December 2019 olume 15 Issue 12 Supplement 6

A SPECIAL MEETING REVIEW EDITION

Highlights From the 2019 Advances in Inflammatory Bowel Diseases Conference A Review of Selected Presentations From the 2019 AIBD Conference • December 12-14, 2019 • Orlando, Florida

Special Reporting on: • A Practical Approach to Anti- in IBD 2020 • Update: ACG Guidelines for the Treatment of Crohn’s Disease • Management of in Adults: ACG Clinical Guidelines • The Road Ahead: Potential Benefits and Risks of Combining Biologics and Novel Agents • A Practical Approach to JAK inhibitors in IBD 2020 • A Practical Approach to Anti-Integrins in IBD 2020 • A Practical Approach to Anti-TNFs in IBD 2020

PLUS Meeting Abstract Summaries

With Expert Commentary by: Gary R. Lichtenstein, MD Professor of Medicine Director, Center for Inflammatory Bowel Disease University of Pennsylvania Health System Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

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A Practical Approach to Anti-Interleukins in IBD 2020

r Bruce E. Sands discussed with (90 mg either every was associated with significantly higher the use of anti-interleukins.1 8 weeks or every 12 weeks) or placebo. corticosteroid-free remission rates at Ustekinumab is the only In both the UNITI-1 and week 44. This rate was 46.9% with the anti-interleukinD agent approved for UNITI-2 trials, a significantly higher every-8-week regimen, 42.6% with the the treatment of patients with IBD. proportion of patients who were treated every-12-week regimen, and 29.8% Through recognition of the shared with ustekinumab compared with pla- with placebo (P=.004 for the compari- p40 protein subunit, ustekinumab can cebo achieved the primary endpoint of son of every 8 weeks vs placebo; P=.035 disrupt proinflammatory cytokines clinical response (defined as a decrease for the comparison of every 12 weeks (IL) 12 and 23 signalling. of ≥100 points in the Crohn’s Disease vs placebo). In a long-term follow-up In patients with Crohn’s disease, the Activity Index [CDAI] from baseline of the UNITI studies, the rate of remis- pivotal induction trials establishing to week 6, or a CDAI score <150). In sion at 2 years among patients receiving the safety and efficacy of ustekinumab UNITI-1, the rates of response at week ustekinumab every 8 weeks was 47%, were UNITI-1 and UNITI-2.2 The 6 were 34.3% in the 130 mg arm and or 88% of the remission rate observed use of ustekinumab in the mainte- 33.7% in the 6 mg/kg arm, vs 21.5% at 1 year (53.1%; Figure 1).3 nance setting was established by the with placebo (P≤.003 for both com- Among patients with ulcerative IM-UNITI trial.2 In the UNITI-1 parisons with placebo). In UNITI-2, colitis, UNIFI was the pivotal induc- and UNITI-2 trials, patients were the rates of response at week 6 were tion and maintenance trial establishing randomly assigned to receive a single 51.7%, 55.5%, and 28.7%, respec- the safety and efficacy of ustekinumab intravenous dose of ustekinumab tively (P≤.001 for both comparisons in these settings.4 The trial randomly (either 130 mg or approximately 6 with placebo). assigned 961 patients with moderate to mg/kg) or placebo. The UNITI-1 trial The primary endpoint for the severe ulcerative colitis to ustekinumab enrolled 741 patients with a primary or IM-UNITI maintenance trial—remis- (130 mg or ~6 mg/kg) or placebo. secondary nonresponse to anti–tumor sion at week 44 (defined as a CDAI Patients with a response to induction necrosis factor (TNF) therapy, or score <150)—was also higher with therapy were randomly assigned again who developed unacceptable toxicity ustekinumab than placebo. This rate was to receive subcutaneous maintenance after treatment with these agents. The 53.1% with ustekinumab given every 8 injections of ustekinumab (90 mg UNITI-2 trial enrolled 628 patients weeks and 48.8% with ustekinumab every 8 weeks or every 12 weeks) or with an inadequate response to con- given every 12 weeks, vs 35.9% with placebo. ventional therapy or who were intoler- placebo (P=.005 for the comparison The primary endpoint of clinical ant to it. Patients with a response in of every 8 weeks vs placebo; P=.04 for remission was defined as a total score either UNITI-1 or UNITI-2 (n=397) the comparison of every 12 weeks vs of 2 or less on the Mayo scale and no were randomly assigned to treatment placebo). Treatment with ustekinumab subscore exceeding 1 on any of the

70 5 of patients in remission of patients in remission 52 weeks after induction 60 100 weeks after induction

50

40

30

20 Placebo (n=131) Ustekinumab 90 mg every 8 weeks (n=128) Proportion of Patients Proportion of Patients 10 Entry into long-term extension 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 Entry into maintenance from Weeks After Induction 8-week induction

Figure 1. Remission through 2 years among patients with Crohn’s disease responding to induction treatment with ustekinumab in the IM-UNITI long-term extension study. Adapted from Sands BE et al. ACG abstract 49. Presented at: American College of Gastroenterology Annual Scientific Meeting; October 5-10, 2018; Philadelphia, PA3 and Sands BE. A practical approach to anti-interleukins in IBD 2020. Paper presented at: Advances in Inflammatory Bowel Diseases Conference; December 12-14, 2019; Orlando, Florida.1

Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 3 SPECIAL MEETING REVIEW EDITION

4 Mayo scale components. The rate 100 P<.001 of clinical remission at week 8 was P<.001 15.6% with ustekinumab at 130 mg, 80 10 15.5% with ustekinumab at 6 mg/kg, 60 and 5.3% with placebo (P<.001 for 60 both comparisons to placebo). Among 6 responding patients, the rate of clini- 40 cal remission at week 44 was 43.8% with ustekinumab given every 8 weeks, 20 38.4% with ustekinumab given every 12 weeks, and 24.0% with placebo Proportion of Patients Proportion of Patients 15 1112 12516 0 (P=.002 and P<.001, respectively). Other outcomes through week 44 are shown in Figures 2 and 3.5 Long-term Placebo SCa Ustekinumab Ustekinumab 90 mg SC 12w 90 mg SC w symptomatic remission was observed in the group of patients who continued to receive ustekinumab in a long-term Figure 2. Clinical response through week 44 among patients with ulcerative colitis treated with extension trial.6 a ustekinumab in the UNIFI trial. Patients with a clinical response to intravenous ustekinumab In summary, ustekinumab was and were randomized to subcutaneous placebo upon entry into the maintenance study. q8w, effective in Crohn’s disease and ulcer- every 8 weeks; q12w, every 12 weeks; SC, subcutaneous. Adapted from Sandborn WJ et al. ative colitis, where it may be useful ECCO abstract OP37. J Crohns Colitis. 2019;13(suppl 1)5 and Sands BE. A practical approach in both the first-line setting and after to anti-interleukins in IBD 2020. Paper presented at: Advances in Inflammatory Bowel Diseases Conference; December 12-14, 2019; Orlando, Florida.1 anti-TNF agent failure. Ustekinumab confers a very good corticosteroid spar- ing and maintenance effect. The onset of efficacy associated with ustekinumab Placebo (n=175) was observed as early as 2 weeks, but Ustekinumab, 90 mg every 12 weeks (n=172) efficacy can increase over 16 weeks and beyond. The safety of ustekinumab has Ustekinumab, 90 mg every 8 weeks (n=176) been well established, with minimal immunogenicity and a minimal need P=.07 for laboratory monitoring. 100 References 90 P=.01 1. Sands BE. A practical approach to anti-interleukins in IBD 2020. Paper presented at: 2019 Advances in 80 65 Inflammatory Bowel Diseases Conference; December 70 n0 5 12-14, 2019; Orlando, Florida. n 2. Feagan BG, Sandborn WJ, Gasink C, et al; UNITI– 60 IM-UNITI Study Group. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J 50 Med. 2016;375(20):1946-1960. n5 3. Sands BE, Kramer BC, Gasink C, et al. Long-term 40 efficacy and safety of ustekinumab with and without 30 concomitant immunosuppressants for Crohn’s disease: results from IM-UNITI long-term extension through 20 two years. Presented at: American College of Gastro-

Patients at Week Week at Patients enterology Annual Scientific Meeting; October 5-10, 10 2018; Philadelphia, PA. Abstract 49. 4. Sands BE, Sandborn WJ, Panaccione R, et al; UNIFI 0 Study Group. Ustekinumab as induction and main- Remission Through Week tenance therapy for ulcerative colitis. N Engl J Med. 2019;381(13):1201-1214. Among Those in Remission 5. Sandborn WJ, Sands BE, Panaccione R, et al. Efficacy at Week 0 in the Maintenance Trial and safety of ustekinumab as maintenance therapy in ulcerative colitis: week 44 results from UNIFI [ECCO abstract OP37]. J Crohns Colitis. 2019;13(suppl 1). Figure 3. Remission through week 44 among patients in remission at week 0 in the UNIFI 6. Sands BE et al. Efficacy and safety of ustekinumab maintenance trial. Adapted from Sandborn WJ et al. ECCO abstract OP37. J Crohns Colitis. for ulcerative colitis through 2 years: UNIFI long-term 5 extension. Presented at: United European Gastroen- 2019;13(suppl 1) and Sands BE. A practical approach to anti-interleukins in IBD 2020. terology Week. Barcelona, Catalonia, Spain, October Paper presented at: Advances in Inflammatory Bowel Diseases Conference; December 12-14, 19-23, 2019. Abstract LB01. 2019; Orlando, Florida.1

4 Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 HIGHLIGHTS FROM THE 2019 ADVANCES IN INFLAMMATORY BOWEL DISEASES CONFERENCE

