incidenceeffective. and mortality from CRC in ages University of Minnesota Medical Center, Minneapolis; cancer screening, they noted. 50 years and older, and now we must rise to the chal- and professor, University of Minnesota department of lenge of delivering CRC screening to this younger group medicine, division of gastroenterology, Minneapolis. A version of this article originally in order to see similar dividends over time and curb the She has no conflicts of interest. appeared on Medscape.com.

MDedge.com/gihepnews / December 2020 17

01_09_to_17_28_31_GIH20_12.indd 17 11/20/2020 3:42:20 PM NEWS FROM THE AGA CGH releases its first GI cancer–themed issue rticles include guidance levels of sex hormones and risk of tors associated with early-onset polyunsaturated fats is associated on cancer progression in esophageal adenocarcinoma and colorectal cancer), and hepatocel- with reduced risk of hepatocellular ABarrett’s esophagus pa- Barrett’s esophagus), colorectal lular carcinoma incidence (e.g., carcinoma) and risk. tients (e.g., Association between cancer surveillance (e.g., Risk fac- High dietary intake of vegetable or Clinical Gastroenterology and Hepatology (CGH) is proud to re- - troenterological cancers. This “issue withinlease its an first issue” themed includes issue a oncollec- gas tion of articles, selected by Editor in Chief Fasiha Kanwal, MD, MSHS, that will provide you with practical research to help guide cancer pre- vention, surveillance, and treatment decisions for your patients. View the themed issue on CGH’s website and access other curated collections on cghjournal.org. Learn where you want [email protected]

Learn what you want Quick Quiz Q1. You perform a colonoscopy for a patient who underwent sigmoid resection for stage 2 colorectal cancer 1 year ago. The colonoscopy reveals one diminu- tive adenoma in the cecum, which Learn how you want you remove with a cold snare. When should you recommend the next colonoscopy? A. 10 years B. 5 years C. 3 years D. 1 year E. 6 months DDSEP Digestive Diseases Self-Education Program Customized by you

Whether preparing for a GI board exam or keeping current All at your fingertips. Q2. Patients with celiac disease subscribing to a strict gluten-free on advances in the field, DDSEP 9 allows you to customize Also available on diet are at particular risk for learning where you want, what you want and how you want. AGA University and A. Fiber Complete versions are available in digital and print formats ddsep.gastro.org B.which Protein nutrient deficiency? C. Folate as well as by chapter, Q&A modules and/or mock exams. D. Thiamine E. Iron EDU19-45 Answers on following page

18 December 2020 / GI & Hepatology News

08_18_19_GIH20_12.indd 18 11/20/2020 3:44:24 PM NEWS FROM THE AGA Congrats to these five AGA members

- We’re proud to share the news of two insights defined the role of gut hormones on Medicine, for “pioneering the study of the gut - AGA members elected to the presti normal physiology and metabolism, pioneering microbiome in IBD, publishing seminal research gious National Academy of Medicine innovative understanding of neuroendocrine cell- on the relationship between diet and the micro and three honored with the 2020 Sherman biology and the role of neurohormonal pathways biomeJessica — enablingAllegretti, multiple MD, MPH areas of research Prize. in the development and progression of neuroen into dietary interventions for IBD.“ Congratulations to AGA members Judy H. Cho, docrine tumors.” , director of clinical- MD,Judy and H. B.Cho, Mark MD Evers, MD, who were recently Being selected to the Academy is one of trials at Brigham and Women’s Hospital, as a elected to the National Academy of Medicine. the highest honors in the fields of health and - “highly regarded expert in the field of fecal mi- , professor of medicine at Icahn medicine and recognizes individuals who have crobiota transplantation (FMT) and microbiome School of Medicine at Mount Sinai, New York, for demonstrated outstanding professional achieve C.therapeutics, difficile establishing the therapy as an ef “establishing that uncommon, loss-of-function ment and commitment to service. fective treatment in IBD patients with recurrent variants in the microbial-sensing domain of NOD2 DavidIn addition, Rubin, MD,the 2020AGAF Sherman Prize was - .” confer risk for Crohn’s disease, and identifying a awarded to the following three AGA members: Presented by the Bruce and Cynthia Sherman- loss-of-function allele in the IL-23 receptor that , chief, section of gastroen- Charitable Foundation, the Sherman Prize is protectsB. Mark against Evers, Crohn’sMD disease and ulcerative - terology, hepatology and nutrition at University of awarded to experts in the field of Crohn’s dis colitis, leading to new, approved therapies.” Chicago Medicine, for his “renown in the IBD com ease and ulcerative colitis who have exhibited - , physician in chief of oncolo munityGary Wu,as a MDbrilliant clinician, creative researcher,- their commitment to advancing inflammatory gy service at University of Kentucky Healthcare, tireless advocate, and trailblazing educator.” bowel disease care and have [email protected] their ca for “his expertise on intestinal hormones and , professor of medicine at Uni reers to overcome these diseases. hormonal arcades in oncogenesis. His seminal versity of Pennsylvania, Perelman School of Experts release new management strategies for malignant colorectal polyps Quick Quiz E - arly identification and removal 1. Management of malignant - there was en bloc resection and - Answers of cancerous colorectal pol polyps must begin with a thorough- adequate histologic assessment, Q1. yps is critical to preventing the and knowledgeable endoscopic as the presence or absence of unfa- progression of colorectal cancer sessment designed to identify fea vorable histologic features, the RationaleCorrect answer: C and improving survival rates. The tures of deep submucosal invasion. patient’s risk for surgical mor U.S. Multisociety Task Force (U.S. - 2. In nonpedunculated lesions tality and morbidity, and patient MSTF) on Colorectal Cancer has with features of deep submucosal preferences. According to the Multi-Society released new guidance for endos invasion, endoscopic biopsy and For more information, review Task Force on Colorectal Cancer, copists on how to assess colorectal tattooing should be followed by the full publication: Endoscopic - colonoscopy should be performed lesions for features associated with surgical resection. Recognition and Management 1 year after resection, and again - cancer, discuss how these factors- 3. Nonpedunculated lesions with Strategies for Malignant Colorec 3 years later, in order to decrease guide management and outline high risk of superficial submucosal tal Polyps: Recommendations of the risk of metachronous colorec - Reference when to advise surgery after ma invasion should be considered for the US Multi-Society Task Force - tal cancer. lignant polyp removal. en bloc resection and proper spec- on Colorectal Cancer. The U.S. Kahi CJ, Boland CR, Dominitz JA. Gastroenterology. Key recommendations from imen handling. - MSTF recommendations are pub- 2016. 150(3):758-68.e11. the U.S. Multisociety Task Force 4. When pathology reports can lished jointly in Gastroenterology, Q2. on Colorectal Cancer, which is cer in a lesion that was complete The American Journal of Gastro RationaleCorrect answer: D comprised of leading experts ly resected endoscopically, the enterology, and [email protected] representing AGA, ACG and ASGE, decision to recommend surgery Endoscopy. include: is based on polyp shape, whether Deficient intake of fiber and folate- may originate in the food choice of AGA Giving Day: Our fight to eradicate the individual, whereas some defi ciencies of intake, such as thiamine, disparities in digestive diseases appear to be celiac specific. The provider should encourage intake - of nutrient-dense foods including O wholegrain foods, enriched if possi n Dec. 3, AGA brought together understand health disparities and tive health care delivery. - ble, legumes, fruits, vegetables, lean- the GI community in an effort create strategies for overcoming - The AGA Research Foundation’s meat, fish, chicken, and eggs. It is - to fund health disparity research them. AGA Giving Day effort help sup - not necessary to prioritize micro with the goal of improving care for AGA Giving Day was the oppor- port state-of-the-art research that- nutrient supplements over achiev the patients who rely on us. tunity to do something about this aligns with the realities of the cur ing nutritional adequacy through We’re so proud of how AGA important societal issue as it di rent multicultural patient popula dietary intake. Iron deficiency is an members stepped up to make this rectly relates to our field. We all- tion and disease states to achieve- effectReference of untreated celiac disease. campaign a success. With money have a role to play in creating a health equity for all. raised through AGA Giving Day, just world free of health dispari- Learn more at gastro.org/[email protected] Shepherd SJ, Gibson PR. J Human Nutr Dietet. the AGA Research Foundation will ties in digestive diseases and free givingday. 2012;26:349-58. fundMDedge.com/gihepnews research projects that help / December of inequities 2020 in access and effec 19

08_18_19_GIH20_12.indd 19 11/20/2020 3:44:25 PM B:21.25" T:21" S:20.5"

Choose STELARA® as your first-line biologic

Learn more at www.ChooseSTELARA.com

TAKE CHARGE OF UC+CD FOR YOUR BIO-NAÏVE PATIENTS STELARA® FOR LASTING* REMISSION *In both the UC and CD studies, many patients achieved clinical remission at 1 Year with STELARA®. Please see supporting data below. B:13.25" S:12.5" RAPID RESPONSE LASTING REMISSION HISTO ENDOSCOPIC MUCOSAL SAFETY PROFILE T:13" Many patients achieved clinical Many patients achieved clinical remission IMPROVEMENT HEMI IN UC The overall safety profile in UC and CD studies response as early as Week 8 in UC at 1 year in the UC and CD clinical trials1,2‡ The fi r s t and only FDA-approved UC was consistent with that seen in other and Week 6 in CD in clinical trials1† treatment to achieve HEMI1§ approved indications1

Clinical Response at Week 8 in UC (Major Secondary Endpoint): Clinical Response at Week 6 (Predominantly TNF Blocker Naïve) INDICATIONS † In UC, clinical response was defined as a decrease from baseline in the modified Mayo • STELARA®: 58% (n=186/322); Placebo: 31% (n=99/319); P<0.001 in CD (Primary Endpoint): STELARA® (ustekinumab) is indicated for the treatment of adult patients with score by ≥30% and ≥2 points, with either a decrease from baseline in the rectal bleeding • STELARA®: 56% (n=116/209); Placebo: 29% (n=60/209); P<0.001 subscore of ≥1 or a rectal bleeding subscore of 0 or 1. In CD, clinical response was defined Clinical Remission at Week 8 in UC (Primary Endpoint): moderately to severely active Crohn’s disease. as reduction in CDAI score of ≥100 points or CDAI score of <15. • STELARA®: 19% (n=62/322); Placebo: 7% (n=22/319); P<0.001 Clinical Response at Week 6 (TNF Blocker Failure) in CD STELARA® (ustekinumab) is indicated for the treatment of adult patients with ‡In UC, clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal (Primary Endpoint): moderately to severely active ulcerative colitis. bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not Clinical Remission at 1 Year in UC (Primary Endpoint): • STELARA®: 34% (n=84/249); Placebo: 21% (n=53/247); P<0.01 include friability). In CD, clinical remission was defined as a CDAI score of <150. • STELARA®: 45% (n=79/176); Placebo: 26% (n=46/175); P≤0.001 STELARA® DOSAGE FORMS AND STRENGTHS: § HEMI was defined as combined endoscopic improvement (Mayo endoscopy subscore of 0 Clinical Remission at 1 Year (Overall Population) in CD SubQ Injection: 45 mg/0.5 mL or 90 mg/mL or 1, modified so that 1 does not include friability) and histologic improvement of the colon Histo-endoscopic Mucosal Improvement at Week 8 in UC (Primary Endpoint): tissue (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, (Other Secondary Endpoint): • STELARA®: 53% (n=68/128); Placebo: 36% (n=47/131); P<0.01 IV Infusion for CD and UC Initial Dose: 130 mg/26 mL (5 mg/mL) ulcerations, or granulation tissue). • STELARA®: 17% (n=54/322); Placebo: 8% (n=26/319); P<0.001 ® SELECTED IMPORTANT SAFETY INFORMATION References: 1. STELARA [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc; CD Study Designs: In CD-1 and CD-2 (Induction Studies, 8 Weeks), 741 and 627 patients, 2019. 2. Data on file. Janssen Biotech, Inc. UC Study Designs: In UC-1 (Induction Study, 8 Weeks), 961 patients were randomized to respectively, were randomized to either a single placebo IV (n=247, n=209) or STELARA® ® ® STELARA is contraindicated in patients with clinically significant hypersensitivity either a single placebo IV (n=319) or STELARA IV dose (based on the body weight of the IV dose (based on the body weight of the patient at the time of dosing) of approximately to ustekinumab or excipients. Serious adverse reactions have been reported CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; IV=intravenous; LTE=long- patient at the time of dosing) of approximately 6 mg/kg administered over at least 1 hour at 6 mg/kg administered over at least 1 hour at Week 0 (n=249, n=209). Eligible patients ® term extension; q8w=every 8 weeks; subQ=subcutaneous; TNF=tumor necrosis factor; in STELARA -treated patients, including bacterial, mycobacterial, fungal, and UC=ulcerative colitis. Week 0 (n=322). Eligible patients (≥18 years of age) had moderately to severely active UC (≥18 years of age) had moderately to severely active CD (CDAI score of 220 to 250) and had (ie, Mayo score of 6 to 12, including a Mayo endoscopy subscore ≥2) and had experienced viral infections, malignancies, hypersensitivity reactions, one case of Reversible failed or were intolerant to treatment with one or more TNF blockers (CD-1) or had failed Posterior Leukoencephalopathy Syndrome (RPLS), and noninfectious pneumonia. an inadequate response to or failed to tolerate previous biologics (ie, TNF blocker and/or or were intolerant to treatment with immunomodulators and/or corticosteroids, but never vedolizumab), corticosteroids, and/or 6-mercaptopurine or azathioprine therapy. In UC-2 failed treatment with a TNF blocker (CD-2). In CD-3 (Maintenance Study, 44 Weeks), STELARA® should not be given to patients with any clinically important active (Maintenance Study, 44 Weeks), 523 patients who achieved clinical response 8 weeks 388 patients who had achieved clinical response (≥100 point reduction in CDAI score) at infection. Patients should be evaluated for tuberculosis prior to initiating ® following the IV administration of the induction dose of STELARA in UC-1 were randomized Week 8 with the induction dose of STELARA® in CD-1 or CD-2 were randomized to receive a treatment with STELARA®. Live vaccines should not be given to patients receiving ® to receive STELARA 90 mg q8w (n=176) or placebo (n=175) for 44 weeks. subQ maintenance regimen of either 90 mg of STELARA® q8w (n=128) or placebo (n=131) STELARA®. If RPLS is suspected or if noninfectious pneumonia is confi rmed, for 44 weeks. After completing the Maintenance Study at Week 44, patients were eligible to discontinue STELARA®. enter the open-label LTE study. Please see related and other Important Safety Information on next page.

