Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study.

BACKGROUND & AIMS: The QUASAR Phase 2b Induction Study evaluated the efficacy and safety of guselkumab, an interleukin-23p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) with prior inadequate response and/or intolerance to corticosteroids, immunosuppressants, and/or advanced therapy. METHODS: In this double-blind, placebo-controlled, dose-ranging, induction study, patients were randomized (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0/4/8. The primary endpoint was clinical response (compared with baseline, modified Mayo score decrease ≥30% and ≥2 points, rectal bleeding subscore ≥1-point decrease or subscore of 0/1) at week 12. Guselkumab and placebo week-12 clinical nonresponders received subcutaneous or intravenous guselkumab 200 mg, respectively, at weeks 12/16/20 (uncontrolled study period). RESULTS: The primary analysis population included patients with baseline modified Mayo scores ≥5 and ≤9 (intravenous guselkumab 200 mg, n = 101; 400 mg, n = 107; placebo, n = 105). Week-12 clinical response percentage was greater with guselkumab 200 mg (61.4%) and 400 mg (60.7%) vs placebo (27.6%; both P < .001). Greater proportions of guselkumab-treated vs placebo-treated patients achieved all major secondary endpoints (clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization) at week 12. Among guselkumab week-12 clinical nonresponders, 54.3% and 50.0% of patients in the 200- and 400-mg groups, respectively, achieved clinical response at week 24. Safety was similar among guselkumab and placebo groups. CONCLUSIONS: Guselkumab intravenous induction was effective vs placebo in patients with moderately to severely active UC. Guselkumab was safe, and efficacy and safety were similar between guselkumab dose groups. CLINICALTRIALS: gov number: NCT04033445.

Long-Term Safety Outcomes of Fecal Microbiota Transplantation: Real-World Data Over 8 Years From the Hong Kong FMT Registry.

BACKGROUND AND AIMS: Prospective long-term real-world safety data after fecal microbiota transplantation (FMT) remain limited. We reported long-term outcomes of FMT from a population-based FMT registry in Hong Kong. METHODS: We recruited patients undergoing FMT for recurrent Clostridioides difficile infection (CDI) and non-CDI indications from clinical trials, from June 2013 to April 2022 in Hong Kong. We captured data on demographics, FMT indications and procedures, clinical outcomes and short- to long-term safety. New medical diagnoses were obtained from electronic medical records and independently adjudicated by clinicians. Long-term safety in patients with recurrent CDI was compared with a control group treated with antibiotics. RESULTS: Overall, 123 subjects (median age 53 years, range 13-90 years; 52.0% male) underwent 510 FMTs and were prospectively followed up for a median of 30.3 (range, 1-57.9) months. The most common indication for FMT was type 2 diabetes mellitus. The most common short-term adverse events within 1 month of FMT included diarrhea and abdominal pain. At long-term follow-up beyond 12 months, 16 patients reported 21 new-onset medical conditions confirmed by electronic medical records. All were adjudicated to be unlikely to be related to FMT. There was no new case of inflammatory bowel disease, irritable bowel syndrome, allergy, diabetes mellitus, or psychiatric disorder. In a subgroup of patients with recurrent CDI, FMT was associated with a significantly higher cumulative survival probability compared with matched control subjects. CONCLUSIONS: This prospective real-world data from Asia's first FMT registry demonstrated that FMT has an excellent long-term safety profile. The risk of developing new medical conditions beyond 12 months after FMT is low.

Upadacitinib Achieves Clinical and Endoscopic Outcomes in Crohn's Disease Regardless of Prior Biologic Exposure.