Update: ACG Guidelines for the Treatment of Crohn’s Disease

r Gary R. Lichtenstein dis- endoscopic-based (mucosal healing) mended for induction therapy. cussed updates to guidelines endpoints. The guidelines note a lack Multiple agents are now avail- from the American College of correlation between symptoms and able for patients with moderate or ofD Gastroenterology (ACG) for the endoscopic findings, and therefore severe Crohn’s disease. Selection of management of Crohn’s disease in identify mucosal healing as a treat- treatment should be based on the adult patients.1,2 The guidelines were ment goal. Endoscopic scores may be specifics of the patient’s disease and updated in 2018, with several notable used to monitor response to treatment. comorbidities, as well as changes. Traditional laboratory evalua- The guidelines recommend evaluation efficacy, speed of onset, and safety. The tion is a component of the diagnosis of within 1 year of resection for postop- guidelines still include corticosteroids Crohn’s disease. There is a role for fecal erative endoscopic recurrence to guide as a recommended therapy for induc- calprotectin at diagnosis to differenti- therapy. Quality of life is another goal, tion of remission. Thiopurines or ate IBD from irritable bowel syndrome with a focus on the management of methotrexate are recommended for (strong recommendation; moderate stress, anxiety, and depression. maintenance therapy. However, for quality of evidence). In contrast, there There is now an understanding induction and maintenance of Crohn’s is no role for serologic markers in the that mild Crohn’s disease is relatively disease, the updated guidelines now diagnosis of Crohn’s disease. Genetic uncommon. For patients with mild include a focus on biologic therapies, testing is also not indicated. Ileocolo- disease, mesalamine is not indicated notably anti-TNF agents (, noscopy is recommended to confirm for either induction or remission , and ), the diagnosis. therapy. Instead, budesonide is recom- anti-integrin agents ( and Approximately 20% to 30% of patients with Crohn’s disease will have an indolent disease course. Most patients require therapies that con- trol inflammation. Hospitalization 60 10 mg I 6 mgkg I is required in up to 80% of patients with Crohn’s disease, and the 10-year 50 risk of surgery is 40% to 55% (this rate may be 30% in the era of biologic P=.039 therapies).1 Factors associated with an 40 increased risk of progressive disease include young age at diagnosis (<30 30 26 years), extensive bowel involvement at 211 presentation, severe perianal or rectal 20 disease, and penetrating or stenos- 1 ing phenotype at diagnosis. A higher number of poor prognostic factors 10 corresponds to a worse prognosis (as defined by the likelihood of requiring 0 surgery). Proportion of Patients in Remission Proportion of Patients n25 n90 n90 n90 n90 The former definition of Crohn’s Placebo 1 2 disease severity relied upon a descrip- tion of symptoms alone (using the ≤1.6 >1.6 to >3.4 to >7.1 CDAI or other indices). In contrast, ≤3.4 ≤7.1 the updated definition of severity adds Serum Ustekinumab Concentration endoscopic findings, such as the pres- gmL at Week ence of deep ulcerations. Moderate to severe disease is now defined as a Simple Endoscopic Score for Crohn’s Figure 4. Clinical remission in the UNITI-1 trial of ustekinumab according to serum Disease (SES-CD) exceeding 6. ustekinumab concentration. Q, quartile. Adapted from Adedokun OJ et al. Gastroenterology. The goals of therapy for Crohn’s 2018;154(6):1660-16713 and Lichtenstein GR. Update: ACG guidelines for the treatment of disease were also updated, with an Crohn’s disease. Paper presented at: Advances in Inflammatory Bowel Diseases Conference; emphasis on symptom-based and December 12-14, 2019; Orlando, Florida.2

Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 5 SPECIAL MEETING REVIEW EDITION

the treatment groups. For the tight control group, failure was based on ABSTRACT SUMMARY Serum Ustekinumab and Anti-Ustekinumab Antibody: Analysis of Over 2000 Patient Results Using Lab Devel- clinical symptoms combined with bio- markers. For the clinical management oped Electrochemiluminescent Immunoassays group, failure was based on clinical symptoms alone. The primary end- Samples from patients treated with ustekinumab were analyzed using point of mucosal healing with absence laboratory-developed immunoassays to measure concentrations of the of deep ulcers at week 48 was met by drug and antidrug antibodies (Abstract P020). Among the 2097 samples, 46% of patients in the tight control 2012 (96%) had no measurable antidrug antibodies. Among these samples, group vs 30% of those in the clinical 38 (1.9%) had an undetectable ustekinumab level (<0.1 µg/mL). These management group (P=.010). This samples would be considered subtherapeutic in 9.2% using a cutoff of 1 µg/ study was the first to demonstrate that mL trough ustekinumab concentration, in 24.6% using a cutoff of 2 µg/mL, timely escalation with tight control of and in 50.4% using a cutoff of 4 µg/mL. Antidrug antibodies were detected anti-TNF agent therapy on the basis in 4% (85/2097 samples). Titers were categorized as low in 52%, intermedi- of clinical symptoms combined with ate in 47%, and high in 3.5%. The mean free ustekinumab drug concentra- biomarkers resulted in better clinical tion was 4.5 µg/mL (2.3% with undetectable levels) in low titer samples and endoscopic outcomes compared and 0.1 µg/mL (67% with undetectable levels) in high titer samples. This with clinical management alone. finding suggests that while low titer antidrug antibodies were not associ- ated with decreased ustekinumab drug levels, high titer antidrug anti- References bodies were associated with very low or absent free ustekinumab levels. 1. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: management of Crohn’s disease in adults. Am J Gastro- enterol. 2018;113(4):481-517. ), and the monoclonal Crohn’s disease.5 Patients were ran- 2. Lichtenstein GR. Update: ACG guidelines for the 1 treatment of Crohn’s disease. Paper presented at: 2019 antibody ustekinumab. Ustekinumab domly assigned to a treatment strategy Advances in Inflammatory Bowel Diseases Conference; is among the newer treatments for consisting of tight disease control or December 12-14, 2019; Orlando, Florida. patients with IBD. Analyses of the clinical management. In both arms, 3. Adedokun OJ, Xu Z, Gasink C, et al. Pharma- cokinetics and exposure response relationships of UNITI trials identified an apparent treatment was escalated in a stepwise ustekinumab in patients with Crohn’s disease. Gastro- exposure-response relationship with manner, initiating with no treatment, enterology. 2018;154(6):1660-1671. this treatment (Figure 4).3,4 to adalimumab induction followed 4. Battat R, Kopylov U, Bessissow T, et al. Association between ustekinumab trough concentrations and clini- With the increasing availability by adalimumab every other week, to cal, biomarker, and endoscopic outcomes in patients of biologic agents, there is now an adalimumab every week, and to weekly with Crohn’s disease. Clin Gastroenterol Hepatol. emphasis on optimizing outcomes. adalimumab and daily azathioprine. 2017;15(9):1427-1434.e2 5. Colombel JF, Panaccione R, Bossuyt P, et al. Effect of The CALM study was a prospec- Escalation was based on treatment tight control management on Crohn’s disease (CALM): tive, multicenter, open-label study in failure criteria, which differed between a multicentre, randomised, controlled phase 3 trial. Lancet. 2018;390(10114):2779-2789.

Management of Ulcerative Colitis in Adults: ACG Clinical Guidelines

r Ashwin N. Ananthakrish- systematic review and meta-analysis findings from the Ocean State Crohn’s nan presented updates to of 2499 patients with IBD.3 In this and Colitis Area Registry cohort of guidelines for the manage- analysis, fecal calprotectin was a more newly diagnosed patients with IBD.4 mentD of ulcerative colitis from the sensitive measure than C-reactive pro- In this cohort of 227 patients with ACG.1 These guidelines for the man- tein (CRP) for both ulcerative colitis reported diarrhea, 49.8% were tested agement of ulcerative colitis in adult and Crohn’s disease. Fecal calprotectin for C difficile infection. Among the patients were updated in 2019, and was more sensitive in ulcerative colitis patients who were tested, 5.1% were include several key recommendations than Crohn’s disease. positive. for patients according to disease sever- The updated guidelines recom- The severity index proposed in the ity.2 Diagnosis of ulcerative colitis is mend against serologic antibody test- ACG guidelines for ulcerative colitis made using colonoscopy. At this time, ing in patients with ulcerative colitis, categorizes disease severity as mild, biopsies of affected and unaffected whether for diagnosis or prognosis. moderate, or severe. The guidelines areas should be taken. Biomarkers Stool tests to rule out Clostridium diffi- also include a definition for disease can be useful to prioritize patients for cile should be performed at diagnosis.2 remission. Mild disease is defined by endoscopic evaluation, as shown in a This recommendation is supported by fewer than 4 stools per day, intermit-

6 Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 HIGHLIGHTS FROM THE 2019 ADVANCES IN INFLAMMATORY BOWEL DISEASES CONFERENCE

tent blood in stools, mild or occasional tinuing mesalamine in patients who peutic drug monitoring. Low trough urgency, normal hemoglobin levels, have escalated to anti-TNF agents. The levels may require optimization of the and an erythrocyte sedimentation rate ACG guidelines recommend against treatment dose. Adequate trough levels (ESR) of less than 30 mm/hr. Moder- the use of thiopurine or methotrexate indicate a need to switch to an agent ate ulcerative colitis is defined by more for induction of remission in moder- from a different therapeutic class. High than 6 stools per day, frequent urgency ately to severely active ulcerative colitis.2 titers of antidrug antibodies require and blood in stools, hemoglobin levels Instead, the following biologic thera- consideration of an alternate anti-TNF less than 75% of normal, and an ESR pies are recommended: an anti-TNF agent. There is insufficient evidence to exceeding 30 mm/hr. Severe disease therapy (infliximab, adalimumab, or recommend proactive therapeutic drug is defined by more than 10 stools per ), an anti-integrin (vedoli- monitoring in unselected patients with day, with continuous urgency and zumab), a Janus kinase (JAK) inhibi- ulcerative colitis in remission.2 blood in stools, low hemoglobin levels tor (tofacitinib), or an anti–IL-12/23 that require transfusion, and an ESR inhibitor (ustekinumab).2 Comparative References exceeding 30 mm/hr. This severity effectiveness of therapies for induc- 1. Ananthakrishnan AN. Management of ulcerative colitis in adults: ACG clinical guidelines. Paper pre- index is limited because it lacks endo- tion of remission is largely inferred sented at: 2019 Advances in Inflammatory Bowel Dis- scopic severity indices, newer inflam- from indirect comparisons in network eases Conference; December 12-14, 2019; Orlando, matory markers (eg, fecal calprotectin), meta-analyses or observational cohorts. Florida. 2. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer and longitudinal representation of the The only comparative efficacy study of BG, Long MD. ACG Clinical Guideline: ulcerative disease course.2 biologics in IBD, the VARSITY trial, colitis in adults. Am J Gastroenterol. 2019;114(3):384- According to the ACG guide- demonstrated that vedolizumab was 413. 3. Mosli MH, Zou G, Garg SK, et al. C-reactive protein, lines, a comprehensive assessment of superior to adalimumab for both clinical fecal calprotectin, and stool lactoferrin for detection ulcerative colitis should also include remission and mucosal healing (Figure of endoscopic activity in symptomatic inflammatory consideration of patient-specific 5).5 In addition to the biologic agents bowel disease patients: a systematic review and meta- analysis. Am J Gastroenterol. 2015;110(6):802-819. predictors of an aggressive course mentioned above, other treatments to 4. Krishnarao A, de Leon L, Bright R, et al. Testing for and need for colectomy. These fac- maintain remission include thiopurines Clostridium difficile in patients newly diagnosed with tors include young age (<40 years) (after corticosteroid-induced remission) inflammatory bowel disease in a community setting. Inflamm Bowel Dis. 2015;21(3):564-569. at diagnosis, extensive colitis, severe and mesalamine (for moderately active 5. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al; endoscopic disease (Mayo subscore of disease). VARSITY Study Group. Vedolizumab versus adalim- 3, Ulcerative Colitis Endoscopic Index Patients who develop a secondary umab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381(13):1215-1226. of Severity >7), hospitalization for nonresponse should undergo thera- colitis, elevated CRP, and low serum albumin. The guidelines recommend that patients with mild disease who have poor prognostic factors should be edolizumab Adalimumab treated with therapies for moderately 45 2 9 to severely active disease. 40 Initial treatment of ulcerative coli- tis should focus on restoration of nor- 35 1 mal bowel frequency, as well as control 30 2 of symptoms such as bleeding and 25 225 urgency. Although histologic healing is associated with improved outcomes, 20