© Janssen Biotech, Inc. 2020 11/20 cp-133641v2

GIHEP_20.indd 2 11/13/2020 8:07:49 AM FS:10" FS:10" F:10.5" F:10.5"

Date: November 11, 2020 3:26 PM Brand: STELARA® Colors: CMYK

File Name: cp-133641v2_854719_v1 Size: 10.5” x 13” Page 1 & 2 85, 100, 9, 0 = Customer Code: cp-133641v2 Description: STELARA® FOR LASTING REMISSION We Are Alexander #: 854719 Pub: GI & Hepatology News (12/1/20 issue) B:21.25" T:21" S:20.5"

Choose STELARA® as your fi rst-line biologic

Learn more at www.ChooseSTELARA.com

TAKE CHARGE OF UC+CD FOR YOUR BIO-NAÏVE PATIENTS STELARA® FOR LASTING* REMISSION *In both the UC and CD studies, many patients achieved clinical remission at 1 Year with STELARA®. Please see supporting data below. B:13.25" S:12.5" RAPID RESPONSE LASTING REMISSION HISTO ENDOSCOPIC MUCOSAL SAFETY PROFILE T:13" Many patients achieved clinical Many patients achieved clinical remission IMPROVEMENT HEMI IN UC The overall safety profi le in UC and CD studies response as early as Week 8 in UC at 1 year in the UC and CD clinical trials1,2‡ The fi r s t and only FDA-approved UC was consistent with that seen in other and Week 6 in CD in clinical trials1† treatment to achieve HEMI1§ approved indications1

Clinical Response at Week 8 in UC (Major Secondary Endpoint): Clinical Response at Week 6 (Predominantly TNF Blocker Naïve) INDICATIONS † In UC, clinical response was defi ned as a decrease from baseline in the modifi ed Mayo • STELARA®: 58% (n=186/322); Placebo: 31% (n=99/319); P<0.001 in CD (Primary Endpoint): STELARA® (ustekinumab) is indicated for the treatment of adult patients with score by ≥30% and ≥2 points, with either a decrease from baseline in the rectal bleeding • STELARA®: 56% (n=116/209); Placebo: 29% (n=60/209); P<0.001 subscore of ≥1 or a rectal bleeding subscore of 0 or 1. In CD, clinical response was defi ned Clinical Remission at Week 8 in UC (Primary Endpoint): moderately to severely active Crohn’s disease. as reduction in CDAI score of ≥100 points or CDAI score of <15. • STELARA®: 19% (n=62/322); Placebo: 7% (n=22/319); P<0.001 Clinical Response at Week 6 (TNF Blocker Failure) in CD STELARA® (ustekinumab) is indicated for the treatment of adult patients with ‡In UC, clinical remission was defi ned as Mayo stool frequency subscore of 0 or 1, Mayo rectal (Primary Endpoint): moderately to severely active ulcerative colitis. bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 (modifi ed so that 1 does not Clinical Remission at 1 Year in UC (Primary Endpoint): • STELARA®: 34% (n=84/249); Placebo: 21% (n=53/247); P<0.01 include friability). In CD, clinical remission was defi ned as a CDAI score of <150. • STELARA®: 45% (n=79/176); Placebo: 26% (n=46/175); P≤0.001 STELARA® DOSAGE FORMS AND STRENGTHS: § HEMI was defi ned as combined endoscopic improvement (Mayo endoscopy subscore of 0 Clinical Remission at 1 Year (Overall Population) in CD SubQ Injection: 45 mg/0.5 mL or 90 mg/mL or 1, modifi ed so that 1 does not include friability) and histologic improvement of the colon Histo-endoscopic Mucosal Improvement at Week 8 in UC (Primary Endpoint): tissue (neutrophil infi ltration in <5% of crypts, no crypt destruction, and no erosions, (Other Secondary Endpoint): • STELARA®: 53% (n=68/128); Placebo: 36% (n=47/131); P<0.01 IV Infusion for CD and UC Initial Dose: 130 mg/26 mL (5 mg/mL) ulcerations, or granulation tissue). • STELARA®: 17% (n=54/322); Placebo: 8% (n=26/319); P<0.001 ® SELECTED IMPORTANT SAFETY INFORMATION References: 1. STELARA [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc; CD Study Designs: In CD-1 and CD-2 (Induction Studies, 8 Weeks), 741 and 627 patients, 2019. 2. Data on fi le. Janssen Biotech, Inc. UC Study Designs: In UC-1 (Induction Study, 8 Weeks), 961 patients were randomized to respectively, were randomized to either a single placebo IV (n=247, n=209) or STELARA® ® ® STELARA is contraindicated in patients with clinically signifi cant hypersensitivity either a single placebo IV (n=319) or STELARA IV dose (based on the body weight of the IV dose (based on the body weight of the patient at the time of dosing) of approximately to ustekinumab or excipients. Serious adverse reactions have been reported CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; IV=intravenous; LTE=long- patient at the time of dosing) of approximately 6 mg/kg administered over at least 1 hour at 6 mg/kg administered over at least 1 hour at Week 0 (n=249, n=209). Eligible patients ® term extension; q8w=every 8 weeks; subQ=subcutaneous; TNF=tumor necrosis factor; in STELARA -treated patients, including bacterial, mycobacterial, fungal, and UC=ulcerative colitis. Week 0 (n=322). Eligible patients (≥18 years of age) had moderately to severely active UC (≥18 years of age) had moderately to severely active CD (CDAI score of 220 to 250) and had (ie, Mayo score of 6 to 12, including a Mayo endoscopy subscore ≥2) and had experienced viral infections, malignancies, hypersensitivity reactions, one case of Reversible failed or were intolerant to treatment with one or more TNF blockers (CD-1) or had failed Posterior Leukoencephalopathy Syndrome (RPLS), and noninfectious pneumonia. an inadequate response to or failed to tolerate previous biologics (ie, TNF blocker and/or or were intolerant to treatment with immunomodulators and/or corticosteroids, but never vedolizumab), corticosteroids, and/or 6-mercaptopurine or azathioprine therapy. In UC-2 failed treatment with a TNF blocker (CD-2). In CD-3 (Maintenance Study, 44 Weeks), STELARA® should not be given to patients with any clinically important active (Maintenance Study, 44 Weeks), 523 patients who achieved clinical response 8 weeks 388 patients who had achieved clinical response (≥100 point reduction in CDAI score) at infection. Patients should be evaluated for tuberculosis prior to initiating ® following the IV administration of the induction dose of STELARA in UC-1 were randomized Week 8 with the induction dose of STELARA® in CD-1 or CD-2 were randomized to receive a treatment with STELARA®. Live vaccines should not be given to patients receiving ® to receive STELARA 90 mg q8w (n=176) or placebo (n=175) for 44 weeks. subQ maintenance regimen of either 90 mg of STELARA® q8w (n=128) or placebo (n=131) STELARA®. If RPLS is suspected or if noninfectious pneumonia is confi rmed, for 44 weeks. After completing the Maintenance Study at Week 44, patients were eligible to discontinue STELARA®. enter the open-label LTE study. Please see related and other Important Safety Information on next page.

© Janssen Biotech, Inc. 2020 11/20 cp-133641v2

GIHEP_21.indd 3 11/13/2020 8:11:09 AM FS:10" FS:10" F:10.5" F:10.5"

Date: November 11, 2020 3:26 PM Brand: STELARA® Colors: CMYK

File Name: cp-133641v2_854719_v1 Size: 10.5” x 13” Page 1 & 2 85, 100, 9, 0 = Customer Code: cp-133641v2 Description: STELARA® FOR LASTING REMISSION We Are Alexander #: 854719 Pub: GI & Hepatology News (12/1/20 issue) B:10.75" T:10.5" S:10"

IMPORTANT SAFETY INFORMATION STELARA® (ustekinumab) is contraindicated in patients with clinically significant Concomitant Therapies hypersensitivity to ustekinumab or to any of the excipients. The safety of STELARA® in combination with other biologic immunosuppressive agents or Infections phototherapy was not evaluated in clinical studies of psoriasis. Ultraviolet-induced skin cancers STELARA® may increase the risk of infections and reactivation of latent infections. Serious developed earlier and more frequently in mice. In psoriasis studies, the relevance of findings bacterial, mycobacterial, fungal, and viral infections requiring hospitalization or otherwise in mouse models for malignancy risk in humans is unknown. In psoriatic arthritis studies, ® clinically significant infections were reported. In patients with psoriasis, these included concomitant methotrexate use did not appear to influence the safety or efficacy of STELARA . In diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral Crohn’s disease and ulcerative colitis induction studies, concomitant use of 6-mercaptopurine, infections, gastroenteritis, and urinary tract infections. In patients with psoriatic arthritis, azathioprine, methotrexate, and corticosteroids did not appear to influence the overall safety or ® this included cholecystitis. In patients with Crohn’s disease, these included anal abscess, efficacy of STELARA . gastroenteritis, ophthalmic herpes zoster, pneumonia, and Listeria meningitis. In patients Noninfectious Pneumonia with ulcerative colitis, these included gastroenteritis, ophthalmic herpes zoster, pneumonia, Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing and listeriosis. pneumonia have been reported during post-approval use of STELARA®. Clinical presentations Treatment with STELARA® should not be initiated in patients with a clinically important included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious active infection until the infection resolves or is adequately treated. Consider the risks and outcomes have included respiratory failure and prolonged hospitalization. Patients improved benefits of treatment prior to initiating use of STELARA® in patients with a chronic infection with discontinuation of therapy and, in certain cases, administration of corticosteroids. If or a history of recurrent infection. Instruct patients to seek medical advice if signs or diagnosis is confirmed, discontinue STELARA® and institute appropriate treatment. symptoms suggestive of an infection occur while on treatment with STELARA® and consider discontinuing STELARA® for serious or clinically significant infections until the infection Allergen Immunotherapy resolves or is adequately treated. STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen Theoretical Risk for Vulnerability to Particular Infections immunotherapy. Therefore, caution should be exercised in patients receiving or who have Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated received allergen immunotherapy, particularly for anaphylaxis. infections from mycobacteria, Salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known Most Common Adverse Reactions ® whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA The most common adverse reactions (≥3% and higher than that with placebo) in adults may be susceptible to these types of infections. Appropriate diagnostic testing should be from psoriasis clinical studies for STELARA® 45 mg, STELARA® 90 mg, or placebo were: considered (eg, tissue culture, stool culture) as dictated by clinical circumstances. nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache Pre-Treatment Evaluation of Tuberculosis (TB) (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively. The safety profile in pediatric Evaluate patients for TB prior to initiating treatment with STELARA®. Do not administer patients with plaque psoriasis was similar to that of adults with plaque psoriasis. In psoriatic STELARA® to patients with active tuberculosis infection. Initiate treatment of latent TB arthritis (PsA) studies, a higher incidence of arthralgia and nausea was observed in patients before administering STELARA®. Closely monitor patients receiving STELARA® for signs and treated with STELARA® when compared with placebo (3% vs 1% for both). In Crohn’s symptoms of active TB during and after treatment. disease induction studies, common adverse reactions (3% or more of patients treated with STELARA® and higher than placebo) reported through Week 8 for STELARA® B:13.25" S:12.5" Malignancies 6 mg/kg intravenous single infusion or placebo included: vomiting (4% vs 3%). In the T:13" ® STELARA is an immunosuppressant and may increase the risk of malignancy. Malignancies Crohn’s disease maintenance study, common adverse reactions (3% or more of patients ® were reported among patients who received STELARA in clinical studies. The safety of treated with STELARA® and higher than placebo) reported through Week 44 for STELARA® ® STELARA has not been evaluated in patients who have a history of malignancy or who have 90 mg subcutaneous injection or placebo were: nasopharyngitis (11% vs 8%), injection site a known malignancy. There have been reports of the rapid appearance of multiple cutaneous erythema (5% vs 0%), vulvovaginal candidiasis/mycotic infection (5% vs 1%), bronchitis ® squamous cell carcinomas in patients receiving STELARA who had risk factors for (5% vs 3%), pruritus (4% vs 2%), urinary tract infection (4% vs 2%) and sinusitis (3% ® developing non-melanoma skin cancer (NMSC). All patients receiving STELARA , especially vs 2%). In the ulcerative colitis induction study, common adverse reactions (3% or more those >60 years or those with a history of PUVA or prolonged immunosuppressant treatment, of patients treated with STELARA® and higher than placebo) reported through Week 8 for should be monitored for the appearance of NMSC. STELARA® 6 mg/kg intravenous single infusion or placebo included: nasopharyngitis Hypersensitivity Reactions (7% vs 4%). In the ulcerative colitis maintenance study, common adverse reactions (3% or Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with more of patients treated with STELARA® and higher than placebo) reported through Week 44 STELARA®. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, for STELARA® 90 mg subcutaneous injection or placebo included: nasopharyngitis (24% vs institute appropriate therapy and discontinue STELARA®. 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea Reversible Posterior Leukoencephalopathy Syndrome (RPLS) (3% vs 2%). One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed in clinical Please see Brief Summary on adjacent pages. Please see full Prescribing studies of psoriasis and psoriatic arthritis. No cases of RPLS were observed in clinical studies of Information and Medication Guide for STELARA® at STELARAhcp.com. Provide Crohn’s disease or ulcerative colitis. If RPLS is suspected, administer appropriate treatment and the Medication Guide to your patients and encourage discussion. discontinue STELARA®. RPLS is a neurological disorder, which is not caused by an infection or demyelination. RPLS can present with headache, seizures, confusion, and visual disturbances. cp-124933v2 RPLS has been associated with fatal outcomes. Immunizations Prior to initiating therapy with STELARA®, patients should receive all age-appropriate immunizations recommended by current guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA®. Exercise caution when administering live vaccines to household contacts of STELARA® patients, as shedding and subsequent transmission to STELARA® patients may occur. Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease.