there is still uncertainty regarding its Patients 15 routine clinical application. Histologic 10 healing is therefore not currently con- sidered a treatment goal.2 5 For patients with mild ulcerative 0 colitis, oral mesalamine is recommended Clinical Remission Mucosal ealing for induction of remission. (Alternative options are budesonide or oral systemic corticosteroids.) For the treatment Figure 5. Outcomes at week 52 in the VARSITY trial of vedolizumab vs adalimumab. of patients with moderate ulcerative Adapted from Sands BE et al. N Engl J Med. 2019;381(13):1215-12265 and Ananthakrishnan colitis, mesalamine monotherapy can AN. Management of ulcerative colitis in adults: ACG clinical guidelines. Paper presented at: be used to induce remission. However, Advances in Inflammatory Bowel Diseases Conference; December 12-14, 2019; Orlando, there is no incremental benefit of con- Florida.1

Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 7 SPECIAL MEETING REVIEW EDITION

The Road Ahead: Potential Benefits and Risks of Combining Biologics and Novel Agents

r Maria T. Abreu discussed anti-TNF agent therapy tend to show sisting of vedolizumab, adalimumab, biologic therapies.1 The wide muted responses to treatment with and methotrexate among patients with variety of approved and inves- subsequent biologic agents, regardless moderately to severely active Crohn’s tigationalD agents targeting different of the mechanistic target.4,5 In a retro- disease who are considered at high- components within the inflammatory spective study, outcomes were similar risk for complications. The primary immune response reflects an increasing among patients treated with first-line outcome of this study is endoscopic understanding that the multifactorial biologic therapy with an anti-TNF remission at week 26. pathogenesis of IBD. Targeting just agent as compared with those who one signaling pathway at a time may received first-line therapy with vedoli- References prove insufficient in some patients. zumab, had an inadequate response, 1. Abreu MT. The road ahead: potential benefits and risks of combining biologics and novel agents. Currently, most patients who are and then received second-line therapy Paper presented at: 2019 Advances in Inflammatory treated with biologic agents for IBD with an anti-TNF agent (Figure 6).6 In Bowel Diseases Conference; December 12-14, 2019; receive these agents in a sequential contrast, receiving vedolizumab in the Orlando, Florida. 2. Cohen BL, Sachar DB. Update on anti-tumor necro- manner, typically beginning with first-line setting does not hamper the sis factor agents and other new drugs for inflammatory an anti-TNF agent. As patients lose response to an anti-TNF agent in the bowel disease. BMJ. 2017;357:j2505. response or become intolerant to second-line, as observed in a real-world 3. Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological thera- treatment, they progress through a population of patients with ulcerative pies in inflammatory bowel disease: systematic review sequence of vedolizumab, tofacitinib, colitis or Crohn’s disease enrolled in and meta-analysis. Am J Gastroenterol. 2011;106(4): and ustekinumab. However, approxi- the EVOLVE trial.7 644-660. 4. Feagan BG, Sandborn WJ, Gasink C, et al. mately one-third of patients never Preliminary work has suggested Ustekinumab as induction and maintenance therapy respond to induction therapy with the that combination regimens are an for Crohn’s disease. N Engl J Med. 2016;375(20):1946- anti-TNF agent, and approximately effective strategy, although results have 1960. 5. Sandborn WJ, Su C, Sands BE, et al; OCTAVE half of those patients who do achieve been inconsistent and require further Induction 1, OCTAVE Induction 2, and OCTAVE a response subsequently lose that investigation. The EXPLORER study Sustain Investigators. Tofacitinib as induction and response within a few years.2,3 (NCT02764762) is an ongoing phase maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723-1736. Unfortunately, patients who fail 4 trial evaluating a triplet regimen con- 6. Bressler B, Yarur A, Kopylov U, et al. Clinical effec- tiveness of first-line anti-TNF therapies and second-line anti-TNF therapy post-vedolizumab discontinuation in patients with ulcerative colitis or Crohn’s disease. Presented at: American College of Gastroenterology Anti-TNF First-line n9 Annual Scientific Meeting; October 25-30, 2019; San Anti-TNF Second-line after vedolizumab n2 Antonio, TX. Abstract 40. 7. Yarur A, Mantzaris GJ, Kopylov U, et al. Real world safety of vedolizumab and anti-TNF therapies 90 in biologic-naïve ulcerative colitis and Crohn’s dis- ease patients: results from the EVOLVE study [ACG 80 abstract P2280]. Presented at the American College of Gastroenterology Annual Scientific Meeting; October 70 656 25-30, 2019; San Antonio, TX. 60 95 Figure 6. Clinical response at 6 months 50 among patients who received an anti- TNF therapy in the first-line setting 40 or after vedolizumab. TNF, tumor necrosis factor. Adapted from Bressler Patients Patients 30 B et al. ACG abstract 40. Presented at: American College of Gastroenterology 20 Annual Scientific Meeting; October 25- 6 10 30, 2019; San Antonio, TX and Abreu MT. The road ahead: potential benefits 0 and risks of combining biologics and novel agents. Paper presented Clinical Response at: Advances in Inflammatory Bowel at 6 Months Diseases Conference; December 12-14, 2019; Orlando, Florida.1

8 Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 HIGHLIGHTS FROM THE 2019 ADVANCES IN INFLAMMATORY BOWEL DISEASES CONFERENCE

.A Practical Approach to JAK inhibitors in IBD 2020

r Edward V. Loftus Jr dis- tofacitinib is approved for ulcerative References cussed JAK inhibitors.1 colitis for initial treatment and for 1. Loftus EV Jr. A practical approach to JAK inhibitors in IBD 2020. Paper presented at: 2019 Advances in Inhibition of JAK signal- long-term use in limited situations. Inflammatory Bowel Diseases Conference; December ingD pathways has proven effective Tofacitinib was associated with 12-14, 2019; Orlando, Florida. in the treatment of moderate to negative outcomes in two phase 2b 2. Sandborn WJ, Su C, Sands BE, et al; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE severe IBD. JAK inhibitors provide clinical studies in moderate to severe Sustain Investigators. Tofacitinib as induction and a potent, fast-acting mechanism of Crohn’s disease.4 Several alternative maintenance therapy for ulcerative colitis. N Engl J action for reducing inflammation in investigational JAK inhibitors have Med. 2017;376(18):1723-1736. 3. Sandborn WJ, Sands BE, Danese S, et al. Efficacy IBD. Tofacitinib inhibits all JAKs, been explored in Crohn’s disease. The and safety of oral tofacitinib as maintenance therapy specifically JAK1, JAK2, and JAK3. selective JAK1 inhibitor filgotinib was in patients with moderate to severe ulcerative colitis: Approval of tofacitinib was based associated with significantly improved results from a phase 3 randomised controlled trial. J Crohns Colitis. 2017;11(suppl 1). Abstract OP032. on the OCTAVE 1 and OCTAVE 2 rates of remission and response com- 4. Panés J, Sandborn WJ, Schreiber S, et al. Tofacitinib induction studies.2 In the OCTAVE pared with placebo in the phase 2 for induction and maintenance therapy of Crohn’s Sustain maintenance trial, the overall FITZROY induction study in moder- disease: results of two phase IIb randomised placebo- 5 controlled trials. Gut. 2017;66(6):1049-1059. rate of infections (including infection ate to severe Crohn’s disease. Another 5. Vermeire S, Schreiber S, Petryka R, et al. Clinical with herpes zoster) was higher with selective JAK1 inhibitor, upadaci- remission in patients with moderate-to-severe Crohn’s tofacitinib vs placebo.3 However, the tinib, has shown efficacy in both the disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, rate of withdrawal due to an adverse CELEST trial in Crohn’s disease and placebo-controlled trial. Lancet. 2017;389(10066): event was lower with tofacitinib than the U-ACHIEVE trial in ulcerative 266-275. placebo. The US Food and Drug colitis (Figure 7).6-8 A novel gut- 6. Sandborn WJ, Feagan BG, Panés J, et al. Safety and efficacy of ABT-494 (upadacitinib), an oral JAK1 Administration (FDA) added throm- selective pan-JAK inhibitor, TD-1473, inhibitor, as induction therapy in patients with Crohn’s boembolism to a boxed warning for was recently shown to have activity in disease: results from CELEST [DDW abstract 874h]. tofacitinib. Concurrently, the FDA moderate to severe ulcerative colitis.9 Gastroenterology. 2017;152(5 suppl 1). 7. Panaccione R, D’Haens GR, Sandborn WJ, et al. mandated a change in the indication This agent was well tolerated, with a Efficacy of upadacitinib as an induction therapy for for the use of tofacitinib in ulcerative minimal risk for systemic immunosup- patients with moderately to severely active ulcerative colitis. The 10-mg twice-daily dose of pression. colitis, with or without previous treatment failure of biologic therapy: data from the dose-ranging phase 2b study U-ACHIEVE [DDW abstract 799]. Gastroenter- ology. 2019;156(6 suppl 1). 8. Sandborn WJ, Schreiber S, Lee SD, et al. Improved endoscopic outcomes and mucosal healing of upadaci- 100 tinib as an induction therapy in adults with moder- ately-to-severely active ulcerative colitis: data from the U-Achieve study [DDW abstract 800]. Gastroenterol- ogy. 2019;156(6 suppl 1). 9. Sandborn WJ, Nguyen D, Ferslew B, et al. Clini- 80 cal, endoscopic, histologic and biomarker activity following treatment with the gut-selective, pan-JAK P<.001 inhibitor TD-1473 in moderately-to-severely active 60 P<.001 ulcerative colitis [DDW abstract 801]. Gastroenterology. 510 P<.001 2019;156(6 suppl 1). 2 2 P<.01 40