GIHEP_22.indd 1 11/13/2020 8:16:17 AM

Date: November 11, 2020 3:26 PM Brand: STELARA® Colors: CMYK File Name: cp-133641v2_854719_v1 Size: 10.5” x 13” Page 3 (Left) 85, 100, 9, 0 = Customer Code: cp-133641v2 Description: STELARA® FOR LASTING REMISSION We Are Alexander #: 854719 Pub: GI & Hepatology News (12/1/20 issue) Brief Summary of Prescribing Information for STELARA® (ustekinumab) STELARA® (ustekinumab) STELARA® Injection, for subcutaneous use See package insert for Full Prescribing Information Table 1: Adverse Reactions Reported by ≥1% of Subjects through Week 12 in Ps STUDY 1 and Ps INDICATIONS AND USAGE: Psoriasis (Ps): STELARA® is indicated for the treatment of patients 6 STUDY 2 years or older with moderate to severe plaque psoriasis who are candidates for phototherapy or STELARA® ® systemic therapy. Psoriatic Arthritis (PsA): STELARA is indicated for the treatment of adult patients Placebo 45 mg 90 mg with active psoriatic arthritis. STELARA® can be used alone or in combination with methotrexate (MTX). Crohn’s Disease (CD): STELARA® is indicated for the treatment of adult patients with Subjects treated 665 664 666 moderately to severely active Crohn’s disease. Ulcerative Colitis: STELARA® is indicated for the Nasopharyngitis 51 (8%) 56 (8%) 49 (7%) treatment of adult patients with moderately to severely active ulcerative colitis. Upper respiratory tract infection 30 (5%) 36 (5%) 28 (4%) ® CONTRAINDICATIONS: STELARA is contraindicated in patients with clinically significant Headache 23 (3%) 33 (5%) 32 (5%) hypersensitivity to ustekinumab or to any of the excipients [see Warnings and Precautions]. Fatigue 14 (2%) 18 (3%) 17 (3%) WARNINGS AND PRECAUTIONS: Infections: STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were Diarrhea 12 (2%) 13 (2%) 13 (2%) observed in patients receiving STELARA® [see Adverse Reactions]. Serious infections requiring Back pain 8 (1%) 9 (1%) 14 (2%) hospitalization, or otherwise clinically significant infections, reported in clinical studies included the Dizziness 8 (1%) 8 (1%) 14 (2%) following: • Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, Pharyngolaryngeal pain 7 (1%) 9 (1%) 12 (2%) osteomyelitis, viral infections, gastroenteritis and urinary tract infections. • Psoriatic arthritis: Pruritus 9 (1%) 10 (2%) 9 (1%) cholecystitis. • Crohn’s disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, Injection site erythema 3 (<1%) 6 (1%) 13 (2%) and listeria meningitis. • Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis. Treatment with STELARA® should not be initiated in patients with any clinically important Myalgia 4 (1%) 7 (1%) 8 (1%) active infection until the infection resolves or is adequately treated. Consider the risks and benefits Depression 3 (<1%) 8 (1%) 4 (1%) ® of treatment prior to initiating use of STELARA in patients with a chronic infection or a history of Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an through week 12 included: cellulitis, herpes zoster, diverticulitis and certain injection site reactions infection occur while on treatment with STELARA® and consider discontinuing STELARA® for (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of RPLS occurred serious or clinically significant infections until the infection resolves or is adequately treated. during clinical studies [see Warnings and Precautions]. Infections: In the placebo-controlled period of Theoretical Risk for Vulnerability to Particular Infections: Individuals genetically deficient in clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including 13.4 weeks for STELARA®-treated subjects), 27% of STELARA®-treated subjects reported infections nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in subject-year of follow-up). Serious infections occurred in 0.3% of STELARA®-treated subjects such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of treatment with STELARA® may be susceptible to these types of infections. Appropriate diagnostic follow-up) [see Warnings and Precautions]. In the controlled and non-controlled portions of psoriasis testing should be considered, e.g., tissue culture, stool culture, as dictated by clinical circumstances. clinical studies (median follow-up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of STELARA®-treated subjects reported infections (0.87 per subject-years of follow-up). Serious Pre-treatment Evaluation for Tuberculosis: Evaluate patients for tuberculosis infection prior to ® ® infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up). Malignancies: initiating treatment with STELARA . Do not administer STELARA to patients with active tuberculosis In the controlled and non-controlled portions of psoriasis clinical studies (median follow-up of infection. Initiate treatment of latent tuberculosis prior to administering STELARA®. Consider anti- 3.2 years, representing 8998 subject-years of exposure), 1.7% of STELARA®-treated subjects tuberculosis therapy prior to initiation of STELARA® in patients with a past history of latent or active reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor follow-up). Non-melanoma skin cancer was reported in 1.5% of STELARA®-treated subjects (0.52 patients receiving STELARA® for signs and symptoms of active tuberculosis during and after per hundred subject-years of follow-up) [see Warnings and Precautions]. The most frequently treatment. Malignancies: STELARA® is an immunosuppressant and may increase the risk of observed malignancies other than non-melanoma skin cancer during the clinical studies were: malignancy. Malignancies were reported among subjects who received STELARA® in clinical prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in studies [see Adverse Reactions]. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of STELARA®-treated patients during the controlled and uncontrolled portions of studies were similar malignancy [see Nonclinical Toxicology (13) in Full Prescribing Information]. The safety of STELARA® in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1 Pediatric Subjects with Plaque Psoriasis: The safety has not been evaluated in patients who have a history of malignancy or who have a known ® malignancy. There have been post-marketing reports of the rapid appearance of multiple cutaneous of STELARA was assessed in two studies of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 adolescents (12 to 17 years old). squamous cell carcinomas in patients receiving STELARA® who had pre-existing risk factors for ® Ps STUDY 4 evaluated safety for up to 56 weeks in 44 children (6 to 11 years old). The safety profile developing non-melanoma skin cancer. All patients receiving STELARA should be monitored for in pediatric subjects was similar to the safety profile from studies in adults with plaque psoriasis. the appearance of non-melanoma skin cancer. Patients greater than 60 years of age, those with a Psoriatic Arthritis: The safety of STELARA® was assessed in 927 subjects in two randomized, medical history of prolonged immunosuppressant therapy and those with a history of PUVA double-blind, placebo-controlled studies in adults with active psoriatic arthritis (PsA). The overall treatment should be followed closely [see Adverse Reactions]. Hypersensitivity Reactions: safety profile of STELARA® in subjects with PsA was consistent with the safety profile seen in Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with adult psoriasis clinical studies. A higher incidence of arthralgia, nausea, and dental infections was STELARA® [see Adverse Reactions]. If an anaphylactic or other clinically significant hypersensitivity observed in STELARA®-treated subjects when compared with placebo-treated subjects (3% vs. 1% reaction occurs, institute appropriate therapy and discontinue STELARA®. Reversible Posterior for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled Leukoencephalopathy Syndrome: One case of reversible posterior leukoencephalopathy syndrome portions of the PsA clinical studies. Crohn’s Disease: The safety of STELARA® was assessed in (RPLS) was observed in clinical studies of psoriasis and psoriatic arthritis. The subject, who had 1407 subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index received 12 doses of STELARA® over approximately two years, presented with headache, seizures [CDAI] greater than or equal to 220 and less than or equal to 450) in three randomized, double- and confusion. No additional STELARA® injections were administered and the subject fully blind, placebo-controlled, parallel-group, multicenter studies. These 1407 subjects included 40 recovered with appropriate treatment. No cases of RPLS were observed in clinical studies of subjects who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In Studies CD-1 and CD-2 there were 470 subjects who received Crohn’s disease or ulcerative colitis. RPLS is a neurological disorder, which is not caused by STELARA® 6 mg/kg as a weight-based single intravenous induction dose and 466 who received demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion placebo [see Dosage and Administration (2.3) in Full Prescribing Information]. Subjects who were and visual disturbances. Conditions with which it has been associated include preeclampsia, responders in either Study CD-1 or CD-2 were randomized to receive a subcutaneous maintenance eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. Fatal outcomes regimen of either 90 mg STELARA® every 8 weeks, or placebo for 44 weeks in Study CD-3. Subjects have been reported. If RPLS is suspected, administer appropriate treatment and discontinue in these 3 studies may have received other concomitant therapies including aminosalicylates, STELARA®. Immunizations: Prior to initiating therapy with STELARA®, patients should receive all immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), MTX], oral corticosteroids age-appropriate immunizations as recommended by current immunization guidelines. Patients (prednisone or budesonide), and/or antibiotics for their Crohn’s disease [see Clinical Studies (14.4) being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given in Full Prescribing Information]. The overall safety profile of STELARA® was consistent with the during treatment with STELARA® or for one year prior to initiating treatment or one year following safety profile seen in the adult psoriasis and psoriatic arthritis clinical studies. Common adverse discontinuation of treatment. Caution is advised when administering live vaccines to household reactions in Studies CD-1 and CD-2 and in Study CD-3 are listed in Tables 2 and 3, respectively. contacts of patients receiving STELARA® because of the potential risk for shedding from the Table 2: Common adverse reactions through Week 8 in Studies CD-1 and CD-2 occurring in ≥3% of household contact and transmission to patient. Non-live vaccinations received during a course of STELARA®-treated subjects and higher than placebo ® STELARA may not elicit an immune response sufficient to prevent disease.Concomitant Therapies: ® In clinical studies of psoriasis the safety of STELARA® in combination with other biologic STELARA immunosuppressive agents or phototherapy was not evaluated. Ultraviolet-induced skin cancers 6 mg/kg single intravenous developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 Placebo induction dose N=466 N=470 and IL-23 or IL-12 alone [see Concomitant Therapies, Nonclinical Toxicology (13.1) in Full Prescribing Information]. Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic pneumonia Vomiting 3% 4% and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA®. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three Other less common adverse reactions reported in subjects in Studies CD-1 and CD-2 included doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients asthenia (1% vs 0.4%), acne (1% vs 0.4%), and pruritus (2% vs 0.4%). improved with discontinuation of therapy and in certain cases administration of corticosteroids. If Table 3: Common adverse reactions through Week 44 in Study CD-3 occurring in ≥3% of STELARA®- diagnosis is confirmed, discontinue STELARA® and institute appropriate treatment [see treated subjects and higher than placebo Postmarketing Experience]. ADVERSE REACTIONS: The following serious adverse reactions are discussed elsewhere in the label: • Infections [see Warnings and Precautions] • Malignancies [see STELARA® Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] 90 mg subcutaneous • Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions] Clinical maintenance dose every Trials Experience: Because clinical trials are conducted under widely varying conditions, Placebo 8 weeks adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates N=133 N=131 in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Nasopharyngitis 8% 11% Subjects with Plaque Psoriasis: The safety data reflect exposure to STELARA® in 3117 adult Injection site erythema 0 5% psoriasis subjects, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, Vulvovaginal candidiasis/mycotic infection 1% 5% 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least Bronchitis 3% 5% four years and 838 exposed for at least five years. Table 1 summarizes the adverse reactions that Pruritus 2% 4% occurred at a rate of at least 1% and at a higher rate in the STELARA® groups than the placebo group during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies (14) in Full Urinary tract infection 2% 4% Prescribing Information]. Sinusitis 2% 3%

GIHEP_23.indd 1 11/13/2020 8:20:22 AM STELARA® (ustekinumab) STELARA® (ustekinumab)

Infections: In patients with Crohn’s disease, serious or other clinically significant infections included organogenesis. Serum concentrations of ustekinumab in pregnant monkeys were greater than anal abscess, gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes 100 times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab zoster were reported in one patient each [see Warnings and Precautions]. Malignancies: With up to weekly for 4 weeks. In a combined embryo-fetal development and pre- and post-natal development one year of treatment in the Crohn’s disease clinical studies, 0.2% of STELARA®-treated subjects toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of (0.36 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per ustekinumab twice weekly at exposures greater than 100 times the human subcutaneous exposure hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non- from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the melanoma skin cancers occurred in 0.2% of STELARA®-treated subjects (0.27 events per hundred offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at patient-years) and in none of the placebo-treated subjects. Hypersensitivity Reactions Including 45 mg/kg. No ustekinumab-related effects on functional, morphological, or immunological Anaphylaxis: In CD studies, two patients reported hypersensitivity reactions following STELARA® development were observed in the neonates from birth through six months of age. Lactation: Risk administration. One patient experienced signs and symptoms consistent with anaphylaxis (tightness Summary: There are no data on the presence of ustekinumab in human milk, the effects on the of the throat, shortness of breath, and flushing) after a single subcutaneous administration (0.1% of breastfed infant, or the effects on milk production. Ustekinumab was present in the milk of lactating patients receiving subcutaneous STELARA®). In addition, one patient experienced signs and monkeys administered ustekinumab. Due to species-specific differences in lactation physiology, symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, animal data may not reliably predict drug levels in human milk. Maternal IgG is known to be present urticaria, and increased body temperature) after the initial intravenous STELARA® dose (0.08% of in human milk. Published data suggest that the systemic exposure to a breastfed infant is expected patients receiving intravenous STELARA®). These patients were treated with oral antihistamines or to be low because ustekinumab is a large molecule and is degraded in the gastrointestinal tract. corticosteroids and in both cases symptoms resolved within an hour. Ulcerative Colitis: The safety However, if ustekinumab is transferred into human milk the effects of local exposure in the of STELARA® was evaluated in two randomized, double-blind, placebo-controlled clinical studies gastrointestinal tract are unknown. The developmental and health benefits of breastfeeding should (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely be considered along with the mother’s clinical need for STELARA® and any potential adverse active ulcerative colitis [see Clinical Studies (14.5) in Full Prescribing Information]. The overall effects on the breastfed child from STELARA® or from the underlying maternal condition. Pediatric safety profile of STELARA® in patients with ulcerative colitis was consistent with the safety profile Use: The safety and effectiveness of STELARA® have been established in pediatric patients 6 to seen across all approved indications. Adverse reactions reported in at least 3% of STELARA®- 17 years old with moderate to severe plaque psoriasis. Use of STELARA® in adolescents is supported treated subjects and at a higher rate than placebo were: • Induction (UC-1): nasopharyngitis (7% vs by evidence from a multicenter, randomized, 60-week trial (Ps STUDY 3) that included a 12-week, 4%). • Maintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain double-blind, placebo-controlled, parallel-group portion, in 110 pediatric subjects 12 years and (7% vs 3%), influenza (6% vs 5%), fever (5% vs. 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue older [see Adverse Reactions, Clinical Studies (14.2) in Full Prescribing Information]. Use of (4% vs 2%), and nausea (3% vs 2%). Infections: In patients with ulcerative colitis, serious or other STELARA® in children 6 to 11 years with moderate to severe plaque psoriasis is supported by clinically significant infections included gastroenteritis and pneumonia. In addition, listeriosis and evidence from an open-label, single-arm, efficacy, safety and pharmacokinetics study (Ps STUDY 4) ophthalmic herpes zoster were reported in one patient each [see Warnings and Precautions]. in 44 subjects [see Adverse Reactions, Pharmacokinetics (12.3) in Full Prescribing Information]. The Malignancies: With up to one year of treatment in the ulcerative colitis clinical studies, 0.4% of safety and effectiveness of STELARA® for pediatric patients less than 6 years of age with psoriasis STELARA®-treated subjects (0.48 events per hundred patient-years) and 0.0% of placebo-treated have not been established. The safety and effectiveness of STELARA® have not been established in subjects (0.00 events per hundred patient-years) developed non-melanoma skin cancer. pediatric patients with psoriatic arthritis, Crohn’s disease or ulcerative colitis. Geriatric Use: Of the Malignancies other than non-melanoma skin cancers occurred in 0.5% of STELARA®-treated 6709 patients exposed to STELARA®, a total of 340 were 65 years or older (183 patients with psoriasis, subjects (0.64 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.40 events 65 patients with psoriatic arthritis, 58 patients with Crohn’s disease and 34 patients with ulcerative per hundred patient-years). Immunogenicity: As with all therapeutic proteins, there is potential for colitis), and 40 patients were 75 years or older. Although no overall differences in safety or efficacy immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and were observed between older and younger patients, the number of patients aged 65 and over is not specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing sufficient to determine whether they respond differently from younger patients. OVERDOSAGE: antibody) positivity in an assay may be influenced by several factors, including assay methodology, Single doses up to 6 mg/kg intravenously have been administered in clinical studies without dose- sample handling, timing of sample collection, concomitant medications and underlying disease. For limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any these reasons, comparison of the incidence of antibodies to ustekinumab in the studies described signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be below with the incidence of antibodies to other products may be misleading. Approximately 6 to instituted immediately. PATIENT COUNSELING INFORMATION: Advise the patient and/or caregiver 12.4% of subjects treated with STELARA® in psoriasis and psoriatic arthritis clinical studies to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Infections: developed antibodies to ustekinumab, which were generally low-titer. In psoriasis clinical studies, Inform patients that STELARA® may lower the ability of their immune system to fight infections and antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab to contact their healthcare provider immediately if they develop any signs or symptoms of infection concentrations and reduced efficacy. In psoriasis studies, the majority of subjects who were [see Warnings and Precautions]. Malignancies: Inform patients of the risk of developing positive for antibodies to ustekinumab had neutralizing antibodies. In Crohn’s disease and ulcerative malignancies while receiving STELARA® [see Warnings and Precautions]. Hypersensitivity colitis clinical studies, 2.9% and 4.6% of subjects, respectively, developed antibodies to ustekinumab Reactions: • Advise patients to seek immediate medical attention if they experience any signs or when treated with STELARA® for approximately one year. No apparent association between the symptoms of serious hypersensitivity reactions and discontinue STELARA® [see Warnings and development of antibodies to ustekinumab and the development of injection site reactions was Precautions]. • Inform patients the needle cover on the prefilled syringe contains dry natural rubber seen. Postmarketing Experience: The following adverse reactions have been reported during post- (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex [see approval of STELARA®. Because these reactions are reported voluntarily from a population of Dosage and Administration (2.4) in Full Prescribing Information] Immunizations: Inform patients that uncertain size, it is not always possible to reliably estimate their frequency or establish a causal STELARA® can interfere with the usual response to immunizations and that they should avoid live relationship to STELARA® exposure. Immune system disorders: Serious hypersensitivity reactions vaccines [see Warnings and Precautions]. Administration: Instruct patients to follow sharps (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and disposal recommendations, as described in the Instructions for Use. urticaria) [see Warnings and Precautions]. Infections and infestations: Lower respiratory tract REFERENCES: 1Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) infection (including opportunistic fungal infections and tuberculosis) [see Warnings and SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973-2007) - Linked Precautions]. Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic To County Attributes - Total U.S., 1969-2007 Counties, National Cancer Institute, DCCPS, Surveillance pneumonia and cryptogenic organizing pneumonia [see Warnings and Precautions]. Skin reactions: Research Program, Surveillance Systems Branch, released April 2010, based on the November 2009 Pustular psoriasis, erythrodermic psoriasis. DRUG INTERACTIONS: Concomitant Therapies: In submission. psoriasis studies the safety of STELARA® in combination with immunosuppressive agents or Prefilled Syringe Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, US License No. phototherapy has not been evaluated [see Warnings and Precautions]. In psoriatic arthritis studies, 1864 at Baxter Pharmaceutical Solutions, Bloomington, IN 47403 and at Cilag AG, Schaffhausen, concomitant MTX use did not appear to influence the safety or efficacy of STELARA®. In Crohn’s Switzerland disease and ulcerative colitis induction studies, immunomodulators (6-MP, AZA, MTX) were used Vial Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, US License No. 1864 at Cilag AG, concomitantly in approximately 30% of subjects and corticosteroids were used concomitantly in Schaffhausen, Switzerland approximately 40% and 50% of Crohn’s disease and ulcerative colitis subjects, respectively. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of STELARA®. © 2012, 2016, 2019 Janssen Pharmaceutical Companies CYP450 Substrates: The formation of CYP450 enzymes can be altered by increased levels of certain cp-125606v3 cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, STELARA®, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation of STELARA® in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Allergen Immunotherapy: STELARA® has not been evaluated in patients who have undergone allergy immunotherapy. STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis. USE IN SPECIFIC POPULATIONS: Pregnancy: Risk Summary: Limited data on the use of STELARA® in pregnant women are insufficient to inform a drug associated risk [see Data]. In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the human exposure at the maximum recommended human subcutaneous dose (MRHD). The background risk of major birth defects and miscarriage for the indicated population(s) are 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 of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data: Human Data: Limited data on use of STELARA® in pregnant women from observational studies, published case reports, and postmarketing surveillance are insufficient to inform a drug associated risk. Animal Data: Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period of

GIHEP_24.indd 1 11/13/2020 8:23:45 AM †LIVER DISEASE Cirrhosis, Child-Pugh score predict ERCP complications

BY WILL PASS caused by ERCP, and mortality from other caus- other while evaluating outcomes of any surgery MDedge News es. Patients with cirrhosis were further analyzed in patients with cirrhosis.” based on etiology of cirrhosis, Child-Pugh class, In 2017, Udayakumar Navaneethan, MD, a gas- irrhosis may increase the risk of compli- and MELD score. troenterologist at AdventHealth Orlando’s Center cations from endoscopic retrograde chol- The analysis revealed that complications were for Interventional Endoscopy, and an assistant Cangiopancreatography (ERCP), according - professor at the University of Central Florida, to a retrospective study involving almost 700 rhosis than in those without cirrhosis (21.30% Orlando, and colleagues published a national patients. vs.significantly 13.51%; P more common in patients with cir database study concerning the safety of ERCP in The study also showed that Child-Pugh class patients with liver cirrhosis (Endosc Int Open. was a better predictor of risk than Model for with cirrhosis =than .015). in thoseNo specific without complications cirrhosis. 2017 Apr;5[4]:E303-14). End-Stage Liver Disease (MELD) score, reported wereIn patients significantly with morecirrhosis, common 41.18% in patients of Child- “[The present] study is important as it high- lead author Michelle Bernshteyn, MD, a third- Pugh class C patients had complications, com- lights the fact that ERCP is associated with year internal medicine resident at State Univer- pared with 15.15% of class B patients and sity of New York, Syracuse, and colleagues. 19.30% of class A patients (P = .010). In con- compared to those without cirrhosis,” Dr. Na- “There remains a scarcity in the literature - vaneethansignificant saidcomplications when asked in cirrhoticto comment. patients “Also, regarding complications and adverse effects ated with adverse events. Child-Pugh score appeared to be more reliable after ERCP in cirrhotic patients, particularly trast,Further MELD analysis scores showed were not that, significantly in patients associ with- than MELD score in predicting complications of those incorporating Child-Pugh class and MELD out cirrhosis, diagnostic-only ERCP and underly- ERCP in cirrhotic patients.” score or type of intervention as predictors,” Dr. ing chronic obstructive pulmonary disease were He went on to explain relevance for practicing Bernshteyn said during a virtual presentation associated with high rates of complications (P = clinicians. “The clinical implications of the study at the American College of Gastroenterology .039 and P = .003, respectively). In patients with annual meeting. “Furthermore, literature review cirrhosis, underlying chronic obstructive pulmo- to be done with patients with liver cirrhosis, demonstrates inconsistency among results.” nary disease and hypertension predicted adverse particularlyare that a detailed with advanced risk-benefit liver discussion disease Child- needs To gain clarity, Dr. Bernshteyn and colleagues events (P = .009 and P = .003, respectively). Pugh class C, irrespective of the etiology,” Dr. reviewed electronic medical records from 692 Navaneethan said. “ERCP should be performed patients who underwent ERCP, of whom 174 had cirrhosis has an impact on the occurrence of cirrhosis and 518 did not. For all patients, the complications“The results duringof our studyERCP,” reaffirm Dr. Bernshteyn that liver said. outweigh the risks.” investigators analyzed demographics, comor- “Child-Pugh class seems to be more reliable as whenThe thereinvestigators is clear evidenceand Dr. Navaneethan that the benefits report- bidities, indications for ERCP, type of sedation, compared to MELD score in predicting compli- type of intervention, and complications within a cations of ERCP in cirrhosis patients,” she added. [email protected] 30-day period. Complications included bleeding, “However, we are also aware that Child-Pugh ed no conflicts of interest. pancreatitis, cholangitis, perforation, mortality and MELD scores are complementary to each SOURCE: Bernshteyn M et al. ACG 2020, Abstract S0982. Lipid profiles distinguish obese and nonobese NAFLD patients