Patients Patients 19

Figure 7. Histologic outcomes at week 8 20 in the U-ACHIEVE trial of upadacitinib 65 in ulcerative colitis. Adapted from Sandborn WJ et al. DDW abstract 800. 0 Gastroenterology. 2019;156(6 suppl 1)8 and Loftus EV Jr. A practical approach to JAK Treatment Placebo Upadacitinib Upadacitinib Upadacitinib Upadacitinib inhibitors in IBD 2020. Paper presented at: Arm 6 5 mgday 15 mgday 0 mgday 5 mgday Advances in Inflammatory Bowel Diseases nN 15 259 252 256 Conference; December 12-14, 2019; Orlando, Florida.1

Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 9 SPECIAL MEETING REVIEW EDITION

A Practical Approach to Anti-Integrins in IBD 2020

r Brian G. Feagan discussed whether a higher dose of adalimumab GEMINI 2 Study Group. Vedolizumab as induction anti-integrins.1 The anti- would improve outcome in patients and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711-721. α4β7 integrin agent vedoli- with ulcerative colitis or Crohn’s dis- 4. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al; zumabD was proven effective and safe in ease.10,11 The higher dose was 160 mg VARSITY Study Group. Vedolizumab versus adalim- ulcerative colitis and Crohn’s disease in given on weeks 0, 1, 2, and 3. The umab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381(13):1215-1226. the GEMINI 1 and GEMINI 2 stud- standard dose was 160 mg given on 5. Feagan BG, Sandborn WJ, Colombel JF, et al. ies, respectively.2,3 In the VARSITY week 0 and 80 mg on week 2. From Incidence of arthritis/arthralgia in inflammatory bowel trial, vedolizumab had a superior week 4, all patients received 40 mg disease with long-term vedolizumab treatment: post hoc analyses of the GEMINI trials. J Crohns Colitis. safety profile when compared with every other week. There were no sig- 2019;13(1):50-57. the anti-TNF agent adalimumab.4 nificant differences between the dosing 6. Loftus EV Jr, Colombel JF, Feagan BG, et al. Long- Additionally, there is evidence that strategies in terms of clinical remission term efficacy of vedolizumab for ulcerative colitis. J Crohns Colitis. 2017;11(4):400-411. vedolizumab is effective for relief of at week 4 or endoscopic response at 7. Vermeire S, Loftus EV Jr, Colombel JF, et al. Long- extraintestinal manifestations of IBD, week 12 (Figure 8). term efficacy of vedolizumab for Crohn’s disease. J including arthralgia.5 Vedolizumab The novel anti-integrin etroli- Crohns Colitis. 2017;11(4):412-424. 8. Colombel JF, Sands BE, Rutgeerts P, et al. The safety can be administered intravenously or zumab selectively targets the b7 sub- of vedolizumab for ulcerative colitis and Crohn’s dis- subcutaneously. Dose intensification, unit of the integrins α4b7 and αEb7. ease. Gut. 2017;66(5):839-851. in which administration is increased The phase 2 EUCALYPTUS trial 9. Moens A, van der Woude CJ, Julsgaard M, et al. Preg- nancy outcomes in inflammatory bowel disease patients from every 8 weeks to every 4 weeks, investigated etrolizumab in patients treated with vedolizumab, anti-TNF or conventional may be necessary and effective in with ulcerative colitis, finding it was therapy: results of the European CONCEIVE study. 20% to 40% of patients.6,7 The rates associated with a higher rate of clini- Aliment Pharmacol Ther. 2020;51(1):129-138. 10. Panés J, Colombel JF, D’Haens G, et al. High ver- 12 of exposure-adjusted incidence of any cal remission at week 10 vs placebo. sus standard adalimumab induction dosing regimens in infections, upper respiratory tract Additional evaluation of this investiga- patients with moderately to severely active ulcerative infections, and lower respiratory tract tional agent in IBD is ongoing. colitis: results from the SERENE-UC induction study [UEG Week abstract OP216]. United European Gastro- and lung infections with vedolizumab enterol J. 2019;7(8 suppl). were not increased compared with pla- References 11. D’Haens G, Sandborn WJ, Loftus EV, et al. High cebo.8 Although clinical safety data in 1. Feagan BG. A practical approach to anti-integrins versus standard adalimumab induction dosing regimens in IBD 2020. Paper presented at: 2019 Advances in in patients with moderately to severely active Crohn’s pregnancy are evolving, no signals have Inflammatory Bowel Diseases Conference; December disease: results from the SERENE-CD induction study been reported.9 Combination therapy 12-14, 2019; Orlando, Florida. [UEG Week abstract LB27]. United European Gastroen- with vedolizumab remains unproven, 2. Feagan BG, Rutgeerts P, Sands BE, et al; GEMINI terol J. 2019;7(8 suppl). 1 Study Group. Vedolizumab as induction and main- 12. Vermeire S, O’Byrne S, Keir M, et al. Etrolizumab but may be beneficial, particularly in tenance therapy for ulcerative colitis. N Engl J Med. as induction therapy for ulcerative colitis: a randomised, high-risk patients. 2013;369(8):699-710. controlled, phase 2 trial. Lancet. 2014;384(9940): The SERENE trials evaluated 3. Sandborn WJ, Feagan BG, Rutgeerts P, et al; 309-318.

Figure 8. Clinical remission at week 4 among patients with Crohn’s disease treated 100 with adalimumab at a standard dose vs a higher dose in the SERENE CD trial. 80 Adapted from D’Haens G et al. UEG P=1.000 Week abstract LB27. United European Gastroenterol J. 2019;7(8 suppl)11 and 60 Feagan BG. A practical approach to anti- 2 integrins in IBD 2020. Paper presented at: 40 Advances in Inflammatory Bowel Diseases

Patients Patients Conference; December 12-14, 2019; Orlando, Florida.1 20 90206 10 0 Standard Induction igher Induction Dosing Dosing

10 Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 HIGHLIGHTS FROM THE 2019 ADVANCES IN INFLAMMATORY BOWEL DISEASES CONFERENCE

A Practical Approach to Anti-TNFs in IBD 2020

r William J. Sandborn dis- sion, as well as mucosal healing, in a proactive therapeutic drug monitoring cussed anti-TNF therapy.1 similar systematic review and network may prove useful, but data from the A systematic review and meta-analysis.3 In patients who had SERENE study suggested that dose networkD meta-analysis assessed com- received previous treatment with anti- escalation may be less effective than parative efficacy and safety of first-line TNF therapy, tofacitinib was ranked anticipated.4 Anti-TNF agents are (biologic-naive) and second-line (pre- highest for induction of clinical associated with a substantial risk for vious exposure to anti-TNF agents) remission and mucosal healing (mod- infection and lymphoma (Figure 9).5 biologic therapy in patients with mod- erate quality of evidence). In patients Highly effective agents without these erate to severe Crohn’s disease.2 Among with ulcerative colitis, vedolizumab risks are needed. biologic-naive patients, infliximab and was ranked safest in terms of serious The anti-TNF agent landscape adalimumab were associated with the adverse events and infection during is changing with the increasing avail- highest ranking for induction of clini- maintenance therapy. ability of biosimilar agents. These bio- cal remission, whereas adalimumab Anti-TNF agents, particularly inf- similars appear to be similarly effective and ustekinumab were ranked highest liximab, remain the preferred option to the branded agents. For example, among patients with prior exposure to for several patient groups, including the biosimilar CT-P13 was shown to anti-TNF agents. Among patients who hospitalized patients, patients with be noninferior to its originator, inflix- achieved a response to induction ther- perianal fistulas, and patients who imab, in a double-blind phase 3 trial apy, adalimumab and infliximab had would benefit from prevention of in patients with active Crohn’s disease.6 the highest ranking of maintenance of postoperative recurrence of Crohn’s remission. Ustekinumab had the low- disease. Switching to a different anti- References est risk of serious adverse events and TNF therapy in the second-line set- 1. Sandborn WJ. A practical approach to anti-TNFs in IBD 2020. Paper presented at: 2019 Advances in infection during maintenance therapy. ting is not highly effective in patients Inflammatory Bowel Diseases Conference; December Among patients with ulcerative with inflammatory bowel disease. 12-14, 2019; Orlando, Florida. colitis who were biologic-naive, inf- This lack of efficacy may be related to 2. Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review and network meta-analysis: first- liximab and vedolizumab were ranked the substantial immunogenicity seen and second-line biologic therapies for moderate- highest for induction of clinical remis- with anti-TNF agents. Reactive and severe Crohn’s disease. Aliment Pharmacol Ther. 2018;48(4):394-409. 3. Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review with network meta-analysis: first- and second-line pharmacotherapy for moderate- RR 61 severe ulcerative colitis. Aliment Pharmacol Ther. 2018;47(2):162-175. 1 095 4. Panés J, Colombel JF, D’Haens G, et al. High versus standard adalimumab induction dosing regimens in 0.9 patients with moderately to severely active ulcerative 0.8 colitis: results from the SERENE-UC induction study RR 26 [UEG Week abstract OP216]. United European Gastro- 0.7 enterol J. 2019;7(8 suppl). 0.6 05 RR 2 5. Lemaitre M, Kirchgesner J, Rudnichi A, et al. Asso- ciation between use of thiopurines or tumor necrosis 0.5 01 factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel dis- 0.4 ease. JAMA. 2017;318(17):1679-1686. 0.3 026 6. Ye BD, Pesegova M, Alexeeva O, et al. Efficacy and safety of biosimilar CT-P13 compared with originator 0.2 infliximab in patients with active Crohn’s disease: an Lymphoma Incidence Lymphoma Per 1000 Patient Years 1000 Patient Per 0.1 international, randomised, double-blind, phase 3 non- inferiority study. Lancet. 2019;393(10182):1699-1707. 0 Figure 9. Risk of lymphoma among patients with inflammatory bowel disease according to treatment. RR, relative risk; TNF, tumor necrosis factor. Uneposed Adapted from Lemaitre M et al. JAMA. 2017;318(17):1679-16865 and Sandborn WJ. A practical approach to anti-TNFs in Anti-TNF MonotherapyCombination Treatment IBD 2020. Paper presented at: Advances in Thiopurine Monotherapy Inflammatory Bowel Diseases Conference; December 12-14, 2019; Orlando, Florida.1

Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 11 SPECIAL MEETING REVIEW EDITION

Highlights From the 2019 Advances in Inflammatory Bowel Diseases Conference: Commentary