BY HEIDI SPLETE - MDedge News cantly decreased in NASH versus NAFLhigh degree in the ofobese desaturation group, which signifi oth obese and nonobese individ- was not observed in the nonobese Buals can develop nonalcoholic group,” they noted. fatty liver disease (NAFLD), and In addition, saturated sphingo- - - tors in both groups, based on data cantly associated with visceral se n e

fromlipid profilesa cross-sectional were effective study predic of 361 c adipositymyelin (SM) in nonobesespecies were NAFLD signifi i L

individuals. s patients, but not in obese NAFLD n Given the strong association be- patients, and SM levels were sig- tween obesity and NAFLD, previous ommo C systemic and adipose tissue insulin

focused on obese White patients, reative rnificantlyesistance. associated with both wroteresearch Youngae on lipidomic Jung, MD, profiles of the have Ko- /C rea Basic Science Institute, Seoul, potential lipid metabolites for non- ikimedia

and colleagues. /W obeseThe subjectsresearchers and identified seven potential five n lipids for obese subjects that in- ephro

data on circulating lipidomics of N cluded DAGs, TAGs, and SMs that nonobese“However, NAFLD there patients,” are insufficient they were distinct between NAFL and added. holic steatohepatitis (NASH), and 48 obese patients with increases from NASH patients in order to predict In a study published in Alimentary controls; the obese group included NAFL to NASH, the researchers the histologic severity of NAFLD. Pharmacology and Therapeutics, the 106 patients with NAFLD, 107 with noted. Overall, these metabolite combi- NASH, and 18 controls. “Levels of DAGs with relatively nations were effective predictors with NAFLD and 66 controls. Over- short chains and a low degree of of NAFLD/NASH in nonobese and all,researchers 130 participants identified were 295 nonobese adults Lipid profiles show obese patients. The areas under (body mass index <25 kg/m2) and predictive promise in NAFL versus no NAFLD, regard- the receiver operator characteristic 231 were obese (BMI, 25 or higher). Overall, changes in diacylglycerol lessdesaturation of obesity,” significantly the researchers increased curve were 0.916 versus 0.813 for The nonobese group included 51 pa- (DAG) and triacylglycerol (TAG) said. “In contrast, levels of DAGs NAFLD versus non-NAFLD in non- tients with NAFLD, 31 with nonalco- appeared in both obese and non- with relatively long chains and a Continued on following page

MDedge.com/gihepnews / December 2020 25

25_26_27_GIH20_12.indd 25 11/20/2020 3:47:55 PM Continued from previous page patients, who were included with obese NAFLD, which are relevant to Zachary Henry, MD, of the Univer- obese patients, and 0.967 versus overweight patients in the non- precision medicine and personal- sity of Virginia, Charlottesville, said 0.812 for NAFLD versus non-NAFLD obese group. ized therapy based on various phe- in an interview. “Imaging methods in the obese patients. However, the results were notypes of NAFLD,” they concluded. such as transient elastography strengthened by the large amount and MR-elastography have been More BMI groups may - Validation needed in introduced and many biochemical yield more information - other populations markers have been evaluated, yet The key study limitation was the pertof data liver and pathologist, the confirmed they diagno added. “Liver biopsy remains the gold stan- all have their limitations. In the cross-sectional study design, the re- ses of NASH and fibrosis by an ex dard for diagnosing NAFLD/NASH current study, the authors report searchers noted. In addition, divid- new insights that aid in the un- but has its own limitations and a high diagnostic accuracy for ing patients into only two groups derstanding“Therefore, of our pathophysiological findings provide risks, so many researchers in this evaluating NAFLD using lipidomic based on BMI may not reveal any mechanisms responsible for the distinct biology among lean NAFLD development and severity of non- alternative to help with diagnosis,” new noninvasive measurement of field are looking for a noninvasive NAFLD.”profiles, which could introduce a Dr. Henry said that he was not

However, “I believe they are im- surprised by the study findings. that shows differences between Apply to be the next patientsportant as with they NASH define versus a lipid patients profile with NAFLD versus patients with- out NAFLD,” he said. “NAFLD is a disease of disordered lipid metab- Editor-in-Chief olism in hepatocytes, and although it stands to reason there would be AGA’s premier publications — Gastroenterology, Clinical Gastroenterology and Hepatology and GI & Hepatology News — interesting to see the changes be- tweendifferences DAGs in and lipid TAGs profiles, especially it is as are seeking new leadership! disease progresses from NAFLD to NASH. Learn more and “Clinically, I do not think this real- mdedge.com/gihepnews apply at gastro.org. September 2019 ly changes practice right now since DAAs reduce Volume 13 / Number 9 it needs to be validated in other mortality, cancer I N S I D E IBD AND INTESTINAL DISORDERS risk in HCV study AGA Clinical Practice populations of NAFLD. However, it Update Large study with significant results. Recommendations for switching between

maGes i BY ANDREW D. BOWSER biologics and biosimilars

etty MDedge News hepatitis C virus (HCV) in IBD. • 21 /G certainly adds to a growing arma- GI ONCOLOGY A group of internists is alleging that the board is monopolizing the irect-acting antivirals MOC market. infection treated at 1 of CRC diagnosis ompilation France (

C delayed or missed in Drisk of hepatocellular 32There hepatology were no centers signs ofin). significantly decrease - patients under 50 in persons with hepatitis NCT01953458 mentarium of noninvasive testing. Class-action suit filed According to survey, carcinoma and mortality treatmentincreased withrisk ofDAAs, hepato pro- young patients were - cellular carcinoma during- often misdiagnosed. against ABIM over MOC C, according to results of futing earlier, single-center • 22 the first prospective, lon viding more evidence re LIVER DISEASE BY ALICIA GALLEGOS gitudinal study to evaluate Women with cirrhosis Hopefully, we are able to combine thethe infection. effect of the drugs on MDedge News reports that had suggested survive hospitalization complications related to an increased incidence - more often than men group of internists is tiff-physicians are asking- a terbalanceearly after atreatment. recent Co- Studying reasons will suing the American judge to find ABIM in viola cutCompared risk of hepatocellu- with no These findings also coun help treatment. treatment, DAA therapy • A tion of federal antitrust law - 23 some of these noninvasive tests in PRACTICE and to bar the board from chrane review that could lar carcinoma by about MANAGEMENT Board of Internal- tioncontinuing on behalf its of MOC all internistsprocess. not confirm or reject a po - one-third and all-cause Why Pharma can’t Medicine over its main The suit is filed as a class ac tential benefit of drugs on tenance of certification mortality by about half -in long-term morbidity and lower prices the study, which includ Report from the Senate (MOC) process, alleging - and subspecialists required patients with chronic mortality. the future to better predict NAFLD that the board is monopo ed about 10,000 adult Lancet, Finance Committee cations.by ABIM The to purchaseplaintiffs seekMOC- to Results of the study, lizing the MOC market. See DAAs hearing. maintain their ABIM certifi published in the · page 23 • The lawsuit, filed Dec. 6, 25 - Distinct features found in young-onset CRC PUB20-020 2018, in Pennsylvania district damages and injunctive re pricescourt, forclaims maintaining that ABIM cer- is lief, plus lawsuit and attorney BY ANDREW D. BOWSER charging inflated monopoly and NASH as well as outcomes such costs statementarising from ABIM’s MDedge News - alleged antitrust violations. tification, that the organi In a oung-onset colorectal review that included more zation is forcing physicians , ABIM expressed disappointment Y than 36,000 patients. Conversely, those younger to purchase MOC, and that at the lawsuit and said the - CRC patients younger ABIM is inducing employers cancer (CRC) has dis patients were less likely to as cirrhosis and hepatocellular car- organization will vigorously than 50 years of age were and others to require ABIM tinct clinical and molecular have BRAF V600 mutations - defend itself, adding that more likely to have distal- certification. The four plain See - features, compared with than were patients 50 years- doing so will “consumeABIM · page re 31 primary tumors, synchro disease diagnosed later- in Cancer.old and older, the investiga nous metastatic disease, - tors reported in the journal life, according to investi and microsatellite instabil gators who conducted a ity (MSI) than were older cinoma,” he said. VerySee young patients were

patients, investigators said. more likely Distinctto have · pagesignet- 22

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10255 W Higgins Road, Higgins W 10255 May 18 & 19, 2019 / San Diego, California GI & Hepatology News Hepatology & GI Register now at pgcourse.gastro.org. need to be validated in non-Korean EDU9-14 populations“I think these of patients lipidomic with profiles NAFLD to determine if these changes are ubiquitous to everyone or if a dif- - ferent genetics and environment,” Dr.ferent Henry profile added. exists “As based the authors upon dif note in their paper, there have been previously published differences Finding the right between populations of NAFLD in Asia as compared to Western coun- Job Alerts

Gastroenterology Physician tries and it is unclear how, if at all, San Francisco, California Full Time job or candidate is those differences.” Nurse Practitioner theseThe lipidomicstudy was profiles funded relateby the to Washington, D.C. Part Time at your fingertips Korea Basic Science Institute, the Korea Health Industry Department Pediatric Gastroenterologist Billings, Montana Institute, and the National Research Full Time New Grad Your career hub across all Foundation of Korea. The research- disciplines and specialties in GI. ers had no financial conflicts to Start your search today at disclose. Dr. Henry [email protected] no financial conflicts to disclose. GICareerSearch.com. SOURCE: Jung Y et al. Aliment Pharma- COM19-024 col Ther. 2020 Sep 6. doi: 10.1111/ apt.16066.

26 December 2020 / GI & Hepatology News

25_26_27_GIH20_12.indd 26 11/20/2020 3:47:57 PM †LIVER DISEASE Semaglutide shows promise in NASH phase 2 study

BY KATE JOHNSON P MDedge News - 6.87; < .001 for the highest semaglutide dose). - served in patients with type 2 diabetes in other lmost 60% of patients with biopsy-con- However, the treatment did not lead to significant trials and with the known effects of GLP-1 re between-group differences in the secondary end ceptor agonists,” with gastrointestinal disorders- A point, which occurred in 43%P of patients on the being the most commonly reported. firmed nonalcoholic steatohepatitis and highest semaglutide dose compared to 33% in the Nausea, constipation, and vomiting were re liver fibrosis showed resolution of NASH - placebo group (OR, 1.42; = .48). ported more often in the 0.4-mg semaglutide - after treatment with semaglutide, according to a Treatment with semaglutide also resulted in - group than in the placebo group (nausea, 42% phase 2, double-blind,. randomized, placebo-con dose-dependent reductions in body weight, as vs. 11%; constipation, 22% vs. 12%; and vomit trolled trial published in the New England Journal- well as in glycated hemoglo ing, 15% vs. 2%). - of Medicine - bin levels. Body weight was The overall incidence of benign, malignant, or “This bodes well for further study of sema reduced by a mean of 5% unspecified neoplasms was 15% in the treat glutide and is supported further by marked im in the 0.1-mg semaglutide ment groups versus 8% in the placebo group. provements in weight, glycemic control, and lipid group, followed by mean Rowen K. Zetterman, MD, who was not involved profile,” commented the study’s senior author reductions of 9% and 13% with the study, noted that “treatment of NASH is Philip N. Newsome, PhD, FRCPE, of the University- in the 0.2-mg and 0.4-mg - currently limited, and no therapies have yet been- of Birmingham (England), in an interview. groups, respectively. This approved by the Food and Drug Administration.” The highest daily dose (0.4 mg) of the glu - Dr. Zetterman compared to a mean reduc The findings are “important but not yet ex cagonlike peptide-1 (GLP-1) receptor agonist, tion of 1% in the placebo - citing,” added Dr. Zetterman, who is professor - semaglutide, which is approved for the treat group. emeritus of internal medicine and associate vice ment of type 2 diabetes, led to levels of NASH Similarly, glycated hemo chancellor for strategic planning for the Univer resolution “which are higher than any previously- globin levels among patients with type 2 diabetes sity of Nebraska Medical Center, Omaha. demonstrated,” noted Dr. Newsome. “This was - dropped by 0.63, 1.07, and 1.15 percentage points “Though reversal of liver fibrosis was not noted, also accompanied by improvement in noninva in the 0.1-mg, 0.2-mg, and 0.4-mg semaglutide the resolution of hepatic inflammation and liver cell- sive markers of liver fibrosis and also less fibro groups, respectively, compared with a drop of injury by semaglutide suggests it may be slowing sis progression, compared to placebo.” 0.01 percentage point in the placebo group. - disease progression,” said Dr. Zetterman. This “war The multicenter study, conducted at 143 sites “The fact that the percentage of patients who - rants additional studies where longer treatment in 16 countries, included 320 patients, aged 18- had an improvement in fibrosis stage was not sig with semaglutide may prove reversal of fibrosis 75 years, with or without type 2 diabetes, who nificantly higher with semaglutide than with place and/or prevention of progression to cirrhosis.” had histologic evidence of NASH and stage 1-3 bo – despite a greater benefit with respect to NASH- The study was sponsored by Novo Nordisk. Dr. liver fibrosis. resolution and dose-dependent weight loss – was Newsome reported disclosures related to Novo - They were randomized in a 3:3:3:1:1:1 ratio to unexpected, given that previous studies have sug- Nordisk during the conduct of the study, and to receive once-daily subcutaneous semaglutide at a gested that resolution of NASH and improvements- Boehringer Ingelheim, Bristol-Myers Squibb, Echo dose of 0.1, 0.2, or 0.4 mg, or placebo for 72 weeks. in activity scores for the components of nonal sens, Gilead, Pfizer, Pharmaxis, and Poxel. Several- The primary endpoint was resolution of NASH coholic fatty liver disease are associated with re of the other study authors reported receiving fees and no worsening of fibrosis, with a secondary gression of fibrosis,” wrote the authors. “However, and grants from various pharmaceutical compa endpoint being improvement of fibrosis by at the temporal association among NASH resolution, nies, including Novo Nordisk One author reported least one stage without worsening of NASH. weight loss, and improvement in fibrosis stage- is pending patents for the use of [email protected] Dr. The study found 40% of patients in the 0.1-mg not fully understood. It is possible that the current Zetterman had no relevant disclosures. semaglutide group, 36% in the 0.2-mg group, - trial was not of sufficient duration for improve SOURCE: Newsome PN et al. N Engl J Med. 2020 Nov 13. and 59% in the 0.4-mg group achieved NASH ments in fibrosis stage to become apparent.” - doi: 10.1056/NEJMoa2028395. resolution with no worsening of fibrosis, com The authors also noted that the safety profile pared with 17% of the placebo group (odds ratio, of semaglutide was “consistent with that ob GLIMMER of hope for itch in primary biliary cholangitis

BY EMILY WILLINGHAM - social and emotional quality of life, determine the mean worst daily itch. During the subsequent 4 weeks of P Dr. Levy reported at the Liver Meet. The primary study endpoint was- placebo, after treatment ended, the atients with primary biliary ing, where she presented findings- the change in worst daily itch from itch relief faded in all groups. cholangitis (PBC) experienced from the phase 2 GLIMMER trial baseline after 12 weeks of treat Scores on the PBC-40 itch domain rapid improvements in itch and- After a single-blind 4-week pla ment. Participants whose self-rated improved significantly in every quality of life after treatment with cebo run-in period for patients itch improved by 2 points on the group, including placebo. However,- linerixibat in a randomized, pla with itch scores of at least 4 on a 10-point scale were considered to only those in the twice-dailyP 40-mg cebo-controlled trial of the safety, 10-point rating scale, those with have had a response to the drug. group saw significantP improve efficacy, and tolerability of the - itch scores of at least 3 were then Participants also completed the ments on the social ( = .0016) and- small-molecule drug. randomly assigned to one of five PBC-40, an instrument to measure emotional ( = .0025) domains. - Moderate to severe pruritus “af- treatment regimens – once-daily quality of life in patients with PBC, Linerixibat is an ileal sodium-de fects patients’ quality of life and is linerixibat at doses of 20 mg, 90 answering questions about itch and pendent bile acid transporter in a huge burden for them,” said in mg, or 180 mg, or twice-daily doses social and emotional status. hibitor, so the gut has to deal with vestigator Cynthia Levy, MD, AGAF of 40 mg or 90 mg – or to placebo. Reductions in worst daily itch the excess bile acid fallout, but the from the University of Miami Health After 12 weeks of treatment, all - from baseline to 12 weeks were diarrhea is likely manageable with System. 147 participants once again received steepest in the 40-mg twice-daily antidiarrheals, said Dr. Levy. With a twice-daily mid-range dose- placebo for 4 weeks. During the tri group, at 2.86 points, and in the A versionDr. Levy of disclosed this article support originally from of the drug for 12 weeks, patients al, participants recorded itch levels 90-mg twice-daily group, at 2.25 appearedGlaxoSmithKline. on Medscape.com. with moderate to severe itch report twice daily. The worst of these daily points. In the placebo group, the edMDedge.com/gihepnews significantly less itch and better / December scores 2020 was averaged every 7 days to mean decrease was 1.73 points. 27

25_26_27_GIH20_12.indd 27 11/20/2020 3:47:58 PM †IBD AND INTESTINAL DISORDERS Black patients found less likely to undergo eradication testing after H. pylori treatment

BY WILL PASS said. “There remains a disappointingly low num- hanges

MDedge News c

o

N Across the entire study period, patients were

3.0/ ber of patients who are tested for cure.”

to receive eradication testing after treatment SA testing if they were treated in the gastroenterology

lackfor Helicobacter patients may pylori be significantly infection than less patients likely BY- significantly more likely to undergo eradication

B /CC of other races/ethnic groups, based on a retrospec- tive analysis of more than 1,700 individuals. medicine,department and (52.4%), other departments compared with (P < rates .001). ranging ommons

This disparity may exacerbate the already in- C fromAcross 33% all to departments, 34.6% for internal Black medicine, patients under- family creased burden of H. pylori infection and gastric

cancer among Black individuals, according to ikimedia than patients of other races/ethnicities, at a rate principal author David A. Leiman, MD, MSHP, of /W ofwent 30.5% eradication versus 32.2% testing for significantly White patients, less often 35.1% atho

Duke University Medical Center in Durham, N.C. P for Asian patients, and 36.7% for patients who “H. pylori infection disproportionately affects ra- were of other backgrounds (P < .001). Compared cial/ethnic minorities and those of lower socioeco- System between June 2016 and June 2018, most with White patients, Black patients were 38% less often (71%) via serum antibody test. Approximate- likely to undergo eradication testing (odds ratio, MD, PhD, of Duke University, and colleagues wrote ly two-thirds of those diagnosed were non-White innomic their status,” abstract Dr. presented Leiman, coauthor at the annual Julius meeting Wilder, (66%) and female (63%). Out of 1,711 patients, of the American College of Gastroenterology. “ACG 622 (36%) underwent eradication testing, of with0.62; a95% study confidence by Shria Kumar, interval, MD, 0.48-0.79). and colleagues guidelines recommend treatment for H. pylori whom 559 (90%) were cured. fromDr. Leimanearlier this noted year, that which these found findings no racial contrast dis- - Despite publication of the ACG H. pylori guideline parity in eradication testing within a Veterans herence to these recommendations varies and its midway through the study (February 2017), test- Health Affairs cohort. infectionimpact on followed practice by patterns confirmation is unclear. of cure. This Adstudy - characterizes the management of H. pylori infection P < dergo testing for eradication than [patients of oth- .0001).ing rates dropped significantly from 43.1% in 2016 “Black patients are significantly less likely to un The investigators analyzed electronic medical to 35.9% in 2017, and finally 25.5% in 2018 ( is needed to understand the mechanisms driving andrecords predictors from 1,711 of guideline patients adherence.” diagnosed with H. py- er races/ethnicities],” Dr. Leiman said. “More work lori infection through the Duke University Health cure“These in patients findings treated are consistent for H. pylori with other work Continued on page 30 that has shown low rates of testing to confirm this disparity.” He suggested a number of possible ,” Dr. Leiman rare adopt the United States’ sed- Address disparities in care entary lifestyle and Western diet AGA Resource Minorities from page 1 (low in fruits and vegetables; high in AGA applauds researchers who - are working to raise our aware- known to worsen outcomes. Com- other studies, race and ethnicity did ars, and processed foods), their gut ness of health disparities in pared with Whites, for example, not affect patterns of medication use, microbiomeproinflammatory shifts saturated and their fats, IBD sugrisk digestive diseases. AGA is com- Black patients with Crohn’s disease surgery, or surgical outcomes if pa- increases markedly. Studies in other mitted to addressing this import- have higher rates of stricture and tients had similar access to care. Such countries have produced similar ant societal issue head on. Learn penetrating lesions and are at greater more about AGA’s commitment risk for postsurgical complications of minority races and ethnicities have not help write the review article. through the AGA Equity Project. and death, even after potential con- accessfindings to “indicate appropriate that specialty when patients care findings,She also said noted Dr. Charabaty,that patients who from did founders such as age, sex, smoking and IBD-related therapy, many pre- communities with a historically status, time to operation, and obesity - low prevalence of IBD may not un- and their symptoms tend to be min- are controlled for. To help close these derstand its chronicity or the need imized. There is a lot of unconscious gaps, Dr. Barnes and his associates viouslyHowever, identified race and disparities ethnicity are do re for long-term treatment. However, bias among providers that factors recommended enhanced recovery affectsolved some or reduced,” aspects theof IBD experts disease said. treatment adherence is a common into this. The barriers are multiple, after surgery (ERAS) protocols, which activity, genetics, and treatment safe- issue for patients of all backgrounds “streamline [the] multidisciplinary with IBD, she said. “What is unique management of patients with IBD have made up the vast majority of re- is barriers to continuity of care – not atand the it levelis important of the patient, to define the them clini- before surgery, incorporating evi- searchty and efficacy.participants, Since studies White patientsof racial being able to get to the treatment and find strategies to overcome them dence-based practices focused on and ethnic minorities are needed to center, not being able to afford treat- The Crohn’s and Colitis Founda- nutrition, prevention of postoperative improve their IBD diagnosis, preven- ment or take time off work if you tioncian, supportedand the health the system.”work. Dr. Barnes ileus, and use of nonopioid analgesia tion, and treatment. Such research live paycheck to paycheck, not being disclosed ties to AbbVie, Gilead, is particularly vital because IBD able to pay someone to care for your Takeda, and Target Pharmasolu- Similar approaches also might incidence is rising three times faster tions. Two coauthors also disclosed improveand goal-directed nonsurgical fluid outcomes therapy.” in in racial and ethnic minorities than Other potential barriers to seeking relevant ties to pharmaceutical minorities with IBD, the experts said. Whites, said Aline Charabaty, MD, IBDkids treatmentwhile you includesee the culturaldoctor.” taboos companies. Dr. Charabaty disclosed In the Sinai-Helmsley Alliance for AGAF, clinical director of the gastro- against discussing lower GI symp- Research Excellence (SHARE) study, enterology division at Johns Hopkins toms or concerns that chronic dis- Janssen, Takeda, and UCB. Black patients had more complicated University in Baltimore, and director ease will harm marriage prospects, relationships with AbbVie,[email protected] Pfizer, IBD at baseline but similar clinical of the IBD Center at Sibley Memorial Dr. Charabaty said. Such challenges outcomes and patterns of medica- Hospital in Washington. only heighten the need to ascertain SOURCE: Barnes EL et al. Gastroenter- tion use as Whites when they were She explained that, when immi- IBD symptoms: “Studies show that ology. 2020 Oct 20. doi: 10.1053/j.gas- treated at academic IBD centers. In grants from countries where IBD is minorities have less follow-up care tro.2020.08.064.

28 December 2020 / GI & Hepatology News

01_09_to_17_28_31_GIH20_12.indd 28 11/20/2020 3:42:21 PM What is the power of the microbiome?

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GIHEP_29.indd 1 10/21/2020 1:26:42 PM †IBD AND INTESTINAL DISORDERS Tool predicted vedolizumab nonresponse in practice

BY AMY KARON a recent study. Noting the lack of zumab during the blinded phase 3 tis who had received vedolizumab MDedge News real-world data on predictors of GEMINI 1 trial. They used this model (199 patients) or TNF antagonists response, the researchers modeled to create the clinical scoring tool, (123 patients) in routine practice mong patients with ul- data from 620 patients who received which they validated in a cohort of during the Vedolizumab for Health cerative colitis who were induction and maintenance vedoli- 322 patients with ulcerative coli- Continued on following page Atreated in routine practice, a point-based clinical scoring tool PERSPECTIVE predicted nonresponse to vedoli- zumab therapy, according to study Clinical Tool includes variables found in clinical record Gastroenterology and Hepatology. he management of moderate to severe ulcerative requires no additional tests or studies to calculate. findingsA cutoff published of 26 points online or less in was Tcolitis has become more complex because of the The value in these types of tools is to assist in early greater number of Food and Drug Adminis- biologic decision-making by providing a interval, 79%-98%) for identifying tration–approved biologic and small-mole- numeric cutoff that can be used to recom- patients93% sensitive who did (95% not confidencereach corti- cule agents currently available. With more mend one agent versus the other. Another costeroid-free remission during 26 options, practitioners are faced with the noted feature of this tool is the potential weeks of treatment and was 88% challenge of choosing the most appropriate sensitive (95% CI, 83%-92%) for agent based on disease- and patient-specif- from dose optimization because lower or identifying patients who required ic risk factors. The goals of early interven- intermediateto identify which scores patients tended may to respondbenefit colectomy, reported Parambir S. tion are to achieve steroid-free remission to dose escalation in vedolizumab partial Dulai, MBBS, of the University of Cal- with mucosal healing and the associated responders. However, because this tool ifornia, San Diego, and his associates. improvements in quality of life, reduced predominantly assists with the choice of The tool was less reliable for predict- colectomy, and lower colon cancer risks. Dr. Ha anti-TNF vs. vedolizumab, one may not be ing response to tumor necrosis factor Rather than randomly choosing among able to extrapolate these results to usteki- (TNF) antagonists, indicating that it treatment options, this study by Dulai and colleagues numab and tofacitinib positioning in ulcerative coli- offers a clinical prediction tool that helps clarify tis. Further studies are needed to determine if these Vedolizumab, an alpha-4- which option, vedolizumab versus anti–tumor necro- variables similarly affect steroid-free remission for beta-7is treatment anti-integrin specific, that they restricts noted. these agents. agent, to achieve the desired steroid-free clinical lymphocytes to the gut, can induce sisremission factor (TNF), outcome. would In this be more tool, theylikely, included as a first-line known Christina Ha, MD, FACG, AGAF, is an associate professor corticosteroid-freethe migration of proinflammatory remissions and high-risk factors for colectomy, severe endoscopic of medicine, Inflammatory Bowel Disease Center, Ce- mucosal healing in patients with activity, and hypoalbuminemia with other vari- dars-Sinai, Los Angeles. She is on the advisory board of ulcerative colitis. In clinical practice, ables, such as prior anti-TNF exposure and disease AbbVie, Janssen, Takeda, Pfizer, Salix, and InDex Phar- 22-week rates of clinical response duration. Importantly, this information is readily maceuticals; has received grant support from Pfizer; and remission were approximate- accessible in a routine clinical record and, therefore, and has received research support from Pfizer and Lilly. ly 51% and 30%, respectively, in