Gary R. Lichtenstein, MD Professor of Medicine Director, Center for Inflammatory Bowel Disease University of Pennsylvania Health System Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

he annual Advances in Inflam- with infliximab as the biologic agent) Vedolizumab has been approved matory Bowel Diseases (AIBD) and azathioprine is superior to mono- by the FDA for the treatment of both conference provides an impor- therapy with each agent. A 2015 study ulcerative colitis and Crohn’s disease. Ttant forum that combines education by Khanna and colleagues showed Approval was based on the GEMINI sessions with presentation of new that combined immunosuppression studies, which showed that vedoli- data. At the 2019 conference, experts decreased the time to hospitalization, zumab can induce clinical remission, in the field provided comprehensive surgery, and complications vs each durable clinical response, mucosal reviews of current treatment options therapy alone.3 Rates of mortality, healing, durable clinical remission, and for patients with inflammatory bowel as well as disease- and drug-related corticosteroid-free remission in these disease (IBD), such as anti-integrin complications, were numerically less settings.6,7 therapy, anti-interleukins, Janus kinase with combination therapy. Data from Prior to 2019, there were no stud- (JAK) inhibitors, and anti–tumor the TREAT registry demonstrated that ies in patients with IBD comparing effi- necrosis factor (TNF) agents. Guide- infliximab is associated with a risk of cacy of one biologic agent to another. line updates were also presented. Sev- serious infections.4 The key, however, The VARSITY trial randomly assigned eral posters provided updates regarding is to initiate treatment with infliximab patients with active ulcerative colitis the management of IBD. and avoid or withdraw corticosteroids. to vedolizumab or adalimumab at the Corticosteroids have been shown labeled doses.8 Twenty percent of the Reviews of Treatment Classes to confer a significantly higher rate patients had received prior treatment Dr Brian G. Feagan discussed anti- of mortality and morbidity. In the with a TNF antagonist. This study is integrin treatment for patients with TREAT registry, risk factors for serious the only head-to-head, randomized, IBD.1 Biologic therapies have changed infections were highest with infliximab comparative effectiveness trial of bio- clinical practice. Infliximab, an anti- and corticosteroids. The hazard ratio logic therapy in IBD. The study had TNF agent, was the first biologic was 4.73 (95% CI, 2.373-9.416) for a treat-through design. The primary approved by the US Food and Drug the combination vs 2.12 (95% CI, endpoint was remission at week 52. Administration (FDA) for IBD. Inf- 1.228-3.657) for infliximab alone. Clinical remission at week 52 with liximab was approved in 1998 for the Infliximab has been associated mucosal healing was seen in 31.3% treatment of Crohn’s disease.2 The use with hypersensitivity reactions, drug- of the vedolizumab arm vs 22.5% of of infliximab has evolved to optimize induced lupus, and psoriasis-like the adalimumab arm (P=.006). Rates outcome. Initially, a single dose was lesions. In the TREAT registry, use of mucosal healing were similar, at given to treat luminal disease, and 3 of infliximab was not an independent 39.7% with vedolizumab vs 27.7% doses were administered for fistulizing risk factor for the development of lym- with adalimumab. Reports of mild, disease. It was recognized, however, phoma.4 More recent data, however, moderate, or severe adverse events that maintenance therapy is needed suggested that monotherapy with an were similar in both treatment groups. in both scenarios to optimize therapy. anti-TNF agent increased the risk It was exciting to see results from a Infliximab is therefore now given as of lymphoma by 2.4.5 The concept trial that compared the efficacy of bio- continued maintenance therapy, and of whether anti-TNF therapy use is logic therapies in IBD. There are now not just episodic treatment. associated with the development of multiple ongoing comparative effec- Combination therapy with an lymphoma in IBD patients remains tiveness trials. Data from these trials anti-TNF agent (as was demonstrated controversial. will help clinicians gauge which drug

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is most effective for different clinical evidence that vedolizumab increased Dr Bruce E. Sands presented data treatment scenarios (Table). risk of arthralgias and arthritis; rather, on anti-interleukin biologic therapy.20 Vedolizumab is currently approved there was a benefit.11-13 Ustekinumab is a monoclonal anti- by the FDA as an intravenous formula- The SERENE trials evaluated body that inhibits the P40 component tion. Data from a phase 3 trial evaluat- whether a higher dose of adalimumab of the interleukin-12/23 complex, ing a subcutaneous formulation were would improve benefit in patients with leading to inhibition of STAT3 and recently submitted for approval.9 This ulcerative colitis or Crohn’s disease.14,15 STAT4 downstream. Ustekinumab is trial enrolled patients with moderately The same dosing strategies were used approved by the FDA for the treat- to severely active ulcerative colitis. for both patient populations. The ment of plaque psoriasis, psoriatic Patients received open-label treatment higher dose was 160 mg on weeks 0, arthritis, Crohn’s disease, and ulcer- with intravenous vedolizumab at 300 1, 2, and 3, and the standard dose was ative colitis. The UNITI-1, UNITI-2, mg at weeks 0 and 2. Patients with a 160 mg on week 0 and 80 mg on week and the IM-UNITI maintenance clinical response at week 6 were ran- 2. From week 4, all patients received trials evaluated ustekinumab among domly assigned to maintenance treat- 40 mg every other week. Similar rates patients with Crohn’s disease who were ment with subcutaneous vedolizumab of clinical remission at week 4 and anti-TNF refractory or who required at 108 mg every 2 weeks, intravenous endoscopic response at week 12 were treatment after conventional therapy.21 vedolizumab at 300 mg every 8 weeks, seen with the higher dose compared Ustekinumab has no black box warn- or placebo. At week 52, the rates of with the standard dose. ing for malignancy or infection. clinical remission were 46.2% for Several studies of vedolizumab in The UNITI trials of patients subcutaneous vedolizumab, 42.6% for pregnancy were recently published.16-18 with Crohn’s disease evaluated intra- intravenous vedolizumab, and 14.3% Dr Feagan noted that there appears to venous ustekinumab at 2 doses: 130 for placebo. be no safety signal in this setting. He mg or 6 mg/kg.21 Ustekinumab was The onset of clinical benefit is also emphasized the low rate of immu- associated with a significantly higher relatively rapid in patients with ulcer- nogenicity in the trials of vedolizumab. rate of response vs placebo. The IM- ative colitis, but somewhat slower in Dr Feagan reviewed data on etro- UNITI trial evaluated subcutaneous Crohn’s disease.8,10 In the GEMINI 2 lizumab, a novel humanized monoclo- ustekinumab at 90 mg every 12 trial of patients with Crohn’s disease, nal antibody, from the EUCALYPTUS weeks or every 8 weeks compared differences emerged between patients trial. Etrolizumab is novel, given that it with placebo.21 At week 44, rates of treated with vedolizumab vs placebo at is a dual mechanism inhibitor. Specifi- clinical remission were 48.8%, 53.1%, 2 weeks.10 Benefits were maintained in cally, it selectively binds the b7 subunit and 35.9%, respectively (P=.040 for patients with extraintestinal manifesta- of the heterodimeric integrins α4b7 the first comparison and P=.005 for tions. Dr Feagan noted that an analysis and αEb7. This agent demonstrated the second). Patients treated with of the GEMINI data showed no benefit over placebo.19 ustekinumab were significantly less

Table. Ongoing Comparative Effectiveness Trials of Biologic Therapies for the Treatment of Inflammatory Bowel Disease

Anticipated Trial Trial Name Agents Studied Disease Completion Date ClinicalTrials.gov Identifier GARDENIA Etrolizumab vs infliximab UC 2020 NCT02136069 HIBISCUS I Etrolizumab vs adalimumab UC 2020 NCT02163759 VEGA + golimumab vs UC 2021 NCT03662542 guselkumab vs golimumab EXPEDITION vs vedolizumab vs UC 2022 NCT03616821 placebo SEAVUE Ustekinumab vs adalimumab CD 2021 NCT03464136 INTREPID Brazikumab vs adalimumab vs CD 2022 NCT03759288 placebo VIVID-1 vs ustekinumab vs CD 2023 NCT03926130 placebo GALAXI Guselkumab vs ustekinumab vs CD 2026 NCT03466411 placebo

CD, Crohn’s disease; UC, ulcerative colitis.

Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 13 SPECIAL MEETING REVIEW EDITION

likely to require corticosteroids. The study randomly assigned patients to granulations. use of immunomodulators did not treatment with ustekinumab at the The question has arisen regarding impact treatment outcomes. These standard intravenous dose of 130 mg, whether this endpoint should be a data led to regulatory approval. ustekinumab at approximately 6 mg/ new standard in trials. In a population Throughout the studies, investiga- kg, or placebo.24 The ulcerative colitis of asymptomatic patients in clinical tors measured trough serum concen- patient population evaluated in this remission who are undergoing routine trations of ustekinumab. The appro- study was relatively refractory. Patients surveillance colonoscopy (based on an priate cutoff level for ustekinumab was could receive concomitant cortico- endoscopy subscore of 0 or 1), the find- less clear than the ones used for anti- steroids or immunomodulators. The ing of persistent microscopic inflam- TNF agents. However, patients in the primary endpoint of clinical remission mation would not necessarily mandate highest quartile of ustekinumab drug at week 8 (defined as a Mayo score ≤2, that a practitioner switch therapy from levels had the best response, whether with no individual subscore >1) was mesalamine to a biologic agent. In this assessing a reduction in the Simple met by 15.6% of patients receiving scenario, however, it might be reason- Endoscopic Score for Crohn’s Disease ustekinumab at 130 mg and 15.5% able to escalate the dose of mesalamine or endoscopic remission. Ustekinumab of those receiving the 6 mg/kg dose, (or, similarly, to optimize the biologic is now routinely used in the induction vs 5.3% of patients treated with pla- agent [while maintaining use of the and maintenance settings in clinical cebo (P<.001 for both comparisons). same agent]). practice. In a 2017 real-world study by Patients without prior biologic failure In the UNIFI study, patients who Ma and colleagues, ustekinumab was had a better outcome, as has been noted received ustekinumab had improve- associated with clinical remission and with most other biologics in clinical ments in the partial Mayo score and corticosteroid-free objective remission trials. Endoscopic “healing” in clinical fecal calprotectin through week 8.24 at 3, 6, and 12 months, as well as at the response was clearly superior among Rates of clinical remission at week end of follow-up.22 This treatment is patients treated with ustekinumab. 44—whether defined as the primary clearly beneficial. Dr Sands noted that The relatively novel endpoint of histo- endpoint of clinical remission or cor- fistula resolution ranged from 24% to endoscopic mucosal healing at week 8 ticosteroid-free secondary remission— 28% in an analysis of data from the was reached by 20.3% of the 130 mg were 38.4% among patients receiving UNITI-1 and UNITI-2 trials.21 Fis- arm and 18.4% of the 6 mg/kg arm, 90 mg of ustekinumab every 12 weeks, tula resolution, a secondary endpoint vs 8.9% of the placebo arm (P<.001 43.8% among patients receiving 90 in the trials, is an important aspect of for both comparisons). This endpoint mg of ustekinumab every 8 weeks, and patient care. refers to an endoscopic Mayo score 24.0% among patients receiving pla- Ustekinumab recently gained of 0 or 1, no more than 5% neutro- cebo (P=.002 for the first comparison FDA approval for the treatment phils in the epithelium, and no crypt and P<.001 for the second). Rates of of ulcerative colitis.23 The UNIFI destruction, erosions, ulcerations, or clinical and endoscopic response were also superior compared with placebo. All of these endpoints have direct ABSTRACT SUMMARY Efficacy and Safety of Ustekinumab in Patients implications for clinical practice. In a With Moderate to Severe Crohn’s Disease: a Real World Study in long-term extension study, patients in Brazil the intention-to-treat group with an inadequate response to therapy at week An open-label, prospective, multicenter study evaluated the real-world effi- 92 could have their dose adjusted. cacy and safety of ustekinumab in Brazilian patients with moderate to severe Ustekinumab was associated with a Crohn’s disease (Abstract P065). The study included 161 patients. At baseline, durable response, which is important many patients were anemic (55.5%), with a mean CRP level of 21.3 mg/L for clinical practice. (interquartile range, 0.08-125) and a mean Harvey-Bradshaw Index (HBI) of The rates of serious adverse events 10.1 (interquartile range, 2-19). Most patients had received previous treat- were low. Ustekinumab was relatively ment with anti-TNF therapy (85.7%). The clinical response rate to ustekinumab safe overall. No malignancies were (defined as a decrease of ≥3 points in the HBI) was 76.9% at week 8. The rate reported. In the UNIFI trial of patients of clinical remission (defined as an HBI score of ≤3) improved from week 8 with ulcerative colitis, the rates of seri- (38.9%) through week 48 (62.5%). The proportion of patients with an elevated ous infections were 3.5% with 90 mg CRP level significantly decreased over the same period. Several factors were every 12 weeks and 1.7% with 90 mg significantly associated with better outcomes, including Montreal system– every 8 weeks, vs 2.3% with placebo. scored inflammatory behavior (B1), no previous exposure to biologic therapy, To summarize, ustekinumab has and disease duration of 2 years or less. No new safety signals were reported. been demonstrated to have a favor- able safety profile and has been shown to be effective for the treatment of