Continued from page 28 Rotonya Carr, MD, of the Hospital of the Universi- contributing factors, including provider knowledge AGA Resource ty of Pennsylvania, Philadelphia, and lead author of gaps, fragmented care, and social determinants of AGA applauds researchers who are working a recent publication addressing racism and health health. to raise our awareness of health disparities “It is clear that a greater emphasis on charac- in digestive diseases. AGA is committed to of the present study add weight to a known equity terizing and addressing the social determinants of addressing this important societal issue gap.disparities Dr. Carr in is gastroenterology, also an advisory saidmember the findings for the health, including poverty, education, and location, head on. Learn more about AGA’s commit- American Gastroenterological Association Equity are needed,” Dr. Leiman said. “Although health ment through the AGA Equity Project. Project. systems are not solely responsible for the known “These data are concerning in view of the two- and ongoing observations of disparities in care, fold higher prevalence of H. pylori seropositivity - search, Atlanta, the higher rate of H. pylori infection and twofold higher incidence of gastric cancer in ed to mitigate these issues.” Such interventions in Black individuals may stem partly from genetic Black patients, compared with White patients,” wouldinterventions likely require must be broad identified participation, and implement he said, factors. “Studies have shown that African Ameri- Dr. Carr said. “These and other data support a including policy makers, health systems, and indi- cans with a higher proportion of African ancestry comprehensive approach to reduce GI dispari- vidual practitioners. have higher rates of H. pylori, suggesting a genetic ties that includes targeted education of both GI “We plan to perform a prospective mixed meth- component to this increased risk,” he said. specialists and referring providers.” ods study to contextualize which social determi- Still, Dr. Hall, who is the author of the book “Clinicians should consider H. pylori therapy an nants are associated with a decreased likelihood Patient-Centered Clinical Care for African Ameri- episode of care that spans diagnosis, treatment, of receiving appropriate eradication testing by cans, went on to emphasize appropriate H. pylori exploring barriers at patient, practitioner, and management and recognition of racial disparities the loop in that episode by ensuring eradication is health-system levels,” Dr. Leiman said. “Ultimately, in medicine. vitaland confirmation to conforming of with cure,” best Dr. practices,Leiman said. and “Closing to re- - duce patients’ long-term risks.” evidence-based intervention to circumnavigate ication of H. pylori infections represents a great The investigators disclosed relationships with we aim to leverage these findings to develop an opportunity“The ability to to improve test for, quality treat, and of life confirm through erad Exact Sciences, Guardant Health, and Phathom observed disparities in H. pylori care.” decreased gastritis, gastric ulcers, and gastric Pharmaceuticals. Dr. Hall and Dr. Carr reported no thoseAccording identified to Gregory barriers, L. therebyHall, MD, eliminating of Northeast the Ohio Medical University, Rootstown, and Case yet another disparity in our clinical care of Afri- [email protected] Western Reserve University, Cleveland, and co- cancancer,” Americans he said. that “[The needs present increased findings] awareness show relevant conflicts of interest. director of the Partnership for Urban Health Re- among providers to these communities.” SOURCE: Reichstein J et al. ACG 2020, Abstract S1332.

30 December 2020 / GI & Hepatology News

01_09_to_17_28_31_GIH20_12.indd 30 11/20/2020 3:42:23 PM Continued from previous page

they had higher vedolizumab trough Outcomes in Inflammatory Bowel concentrations to begin with, the re- Diseases (VICTORY) study. searchers said. They called for pro- In the final multivariable model, spective validation of this finding, predictors of steroid-free remission “ideally in a randomized, controlled were TNF-antagonist naivety, at trial setting.” least a 2-year history of ulcerative The derivation and validation co- colitis, moderate rather than severe horts differed in several important endoscopy activity, and baseline al- ways. The validation cohort included bumin concentration. The resulting significantly more females, smokers, Principles clinical scoring tool included these patients with moderate endoscopic four variables and multiplied them disease, and patients who had failed by factors ranging from 0.0647 (for prior TNF-antagonist therapy. These baseline albumin concentration) to patients also had a significantly of GI for the 0.2820 (for no prior TNF-antagonist higher median albumin level and exposure). In the validation cohort, a longer history of disease. “The patients were categorized as “high lower bound of the confidence in- probability” (of response) if they terval for the [model’s] performance NP and PA scored 33 points or more on the tool reached 0.5, suggesting that model and “low probability” if they scored discrimination may not be ideal,” the 26 points or fewer. Rates of cortico- researchers said. “Further validation steroid-free remissions were sub- will therefore be needed to under- On-Demand stantially different at 32% and 12%, stand external validity on additional respectively. The tool also predicted cohorts.” responses to vedolizumab more ac- An American Gastroenterological curately than it predicted responses Association Research Scholar Award to TNF antagonists, indicating that it supported the work. Dr. Dulai report- was drug specific. ed holding a provisional patent for In the validation cohort, 46% (10 the prediction model and consulting of 22) of low- or intermediate-prob- relationships and other ties to Take- ability patients showed least a 50% da, Janssen, Pfizer, and AbbVie. His decrease in symptom activity after coinvestigators [email protected] ties to nu- their vedolizumab infusion interval merous pharmaceutical companies. was shortened to address an insuf- SOURCE: Dulai PS et al. Clin Gastroenterol ficient initial response. “However, Hepatol. 2020 Feb 13. doi: 10.1016/j. none of the high-probability patients cgh.2020.02.010. showed a clinical response to inter- val shortening,” probably because Life expectancy gap persists for IBD patients BY HEIDI SPLETE MDedge News people without IBD in 2011. Expert guidance on GI care: Overall, life expectancy for IBD L patients increased from 75.5 years to ife expectancy increased for adults 78.4 years for women and from 72.2 Become empowered with stronger with inflammatory bowel disease years to 75.5 years for men between diagnostic and therapeutic skills. (IBD) over recent decades, but still 1996 and 2011. However, health-ad- remained lower than that for individ- justed life expectancy, defined as the Learn the latest techniques from GIs uals without IBD, according to data number of years a person is expected from a retrospective cohort study us- to live in full health, decreased by and APPs leading patient care teams. ing Canadian health databases. 3.9 years for men with IBD between M. Ellen Kuenzig, PhD, of the Chil- 1996 and 2008, but did not change Enhance your value to your team dren’s Hospital of Eastern Ontario significantly for women with IBD. and patients. and colleagues said, “Most studies The study was supported by the In- evaluating mortality were con- stitute for Clinical Evaluative Services Earn 15.25 CME where you want and ducted before the biologic era, and (Canada). Lead author Dr. Kuenzig none evaluated life expectancy or received a Post-Doctoral Fellowship when you want. health-adjusted life expectancy.” Award from the Canadian Institutes In a study published in the Cana- of Health Research, Canadian As- Purchase today at dian Medical Association Journal, sociation of Gastroenterology, and the researchers used Canadian data- Crohn’s and Colitis [email protected] The re- nppa.gastro.org. bases to identify a study population searchers had no conflicts.

of 32,818 people with IBD matched SOURCE: Kuenzig ME et al. CMAJ. 2020 Nov EDU20-080 to 163,284 people without IBD in 9. doi: 10.1503/cmaj.190976. 1996 that increased to 83,672 peo- pleMDedge.com/gihepnews with IBD matched to 418,360 / December 2020 31

01_09_to_17_28_31_GIH20_12.indd 31 11/20/2020 3:42:32 PM †OBESITY ‘Disordered eating’ drops after bariatric surgery in teens

BY MARLENE BUSKO sistent severe obesity are at high al takeaway for clinicians is that unplanned and repetitious way be- risk for poor health and well-being,” “disordered eating is associated tween meals and snacks), objective mong young patients with Dr. Decker said in an interview. with other mental health problems overeating (eating a “large” amount severe obesity and disor- “This means disordered eating and self-worth. Clinicians treating of food without loss of control), Adered eating behaviors – behaviors should be closely mon- obesity must address problems re- and objective binge eating (eating a continuous eating, overeating, and itored” in all such patients, both lated to eating disorders to improve “large” amount of food with loss of binge eating – those who had bar- those who undergo surgery and outcomes and well-being,” she control). iatric surgery saw an improvement those who don’t, she stressed. stressed. At baseline, rates of continuous in the eating behaviors. eating, overeating, and binge eating Kristina M. Decker, PhD, a post- Robust findings are due to Effects of bariatric surgery were higher in the surgical group doctoral fellow at Cincinnati Chil- long follow-up and controls impact on overeating, binge (50%, 40%, and 30%, respectively) dren’s Hospital Medical Center, eating, in teens questioned than the nonsurgical group (40%, based on adult bariatric literature, “For teens with severe obesity, 22%, and 11%, respectively). virtual ObesityWeek 2020. butThe arefindings “novel are because not unexpected, of the age metabolic and bariatric surgery is Six years later, when participants presentedDr. Decker these and findings associates during exam- the of the patients,” senior author the most effective treatment for were aged 19-24 years, rates of ined rates of disordered eating in Margaret H. Zeller, PhD, Cincinnati improved cardiometabolic function- continuous eating, overeating, and more than 200 adolescents (aged Children’s Hospital Medical Center binge eating had declined in the 13-18 years) who were severely and professor at the University of surgical group (to 17%, 5%, and obese, of whom 141 underwent Cincinnati, added. However, an important additional 1%, respectively). In the nonsurgi- bariatric surgery and the remainder In a comment, psychologist Kajsa takeaway for clinicians is that cal group, only continuous eating did not. Järvholm, PhD, of the Childhood and overeating declined (to 24% At baseline (presurgery), the teens Obesity Unit at Skåne University ‘disordered eating is associated and 7%, respectively), and binge in both groups had rates of disor- with other mental health eating increased slightly (to 13%). dered eating ranging from 11% to published related work, said that 50%, with higher rates in those who thisHospital, is “a neededMalmö̈, study.”Sweden, who has problems and self-worth.’ Disordered eating associated went on to have bariatric surgery. Notably, it had “long-term fol- with low self-worth, Six years later, rates of disordered low-up and a control group,” and it anxiety, and depression eating were much lower in those ing, weight loss, and improved qual- In young adulthood in both groups, who had bariatric surgery. better control of their eating after ity of life,” Dr. Decker stressed. disordered eating was associated The data nevertheless “under- surgery.”“confirms that adolescents are in However, pre- and postsurgical with lower self-worth. In the sur- score that young adults with per- However, an important addition- disordered eating behaviors have gical group, it was also associated been associated with a lower per- with lower weight-related quality centage change in body mass index, of life, and in the nonsurgical group, although this has not been well it was also associated with anxiety studied. and/or depression. To investigate how disordered eat- ing is affected by bariatric surgery us whether disordered eating is a in adolescents with severe obesity, direct“The result current or findingscaused by cannot anxiety, tell ® researchers used data from Teen- depression, low self-worth, or poor CROHN’S & COLITIS CONGRESS LABS, which enrolled 242 partici- quality of life,” Dr. Decker said. Connecting Virtually | January 21–24, 2021 pants aged 19 years and under who mainly underwent Roux-en-Y gastric about what other areas of clinical bypass (67%) or sleeve gastrectomy concern“These might findings present do give together us insight [in] - young adults (e.g., disordered eat- olescent bariatric surgery centers. ing, low self-esteem).” (28%)The currentfrom 2007 analysis to 2012 examined at five ad Bariatric surgery affects the TRANSFORMING IBD CARE data from 141 participants in Teen- amount of food people can eat at LABS who underwent bariatric one time, she noted in reply to Get inspired to transform IBD care at the premier surgery at a mean age of 16.8 years. a question from the audience. If conference for IBD clinicians and researchers. Mean BMI was 51.5, most were girls people eat too much at a time they In 2021, the Crohn’s & Colitis Congress® goes virtual. You’ll (80%), and they had diverse race/ can experience vomiting, dump- get all the benefits and quality programming you have ethnicity (66% were White). ing syndrome (where certain food come to expect from the Crohn’s & Colitis Foundation and is “dumped” into the small intestine AGA — all from the safety of your home or office. There will control group of 83 adolescents of without being digested, causing also be new and exciting ways to network with fellow IBD a similarResearchers age and also gender identified who ahad nausea and vomiting), and plugging leaders, learn best practices, hear what’s on the horizon in diverse race/ethnicity (54% White) (a sense of food becoming stuck). potential treatments and receive practical takeaways you’ll and a mean BMI of 46.9. The home environment and tran- be able to implement immediately. At year 6, data were available for sition to adulthood might impact 123 young adults in the surgery disordered eating in young adults, group (who by then had a mean she said in reply to another ques- #CCCongress21 BMI of 39.7) and 63 young adults in tion, but these issues were not ex- the nonsurgery group (who had a amined in this study. REGISTER TODAY. mean BMI of 52.6). www.crohnscolitiscongress.org At baseline and year 6, partici- disclosures for Dr. Decker or Dr. pants replied to questionnaires that Järvholm.There are no relevant financial A version of this article originally continuous eating (eating in an appeared on Medscape.com. identified three eating disorders: 32 December 2020 / GI & Hepatology News

32_to_35_GIH20_12.indd 32 11/24/2020 9:24:14 AM †UPPER GI TRACT Antibody promising in eosinophilic gastritis/duodenitis

BY JIM KLING somewhat of a disconnect between with active, uncontrolled eosinophilic age change in total symptom score MDedge News symptom reduction and reduction gastritis or duodenitis, or both, to re- was –48 versus –22 in the placebo of the eosinophil counts. Sometimes ceive four monthly low- (0.3, 1, 1, and group (P = .004). In the per-protocol n a phase 2 trial in eosinophilic 1 mg/kg) or high-dose lirentelimab analysis, 69% responded versus 5% gastritis and duodenitis, an anti– enough]. Maybe there is other dam- (0.3, 1, 3, and 3 mg/kg), or placebo. A (P < .001). The mean percentage ISiglec-8 antibody greatly reduced agejust toblocking the bowel.” the inflammation [isn’t total of 10 patients had gastritis, 25 change in total symptom score was numbers of eosinophilic cells and led The research, led by Evan S. Dellon, had duodenitis, and 30 had both. –53 versus –24 (P = .001). to improved symptoms. The spon- MD, MPH, of the University of North In the intention-to-treat analysis, About 60% in the treatment group soring company, Alkalos, is currently Carolina at Chapel Hill, and Ikuo Hi- there was a mean 86% reduction in had an infusion-related reaction ver- conducting a phase 3 trial in eosino- rano, MD, of Northwestern University, eosinophil count in patients in the sus 23% who received placebo; 93% philic gastritis or duodenitis. Chicago, appeared in the New En- treatment groups, compared with a of reactions were mild to moderate. The news is welcome to clinicians gland Journal of Medicine. 9% increase in controls (P < .001). In Serious adverse events occurred in who treat these rare conditions, since The antibody (lirentelimab) targets the per-protocol analysis, there was a 9% of the treatment group and 14% the only current treatment is ste- sialic acid–binding immunoglobulin-­ 95% reduction vs. a 10% increase (P of patients on placebo: 86% of pa- roids. This is particularly challenging like lectin 8 (Siglec-8), which is an < .001). Of treated patients, 95% had tients in the treatment group experi- because most patients with these inhibitory receptor found on mature a gastrointestinal eosinophil count enced transient lymphopenia, as did conditions present in their 30s and eosinophils and mast cells, and ex- 47% of the placebo group, but there 40s, according to Carol Semrad, MD, pressed at low levels on basophils. compared with 0% with placebo. were no clinical consequences. professor of medicine at the Universi- The antibody reduces eosinophil cells of In6 orthe fewer intention-to-treat per high-powered analysis, field, The study was funded by Alkalos. ty of Chicago, who was asked to com- through natural killer cell–mediated 63% of treated patients had a treat- ment on the study. She noted that the cellular cytotoxicity and apoptosis, disclosures. study’s results were impressive, but and other antibodies against the same a 30% reduction in total symptom Dr. Semrad has no [email protected] financial it will take a phase 3 trial to convince. target have been shown to inhibit scorement response,and at least defined a 75% as reduction at least mast cell activation. in eosinophil count. About 5% of pa- SOURCE: Dellon ES et al. N Engl J tracks with the impressive reduction At 22 sites across the United States, tients had a response in the placebo Med. 2020 Oct 22. doi: 10.1056/NEJ- seenIt’s also in eosinophilunclear if the count. clinical “There’s benefit researchers randomized 65 adults group (P < .001). The mean percent- Moa2012047. CLASSIFIEDS Also available at MedJobNetwork.com

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32_to_35_GIH20_12.indd 33 11/20/2020 3:50:28 PM †PRACTICE MANAGEMENT TOOLBOX Value-based care stunted from delayed Stark, anti-kickback reform BY JOSEPH LOSURDO, MD, AGAF pany model frameworks necessarily violate the implement MACRA law as Congress intended. AKSs and the OIG’s Advisor Opinions FAQ states AGA and the physician community have nti-kickback statutes (AKSs) were orig- no person or entity can rely on an advisory opin- long sought to update Stark self-referral and inally enacted in 1931 to stop Great ion issued to someone else. However, Advisory AKSs. Last year, Centers for Medicare & Med- ADepression–era employers from circum- Opinion No. 12-06 has been cited in AKS investi- icaid Services proposed exceptions directed venting wage provisions in federal contracts. gations ever since. at value-based arrangements that would have Since its enactment, AKSs’ main focus has When Congress passed the Medicare Access allowed providers to participate in value-based changed and is currently aimed at the health and CHIP Reauthorization Act (MACRA) in 2015, arrangements while still protecting the Medicare care industry. In addition to AKSs, Stark laws it changed how physicians would be paid under program from potential abuses. Many of the were enacted over 30 years ago to address Medicare and sought to transition physicians to changes that CMS proposed would have allowed physician self-referral of physician practices to engage in value-based ar- Medicare patients. Both laws S. 2051/H.R. 4206, the Medicare Care rangements that would improve patient care and comprise the government’s AGA provided comments on both the Stark and Coordination Improvement Act, would AKS proposed rules. However, CMS has not yet waste, and abuse. However, allow innovative payment models AKSsmain toolsand Stark for fighting laws have fraud, not developed by gastroenterologists to be been updated to keep pace opportunityissued the final to improverules and health has indicated care delivery. that they with changes in how medical implemented in the Medicare program. willOn not the issue legislative a final front, rule on AGA Stark supports which S. is a lost practices do business and Unfortunately, this legislation has 2051/H.R. 4206, the Medicare Care Coordina- care for patients. tion Improvement Act, which would provide Over the years, additional Dr. Losurdo received little traction in Congress. CMS with the regulatory authority to create - exceptions under the Stark law for APMs and to cation has been issued by the Department of a more value-based payment system. Physicians remove barriers in the current law to the devel- interpretation and clarifi - were incentivized to develop physician-driven opment and operation of such arrangements. spector General. In HHS’s June 1, 2012, Advisory - OpinionHealth & No. Human 12-06, Services there is and guidance the Office regarding of In tient outcomes. However, existing Stark self-re- Stark laws for physicians seeking to develop and legality of anesthesia services providers’ con- ferralpayment laws models prohibit to improvephysicians efficiency from referring and pa operateThe legislation APMs similar would toallow what CMS Congress to waive allowed the tract with physician-owned professional corpo- - rations or limited liability companies to provide cial interest. As a result, physician practices are payment models developed by gastroenterol- unablepatients to to participate an entity in in which many theyadvanced have alterna-a finan ogistsfor ACOs. to be The implemented legislation would in the allowMedicare innovative pro- the “company model” where owners of an am- tive payment models. gram. Unfortunately, this legislation has received bulatoryanesthesia surgery services. center Specifically, (ASC) create it focused a separate on Stark laws, which have not been updated since little traction in Congress. company for anesthesia services which directly their enactment 30 years ago, pose barriers to Until meaningful regulatory and legislative contracts with anesthesia providers and charges care coordination since they prohibit payment reform updating both Stark and AKSs occur, for the anesthesia services while the ASC arrangements that consider volume or value innovative payment models must wait and gas- charges for facility fees. of referrals or other business generated by the troenterologists and other providers will remain vulnerable to these outdated regulations. You an advisory opinion from the OIG about the in delivering care by inhibiting practices from can help us advance these issues by sharing how applicationAnyone with of OIG’s specific fraud questions and abuse may authorities request incentivizingparties. These their prohibitions physicians stifle to deliverinnovations patient and existing or proposed business arrange- value-based arrangements you would participate ments. An OIG advisory opinion is legally bind- cannot use resources from designated health inthey and impact how would your practice. they improve Tell us patient what types care andof servicescare more in efficiently,rewarding because or penalizing the practices adherence to any other governmental department or agency. new clinical care pathways. ing on the requesting party and HHS, but not on- Congress recognized that the Stark law was a Dr.efficacy Losurdo at [email protected]. is the AGA’s Alternate Advisor to the barrier to new health care delivery models. Con- American Medical Association’s CPT Editorial opinionWhile advisory may not opinions be relied are on specific by any personsto the enti gress, therefore, authorized the HHS Secretary to Panel, a member of the AGA Practice Management ty that requested it and specifically states, “This waive Stark self-referral and anti-kickback laws for and Economics Committee’s Coverage and Reim- this opinion. ...” - bursement Subcommittee and is a partner with otherIt captured than [name the attention redacted], of thethe requestormedical com- of er was not extended to physician-driven alterna- Elgin Gastro Endoscopy, who owns an ASC, and tiveaccountable payment care models organizations (APMs), that (ACOs). also need This thesewaiv Managing Partner and Medical Director of Illinois should not be interpreted to mean that all com- exceptions to drive innovation in health care and to Gastroenterology Group/GI Alliance, Elgin, Ill. munity. The AGA has argued that this opinion †COVID-19 ROUNDUP Obesity increases pneumonia risk, mutation ups contagiousness

BY LUCAS FRANKI - younger than 50 years after other Common mutation making MDedge News lation increased in patients with factors were adjusted for. SARS-CoV-2 more contagious obesity,and requiring independent mechanical of age, venti sex, di- However, the study also found While there was a wide variety of After age and male sex, abetes, hypertension, dyslipidemia, an “obesity paradox” for mortality SARS-CoV-2 strains early in the obesity biggest risk for and smoking. after admission to the ICU, where pandemic, 99.9% of circulating COVID-19 pneumonia For each 5-kg/m2 increase in patients with a BMI of 25-39.9 had SARS-CoV-2 strains in the study In a large international study pub- body mass index, there was a 27% a lower risk of death than those feature the D614G mutation on the increased risk of mechanical ven- with a BMI of less than 25, although spike protein, which is associated at ObesityWeek 2020, the likelihood tilation in the overall cohort and patients with a BMI over 40 had the with increased nasopharynx viral oflished developing in The Lancet severe andpneumonia presented a 65% increased risk in women highest mortality rate. Continued on following page

34 December 2020 / GI & Hepatology News

32_to_35_GIH20_12.indd 34 11/20/2020 3:50:29 PM Continued from previous page not patient care according to a AGA Resource The authors recognize that HCPs, loads at diagnosis. study conducted by the Minnesota For the latest clinical guidance, like the rest of the community, are The mutation likely dominates Department of Health. Nonwork education, research and experiencing COVID fatigue and because it increases the spike pro- exposures were more likely to lead physician resources about that facilities have to constantly tein’s ability to open cells for the to infection. coronavirus, visit the AGA be innovative and vigilant to help virus to enter, but the mutation is Between March and July 2020, COVID-19 Resource Center at HCPs maintain rigorous safety pre- not associated with worse clinical researchers evaluated 21,406 cas- www.gastro.org/COVID. cautions. COVID-19 severity and will likely Frontline associate editor Lucas COVID-19 cases. Franki compiled this column from any current treatment or vaccine in es“Since of HCP the exposure time period to confirmed covered in outside of work due to household reports first published on MDedge. development.not interfere with the efficacy of or social contacts,” said lead author com, Medscape.com, and Kaiser “As bad as SARS-CoV-2 is, we may increase in the proportion of HCPs Ashley Fell, MD, MPH, from the Min- Health News. have dodged a bullet in terms of whothis report, have had we’ve higher-risk seen a significant exposures nesota Department of Health. [email protected] how quickly it mutates,” said Ilya Finkelstein, PhD, of the Finkelstein Lab at the University of Texas, Aus- tin, adding that the slower mutation rate will give researchers a greater chance to stay one step ahead.

VA joins Pentagon in recruiting volunteers for COVID-19 vaccine trials Renew your - partment of Veterans Affairs and OperationAccording Warpto officials Speed, from the theVA willDe membership recruit 8,000 volunteers for phase 3 clinical trials of at least four Continue learning. COVID-19 vaccine candidates at 20 U.S. federal medical facilities. Continue growing. This announcement follows a September announcement by the Continue improving digestive Department of Defense that it has health with AGA membership to partnered with AstraZeneca to re- support your needs. facilities. Since active troops are essentialcruit volunteers to national at five security, of its medical and Renew by Dec. 1 at veterans are extremely vulnerable to COVID-19, both departments www.gastro.org/renew have a vested interest in supporting MEM20-028 the development of safe, effective vaccines, said J. Stephen Morrison, senior vice president and director of global health policy at the Center for Strategic and International Studies, a bipartisan think tank in Washington.

COVID exposure risk outside of work increasing for clinicians One-third of COVID-19 exposures With the right planning and care, women with among health care providers inflammatory bowel disease (IBD) can have (HCPs) in Minnnesota are caused healthy pregnancies and healthy babies. by family or community exposure, We help GIs provide care for them.

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MDedge.com/gihepnews / December 2020 35

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