14 Gastroenterology & Hepatology Volume 15, Issue 12, Supplement 6 December 2019 HIGHLIGHTS FROM THE 2019 ADVANCES IN INFLAMMATORY BOWEL DISEASES CONFERENCE

Crohn’s disease and ulcerative colitis. clear benefit of filgotinib (200 mg) vs be important to assess which patients Ustekinumab can be initiated as a placebo for patients with moderately benefit most from each of these JAK first-line biologic agent, as well as to severely active disease who had been inhibitors, and whether adverse events given to patients previously treated treated with other agents.29 Upadaci- differ based upon patient profiles. JAK with anti-TNF therapy. The onset of tinib, similar to filgotinib, is an orally inhibitors provide a potent, fast-acting effect is as early as 2 weeks, and this administered selective JAK1 inhibitor. mechanism of action that reduces effect can increase over the next 4 A study of upadacitinib evaluated inflammation in patients with IBD. months and beyond. Ustekinumab has several dosing strategies: 3 mg, 6 mg, Selective JAK1 inhibition seems to a very good corticosteroid sparing and or 12 mg twice daily, or 24 mg once have efficacy in moderately to severely maintenance effect. Among patients daily. The study enrolled patients with active Crohn’s disease. with Crohn’s disease, the rate of endo- Crohn’s disease who had an inad- Dr William J. Sandborn discussed scopic response is approximately 25% equate response to immunosuppressive data on anti-TNF therapy.35 A high- at 8 weeks and 50% at 6 months. In therapy or an anti-TNF agent. Upa- light of his discussion was the recent a real-world analysis, the rate of endo- dacitinib improved clinical and endo- data for a network meta-analysis evalu- scopic response in ulcerative colitis was scopic remission, clinical response, ating inductive pharmacotherapy for approximately 50%. In post hoc analy- and endoscopic response. Preliminary moderate to severe Crohn’s disease.36 ses, less than a third of patients had data on corticosteroid-free remission The analysis showed that infliximab fistulas. These impressive data have led appear to be promising. Adverse events and vedolizumab had somewhat higher to the addition of ustekinumab to the included 1 case of herpes zoster, which rates of efficacy in patients who were medical armamentarium for treatment is a class effect for these agents. There naive to biologic therapies. Tofacitinib of patients with Crohn’s disease and were no perforations. Upadacitinib is was associated with better outcomes ulcerative colitis. also effective in patients with ulcerative in the second-line settings. However, Dr Edward V. Loftus Jr reviewed colitis.30,31 Large phase 3 clinical trials Dr Sandborn noted that this analysis data on the JAK inhibitors.25 Inhi- will provide more insight into the ben- is outdated already, as it lacks studies bition of JAK1, JAK2, JAK3, and efit of this drug.32,33 of ustekinumab. Dr Sandborn empha- TYK2 impacts different cytokines. TD-1473 is a pan-JAK inhibi- sized that a network meta-analysis does Tofacitinib is approved by the FDA tor with colonic release. In a phase not substitute for prospective random- for the treatment of moderate to severe 1b study of patients with moderately ized comparative effectiveness trials. ulcerative colitis. This agent improves to severely active ulcerative colitis, A 2003 report by Baert and col- outcomes at 8 and 52 weeks, and it TD-1473 improved clinical response, leagues showed that patients who induces and maintains remission.26 endoscopic healing, rectal bleeding, develop immunogenicity to infliximab The FDA recently suggested that the and endoscopy subscores in patients had shortened intervals of effectiveness use of tofacitinib is associated with with active ulcerative colitis.34 It will and lessened durations of response.37 thromboembolism. The FDA required a safety study of tofacitinib in patients with rheumatoid arthritis who are older than 50 years and have at least ABSTRACT SUMMARY Biosimilar BI 695501 Demonstrates Non- 1 cardiovascular risk factor. The study Inferior Efficacy and Comparable Safety to Adalimumab Reference evaluated tofacitinib at doses of 5 Product in Patients With Active Crohn’s Disease mg or 10 mg twice daily. An interim analysis led to discontinuation of the A double-blind, multicenter, randomized, noninferior, phase 3 trial com- 10 mg twice-daily arm, which was pared the biosimilar BI 695501 with its reference product, adalimumab, associated with a higher rate of throm- in 140 patients with moderate to severe Crohn’s disease (Abstract P052). boembolism. The same association Patients had a disease duration of at least 4 months, mucosal ulceration, has not been reported in patients with and a CDAI score between 220 and 450. Patients were either naive to ulcerative colitis. However, based on anti-TNF agents, or had previously developed resistance or intolerance to these data, the FDA has suggested that infliximab. The primary endpoint of a CDAI response at week 4 (defined practitioners avoid the 10 mg twice- as a ≥70-point decrease in CDAI from baseline) was reported in 89.7% of daily dose in patients with ulcerative the BI 695501 arm and 94.4% of the adalimumab arm. This difference cor- colitis, when possible.27 Tofacitinib is responds to a risk ratio of 0.945 (90% CI, 0.870-1.028). The lower bound not an effective treatment for Crohn’s of the 90% CI was higher than 0.76, the exploratory noninferiority limit. disease.28 Similar safety profiles were observed with the 2 agents to week 24. There Filgotinib is a selective JAK1 were no unexpected safety signals. inhibitor administered orally. The phase 2 FITZROY study showed a

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Several studies have provided further Disease Questionnaire, did not differ therapy is immunogenic. Optimally, insights since that time. Immunoge- between the treatment arms. Clinical it is administered as a component of nicity can be seen with all treatments, response, but not endoscopic remis- combination therapy. In the SONIC particularly anti-TNF agents. Dr sion, was better with the higher dose trial, anti-TNF therapy was adminis- Sandborn discussed therapeutic drug in patients with ulcerative colitis. The tered with azathioprine.38 Combina- monitoring. To date, the best evidence SONIC trial reviewed the efficacy of tion therapy was more effective than supports a reactive, rather than proac- combination therapy.38 Patients treated monotherapy with each agent. Reactive tive, approach to therapeutic drug with infliximab plus azathioprine or and proactive therapeutic drug moni- monitoring. However, studies of the infliximab monotherapy were more toring can be used to guide treatment. proactive strategy that showed nega- likely to achieve corticosteroid-free The SERENE data suggested that dose tive results may have been limited by remission than patients receiving aza- escalation might be less effective than flaws in the trial design. This area is thioprine monotherapy. previously thought in patients who are still under investigation. Recent data have highlighted that receiving adalimumab.14,15 Measurement of biologic drug higher serum anti-TNF levels are asso- levels can help provide insight into ciated with perianal fistula healing and Guideline Update patient prognosis. In general, patients fistula closure in patients with Crohn’s Dr Ashwin N. Ananthakrishnan dis- with higher drug levels have a better disease.39 This strategy has been used cussed updates to the American College outcome. During treatment with anti- in clinical practice since the initial of Gastroenterology guidelines for the TNF agents, levels of serum albumin SENTINEL trial was reported 20 management of ulcerative colitis.42,43 are a strong predictor of response. The years ago.40 A 2016 study showed that He reviewed diagnosis, induction, SERENE trials recently compared infliximab was not superior to placebo maintenance, and management of acute adalimumab induction therapy at in preventing clinical recurrence after and severe colitis, as well as cancer sur- the standard dose (160 mg on week resection related to Crohn’s disease.41 veillance. Dr Ananthakrishnan noted 0 and 80 mg on week 2) vs a higher Infliximab did reduce rates of severe that during diagnosis, it is important to dose (160 mg on weeks 0, 1, 2, and endoscopic recurrence. exclude pathogens such as Clostridium 3) for patients with Crohn’s disease Dr Sandborn concluded that anti- difficile. Current data do not support or ulcerative colitis.14,15 The primary TNF agents are an important first-line the use of serologic antibody testing endpoints were clinical remission therapy for the treatment of patients for diagnosis or predicting prognosis. and endoscopic response. Rates of with Crohn’s disease. After the initial Diagnostic assessment should include endoscopic improvement and fecal use of a TNF antagonist, subsequent biomarkers such as C-reactive protein, calprotectin less than 150 µg, as well use of anti-TNF therapy as second- fecal calprotectin, and fecal lactoferrin. as scores on the Inflammatory Bowel line therapy is less effective. Anti-TNF These levels should be tested throughout treatment to see if they parallel disease activity. Not all patients have high levels of C-reactive protein or calprotectin. In ABSTRACT SUMMARY Patterns of Care Among Patients Treated With a recent meta-analysis, the sensitivity for Ustekinumab for Crohn’s Disease: Results From a Chart Review assessing disease activity in patients with ulcerative colitis was 49% for C-reactive Ruetsch and colleagues described findings from a retrospective chart review protein, 82% for lactoferrin, and 88% of 100 patients with Crohn’s disease who initiated ustekinumab and com- for fecal calprotectin.44 Measurement of pleted at least 6 months of treatment (Abstract P037). Patients were drawn these biomarkers may provide a way to from 7 US gastroenterology practices. Most patients were female (65.0%). track the disease course. Their mean age was 42.2 ± 14.9 years. Previous treatment with biologic It is important to assess whether therapy was reported in 82.0%. These treatments included adalimumab in the patient is in remission, or has mild, 49.1%, vedolizumab in 21.1%, infliximab in 17.5%, and certolizumab pegol moderate, or severe disease activity. in 12.3%. More than half of patients (54.9%) had received at least 2 biologic Disease activity can inform prognosis. agents before starting ustekinumab. The most frequent reason for initiat- Patients have more aggressive disease ing ustekinumab among patients with prior biologic agent exposure was and a higher risk of colectomy if they secondary loss of response to treatment (48%). The most frequent reason have low serum albumin, have elevated in patients who were biologic-naive was nonresponse to treatment (with a serum C-reactive protein, were hospi- physician recommendation based on symptoms). Nearly half of the charts talized for colitis, have a Mayo sub- (44%) reported no laboratory results or testing before or after initiation of score of 3, have an Ulcerative Colitis ustekinumab. Only 2 charts recorded endoscopic scores. Endoscopic Index of Severity score of 7 or higher, or are younger than 40 years.42,43

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Treatment goals for patients with an alternate anti-TNF agent, an concentrations. The therapeutic range ulcerative colitis include normal bowel anti-integrin, or an interleukin 12/23 is not yet confirmed. The range appears frequency and control of bleeding antagonist. If the patient has adequate to be in the single digits—1 µg/mL, and urgency. A patient who is able to trough levels but is not responding, 2 µg/mL, or 4 µg/mL—and therefore achieve mucosal healing (a Mayo score then the treatment is inadequate and clinicians should try to choose an assay of 0 or 1) has an increased chance of the case is considered a mechanistic with adequate sensitivity. This analysis sustained corticosteroid-free remission failure. suggests that therapeutic drug moni- and decreased risks of hospitalizations During the initial care of these toring for ustekinumab requires better and surgery. Histologic healing is a patients, the clinician should check for target concentrations. desirable, although not mandatory, C difficile, document disease activity, A retrospective chart review by endpoint. Measurement of calprotec- exclude cytomegalovirus (by means Dr Charles Ruetsch and colleagues tin can be used as a surrogate when of endoscopic mucosal biopsy), and evaluated patterns of care among 100 endoscopy is not available or feasible. provide deep venous thrombosis patients treated with ustekinumab.47 Calprotectin levels can provide insight prophylaxis when appropriate. Broad- More than 80% of patients had docu- into whether the mucosa is improving. spectrum antibiotics or total parenteral mented prior use of another biologic. The use of mesalamine is effective in nutrition can be used when needed. More than 90% of patients who begin patients with active ulcerative colitis. If the patient did not respond to treatment with ustekinumab receive it Corticosteroids plus budesonide oral corticosteroids, then parenteral for at least 6 months. Most patients had MMX might be considered for administration can be considered. no ongoing Crohn’s disease–related patients who do not respond or have Biologics such as infliximab or cyclo- complications. Six months before the a partial response. sporine might be considered as salvage initiation of ustekinumab, 15% of Dr Ananthakrishnan reviewed therapy in patients who fail paren- patients were using corticosteroids. the subsequent use of biologics teral corticosteroids. Patients should This rate decreased to 6% by 6 months in patients with ulcerative colitis. undergo surveillance for colorectal after initiation of ustekinumab. More Approved therapies include the anti- cancer after 8 years of disease, and then than half of patients did not have TNF agents infliximab, adalimumab, subsequently every 1 to 3 years (with laboratory results. Only 2 patients and golimumab; vedolizumab; targeted biopsies of raised lesions). It is had undergone endoscopic examina- ustekinumab; and tofacitinib. Tofaci- uncertain whether segmental, random tion during the study period. This last tinib is approved as a pill formulation. biopsies are required. In a French study finding is of interest because many Initial dosing is 10 mg orally twice of approximately 1000 colonoscopies, clinicians advocate—albeit without daily for 8 weeks. If this treatment is the yield for random biopsies was low, evidence-based data—that patients beneficial, then attempting to lower identifying an additional 1.2% of treated with biologic therapy undergo the dose to 5 mg orally twice daily is patients.45 Among patients with neo- monitoring for relevant laboratory advocated. If no benefit is observed plasia, segmental random biopsies had parameters at least every 3 months. after 8 weeks, then further observation a yield of 12.8%. Dr Stephen B. Hanauer and col- at 10 mg orally twice daily is recom- When using high-definition leagues evaluated whether BI 695501, mended. Combination therapy with colonoscopy, narrow-band imaging a biosimilar to adalimumab, was infliximab and azathioprine is superior or dye spray chromoendoscopy with noninferior to the reference product to monotherapy with either agent. methylene blue or indigo carmine is in patients with moderate to severe Data from the OCTAVE trials preferred. When the dysplasia is dis- Crohn’s disease.48 Rates of clinical demonstrated that tofacitinib can crete or has been removed, colectomy response and remission at week 4 were induce remission in patients with may not be needed. In these cases, the high in this control study. The biosimi- active ulcerative colitis.26 Data from surveillance intervals should be short- lar had noninferior efficacy compared the comparative effectiveness VAR- ened. Colectomy should be considered with adalimumab after 4 weeks. There SITY trial showed that vedolizumab in cases of unresectable or multifocal were no unexpected safety signals, was superior to adalimumab in induc- dysplasia. which is comforting, although the ing and maintaining remission.8 primary aim of this study was not to Dr Ananthakrishnan discussed Posters of Interest assess safety. the role of therapeutic drug moni- Dr Kelly Y. Chun and coworkers evalu- A real-world study from Brazil toring among patients who do not ated ustekinumab levels in more than evaluated the ability of ustekinumab respond to treatment. When patients 2000 patient samples.46 Antibodies to induce and maintain remission have low trough levels but no anti- to ustekinumab were present in 4%. and to improve laboratory studies bodies, the dose must be optimized. There was an inverse relationship among patients with moderate to Among patients with high titers of between trough ustekinumab drug severe Crohn’s disease.49 Patients who antidrug antibodies, options include levels and anti-ustekinumab antibody were refractory to anti-TNF therapy

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did well. Both induction and main- ciation between use of thiopurines or tumor necrosis in IBD 2020. Paper presented at: 2019 Advances in factor antagonists alone or in combination and risk of Inflammatory Bowel Diseases Conference; December tenance regimens were well-tolerated lymphoma in patients with inflammatory bowel dis- 12-14, 2019; Orlando, Florida. by patients. The safety and efficacy ease. JAMA. 2017;318(17):1679-1686. 21. Feagan BG, Sandborn WJ, Gasink C, et al; profiles provide further support for the 6. Feagan BG, Rutgeerts P, Sands BE, et al; GEMINI UNITI–IM-UNITI Study Group. Ustekinumab as 1 Study Group. Vedolizumab as induction and main- induction and maintenance therapy for Crohn’s disease. use of ustekinumab in clinical practice. tenance therapy for ulcerative colitis. N Engl J Med. N Engl J Med. 2016;375(20):1946-1960. 2013;369(8):699-710. 22. Ma C, Fedorak RN, Kaplan GG, et al. Clini- Disclosure 7. Sandborn WJ, Feagan BG, Rutgeerts P, et al; GEM- cal, endoscopic and radiographic outcomes with INI 2 Study Group. Vedolizumab as induction and ustekinumab in medically-refractory Crohn’s disease: AbbVie (Consultant), American College maintenance therapy for Crohn’s disease. N Engl J Med. real world experience from a multicentre cohort. Ali- of Gastroenterology (Honorarium for 2013;369(8):711-721. ment Pharmacol Ther. 2017;45(9):1232-1243. Associate Editor of American Journal of 8. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al; 23. FDA approves Stelara for ulcerative colitis. Helio. VARSITY Study Group. Vedolizumab versus adalim- https://www.healio.com/gastroenterology/inflamma- Gastroenterology), CellCeutix (Consul- umab for moderate-to-severe ulcerative colitis. N Engl tory-bowel-disease/news/online/%7B31db6681-0f1d- tant), Celgene (Research, Consultant), J Med. 2019;381(13):1215-1226. 4635-b82b-390ad6bb4113%7D/fda-approves-stelara- Clinical Advances in Gastroenterology 9. Sandborn WJ, Baert F, Danese S, et al. Efficacy and for-ulcerative-colitis. Posted October 22, 2019. Accessed safety of vedolizumab subcutaneous formulation in December 29, 2019. (Associate Editor–Honorarium), Fer- a randomized trial of patients with ulcerative colitis 24. Sands BE, Sandborn WJ, Panaccione R, et al; ring (Consultant), Gastroenterology [published online August 28, 2019]. Gastroenterology. UNIFI Study Group. Ustekinumab as induction and & Hepatology [Gastro-Hep Com- doi:10.1053/j.gastro.2019.08.027. maintenance therapy for ulcerative colitis. N Engl J 10. Feagan BG, Lasch K, Lissoos T, et al. Rapid response Med. 2019;381(13):1201-1214. munications] (Editor-Honorarium), to vedolizumab therapy in biologic-naive patients with 25. Loftus EV Jr. A practical approach to JAK inhibi- Gilead (Consultant), Janssen Ortho inflammatory bowel diseases. Clin Gastroenterol Hepa- tors in IBD 2020. Paper presented at: 2019 Advances in Biotech (Consultant, Research, Funding tol. 2019;17(1):130-138.e7. Inflammatory Bowel Diseases Conference; December 11. Feagan BG, Sandborn WJ, Colombel JF, et al. Effect 12-14, 2019; Orlando, Florida. to University of PA [IBD Fellow Educa- of vedolizumab treatment on extraintestinal manifesta- 26. Sandborn WJ, Su C, Sands BE, et al; OCTAVE tion]), Eli Lilly (Consultant, DSMB), tions in patients with Crohn’s disease: a GEMINI 2 Induction 1, OCTAVE Induction 2, and OCTAVE Luitpold/American Regent (Consulting, post hoc analysis. Presented at: European Crohn’s and Sustain Investigators. Tofacitinib as induction and Colitis Organisation 2017 Congress; February 15-18, maintenance therapy for ulcerative colitis. N Engl J Honorarium [CME Programs]), Merck 2017; Barcelona, Spain. Abstract DOP019. Med. 2017;376(18):1723-1736. (Consulting, Honorarium [CME Pro- 12. Rubin D, Feagan B, Dryden G, et al. The effect 27. FDA approves Boxed Warning about increased risk gram]), McMahon Publishing (Author of vedolizumab on extraintestinal manifestations in of blood clots and death with higher dose of arthritis patients with Crohn’s disease in GEMINI 2 [Advances and ulcerative colitis medicine tofacitinib (Xeljanz, Xel- [Honorarium]), Pfizer Pharmaceuticals in Inflammatory Bowel Diseases, Crohn’s and Colitis janz XR). US Food & Drug Administration. https:// (Consultant, Research, Funding to Foundation’s Clinical and Research Conference abstract www.fda.gov/drugs/drug-safety-and-availability/fda- University of PA [IBD Fellow Educa- P-105]. Inflamm Bowel Dis. 2016;22(suppl 1):S42-S43. approves-boxed-warning-about-increased-risk-blood- 13. Ungaro R, Blake A, Bhayat F, et al. A description clots-and-death-higher-dose-arthritis-and. Updated tion]), Prometheus Laboratories, Inc of joint-related events in patients receiving vedolizumab February 25, 2019. Accessed December 27, 2019. (Consultant), Romark (Consultant, from clinical and post-marketing safety experience 28. Panés J, Sandborn WJ, Schreiber S, et al. Tofaci- Honorarium for CME), Salix Pharma- [Advances in Inflammatory Bowel Diseases, Crohn’s tinib for induction and maintenance therapy of Crohn’s and Colitis Foundation’s Clinical and Research Con- disease: results of two phase IIb randomised placebo- ceuticals/Valeant (Consultant, Research), ference abstract P-135]. Inflamm Bowel Dis. 2017;23 controlled trials. Gut. 2017;66(6):1049-1059. Shire Pharmaceuticals (Consultant, (suppl 1):S47-S48. 29. Vermeire S, Schreiber S, Petryka R, et al. Clinical Research), SLACK, Inc (Book Royalty), 14. Panés J, Colombel JF, D’Haens G, et al. High ver- remission in patients with moderate-to-severe Crohn’s sus standard adalimumab induction dosing regimens in disease treated with filgotinib (the FITZROY study): Springer Science and Business Media patients with moderately to severely active ulcerative results from a phase 2, double-blind, randomised, (Editor-Honorarium), Takeda (Consul- colitis: results from the SERENE-UC induction study placebo-controlled trial. Lancet. 2017;389(10066): tant, Funding to University of PA [IBD [UEG Week abstract OP216]. United European Gastro- 266-275. enterol J. 2019;7(8 suppl). 30. D’Haens G, Lindsay JO, Loftus EV, et al. Efficacy Fellow Education]), UCB (Consultant, 15. D’Haens G, Sandborn WJ, Loftus EV, et al. High of upadacitinib as an induction therapy in severe and Research), Up-To-Date (Author-Hono- versus standard adalimumab induction dosing regimens refractory ulcerative colitis: sub-group analysis of the rarium). in patients with moderately to severely active Crohn’s phase 2b study U-ACHIEVE. Presented at: American disease: results from the SERENE-CD induction study College of Gastroenterology Annual Scientific Meet- [UEG Week abstract LB27]. United European Gastroen- ing; October 25-30, 2019; San Antonio, TX. Abstract References terol J. 2019;7(8 suppl). P0486. 1. Feagan BG. A practical approach to anti-integrins 16. Mahadevan U, Vermeire S, Lasch K, et al. Vedoli- 31. Higgins P, Hébuterne X, Siffledeen J, et al. Efficacy in IBD 2020. Paper presented at: 2019 Advances in zumab exposure in pregnancy: outcomes from clinical and safety of upadacitinib as an induction therapy for Inflammatory Bowel Diseases Conference; December studies in inflammatory bowel disease. Aliment Phar- patients with moderately-to-severely active ulcerative 12-14, 2019; Orlando, Florida. macol Ther. 2017;45(7):941-950. colitis: combined results from 382 subjects in the phase 2. Melsheimer R, Geldhof A, Apaolaza I, Schaible T. 17. Shitrit AB, Goldin E, Grisaru-Granovsky S. Inflam- 2b study U-ACHIEVE. Presented at: American College Remicade® (infliximab): 20 years of contributions to matory bowel diseases and pregnancy [in Hebrew]. of Gastroenterology Annual Scientific Meeting; Octo- science and medicine. Biologics. 2019;13:139-178. Harefuah. 2014;153(12):742-746. ber 25-30, 2019; San Antonio, TX. Abstract P1935. 3. Khanna R, Bressler B, Levesque BG, et al; REACT 18. Moens A, van der Woude CJ, Julsgaard M, et al. 32. ClinicalTrials.gov. A study to evaluate the long- Study Investigators. Early combined immunosup- Pregnancy outcomes in inflammatory bowel disease term safety and efficacy of upadacitinib (ABT-494) pression for the management of Crohn’s disease patients treated with vedolizumab, anti-TNF or con- in subjects with ulcerative colitis (UC). https:// (REACT): a cluster randomised controlled trial. Lancet. ventional therapy: results of the European CONCEIVE clinicaltrials.gov/ct2/show/NCT03006068. Identifier: 2015;386(10006):1825-1834. study. Aliment Pharmacol Ther. 2020;51(1):129-138. NCT03006068. Accessed December 29, 2019. 4. Lichtenstein GR, Feagan BG, Cohen RD, et al. Drug 19. Vermeire S, O’Byrne S, Keir M, et al. Etrolizumab 33. ClinicalTrials.gov. A study of the efficacy and safety therapies and the risk of malignancy in Crohn’s disease: as induction therapy for ulcerative colitis: a randomised, of upadacitinib (ABT-494) in subjects with moderately results from the TREAT™ Registry. Am J Gastroenterol. controlled, phase 2 trial. Lancet. 2014;384(9940): to severely active Crohn’s disease who have inadequately 2014;109(2):212-223. 309-318. responded to or are intolerant to biologic therapy. 5. Lemaitre M, Kirchgesner J, Rudnichi A, et al. Asso- 20. Sands BE. A practical approach to anti-interleukins https://clinicaltrials.gov/ct2/show/NCT03345836.

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Identifier: NCT03345836. Accessed December 29, closure in Crohn’s disease. Eur J Gastroenterol Hepatol. 46. Chun KY, Fernando M, Gonzales ZG, et al. Serum 2019. 2020;32(1):32-37. ustekinumab and corresponding anti ustekinumab 34. Sandborn WJ, Nguyen D, Ferslew B, et al. Clini- 40. Present DH, Rutgeerts P, Targan S, et al. Infliximab antibody: analysis of over 2000 patient results using lab cal, endoscopic, histologic and biomarker activity fol- for the treatment of fistulas in patients with Crohn’s developed chemiluminescent immunoassays (ECLIA). lowing treatment with the gut-selective, pan-JAK disease. N Engl J Med. 1999;340(18):1398-1405. Abstract presented at: 2019 Advances in Inflammatory inhibitor TD-1473 in moderately-to-severely active 41. Regueiro M, Feagan BG, Zou B, et al; PREVENT Bowel Diseases Conference; December 12-14, 2019; ulcerative colitis [DDW abstract 801]. Gastroenterology. Study Group. Infliximab reduces endoscopic, but not Orlando, Florida. Poster P020. 2019;156(suppl 1):S171. clinical, recurrence of Crohn’s disease after ileocolonic 47. Ruetsch C, Davis T, Clerie J, et al. Patterns of care 35. Sandborn WJ. A practical approach to anti-TNFs resection. Gastroenterology. 2016;150(7):1568-1578. among patients treated with ustekinumab for Crohn’s in IBD 2020. Paper presented at: 2019 Advances in 42. Ananthakrishnan AN. Management of ulcerative disease: results from a chart review. Abstract presented Inflammatory Bowel Diseases Conference; December colitis in adults: ACG guidelines. Paper presented at: at: 2019 Advances in Inflammatory Bowel Diseases 12-14, 2019; Orlando, Florida. 2019 Advances in Inflammatory Bowel Diseases Con- Conference; December 12-14, 2019; Orlando, Florida. 36. Singh S, Fumery M, Sandborn WJ, Murad ference; December 12-14, 2019; Orlando, Florida. Poster P037. MH. Systematic review and network meta-analysis: 43. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer 48. Hanauer S, Schreiber S, Balser S, Liedert B. Bio- first- and second-line biologic therapies for moderate- BG, Long MD. ACG clinical guideline: ulcerative coli- similar BI 695501 demonstrates non-inferior efficacy severe Crohn’s disease. Aliment Pharmacol Ther. tis in adults. Am J Gastroenterol. 2019;114(3):384-413. and comparable safety to adalimumab reference prod- 2018;48(4):394-409. 44. Mosli MH, Zou G, Garg SK, et al. C-reactive pro- uct in patients with Crohn’s disease. Abstract presented 37. Baert F, Noman M, Vermeire S, et al. Influence of tein, fecal calprotectin, and stool lactoferrin for detec- at: 2019 Advances in Inflammatory Bowel Diseases immunogenicity on the long-term efficacy of inflix- tion of endoscopic activity in symptomatic inflamma- Conference; December 12-14, 2019; Orlando, Florida. imab in Crohn’s disease. N Engl J Med. 2003;348(7): tory bowel disease patients: a systematic review and Poster P052. 601-608. meta-analysis. Am J Gastroenterol. 2015;110(6):802- 49. Parra RS, Chebli JMF, Chebli LA, et al. Efficacy 38. Colombel JF, Sandborn WJ, Reinisch W, et al; 819. and safety of ustekinumab in patients with moderate SONIC Study Group. Infliximab, azathioprine, or 45. Moussata D, Allez M, Cazals-Hatem D, et al; the to severe Crohn’s disease: a real world study in Brazil. combination therapy for Crohn’s disease. N Engl J Med. GETAID. Are random biopsies still useful for the Abstract presented at: 2019 Advances in Inflammatory 2010;362(15):1383-1395. detection of neoplasia in patients with IBD undergo- Bowel Diseases Conference; December 12-14, 2019; 39. Plevris N, Jenkinson PW, Arnott ID, Jones GR, ing surveillance colonoscopy with chromoendoscopy? Orlando, Florida. Poster P065. Lees CW. Higher anti-tumor necrosis factor levels Gut. 2018;67(4):616-624. are associated with perianal fistula healing and fistula

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