BACKGROUND & AIMS: Upadacitinib, an oral Janus kinase inhibitor, achieved significantly higher rates of clinical remission and endoscopic response vs placebo during induction (U-EXCEL [NCT03345849], U-EXCEED [NCT03345836]) and maintenance (U-ENDURE [NCT03345823]) treatment in patients with moderate-to-severe Crohn's disease. Prior biologic failure is often associated with reduced responses to subsequent therapies. This post hoc analysis assessed upadacitinib efficacy by prior biologic failure status. METHODS: Patients were randomized to placebo or upadacitinib 45 mg (UPA45) for 12 weeks (induction). UPA45 clinical responders were enrolled in U-ENDURE and rerandomized to placebo, upadacitinib 15 mg, or upadacitinib 30 mg (UPA30) for 52 weeks. Assessments were by prior biologic failure. RESULTS: Of 1021 patients, 733 (71.8%) had prior biologic failure. Across outcomes and subgroups, upadacitinib-treated patients achieved higher rates vs placebo. During induction, upadacitinib had higher rates vs placebo for clinical remission based on stool frequency/abdominal pain score (without failure: 54.0% vs 28.3%; with failure: 42.2% vs 14.1%) and endoscopic response (without failure: 52.0% vs 16.2%; with failure: 35.7% vs 5.3%). In maintenance, the greatest treatment effect (upadacitinib vs placebo) was among patients with prior biologic failure treated with UPA30 (clinical remission without failure: 58.5% vs 32.7%; with failure: 42.5% vs 8.7%; endoscopic response without failure: 43.9% vs 17.9%; with failure: 38.9% vs 4.0%). Patients without vs with prior biologic failure had fewer adverse events. CONCLUSIONS: Upadacitinib led to higher absolutes rates of clinical and endoscopic outcomes in patients without vs with prior biologic failure. Patients treated with upadacitinib achieved greater rates of clinical and endoscopic improvements vs placebo, regardless of prior biologic exposure. CLINICALTRIALS: gov: NCT03345849, NCT03345836, NCT03345823.

Perianal Fistulizing Crohn's Disease-Associated Anorectal and Fistula Cancers: Systematic Review and Expert Consensus.

BACKGROUND & AIMS: Perianal fistulizing Crohn's disease (PFCD)-associated anorectal and fistula cancers are rare but often devastating diagnoses. However, given the low incidence and consequent lack of data and clinical trials in the field, there is little to no guidance on screening and management of these cancers. To inform clinical practice, we developed consensus guidelines on PFCD-associated anorectal and fistula cancers by multidisciplinary experts from the international TOpClass consortium. METHODS: We conducted a systematic review by standard methodology, using the Newcastle-Ottawa Scale quality assessment tool. We subsequently developed consensus statements using a Delphi consensus approach. RESULTS: Of 561 articles identified, 110 were eligible, and 76 articles were included. The overall quality of evidence was low. The TOpClass consortium reached consensus on 6 structured statements addressing screening, risk assessment, and management of PFCD-associated anorectal and fistula cancers. Patients with long-standing (>10 years) PFCD should be considered at small but increased risk of developing perianal cancer, including squamous cell carcinoma of the anus and anorectal carcinoma. Risk factors for squamous cell carcinoma of the anus, notably human papilloma virus, should be considered. New, refractory, or progressive perianal symptoms should prompt evaluation for fistula cancer. There was no consensus on timing or frequency of screening in patients with asymptomatic perianal fistula. Multiple modalities may be required for diagnosis, including an examination under anesthesia with biopsy. Multidisciplinary team efforts were deemed central to the management of fistula cancers. CONCLUSIONS: Inflammatory bowel disease clinicians should be aware of the risk of PFCD-associated anorectal and fistula cancers in all patients with PFCD. The TOpClass consortium consensus statements outlined herein offer guidance in managing this challenging scenario.

Clinical Application of Intestinal Ultrasound in Inflammatory Bowel Disease.

PURPOSE OF REVIEW: Intestinal ultrasound (IUS) is a non-invasive, accurate, and well-tolerated tool that provides real-time assessment of inflammatory bowel disease (IBD) activity and is therefore an ideal monitoring tool. This review describes the evolving role of IUS in each phase of clinical management of IBD. RECENT FINDINGS: Accumulating evidence has demonstrated that IUS is an excellent tool for the assessment of suspected IBD, with a very high negative predictive value. It accurately assesses disease activity, disease complications, and in the pre-treatment phase, provides a benchmark for subsequent follow-up. IUS can detect early therapeutic response and correlates well with other established monitoring modalities with arguably superior predictive capabilities and ability to assess a deeper degree of remission, transmural healing (TH). IUS has a crucial role in the management of IBD and has ushered in a new era of monitoring with more rapid evaluation and the opportunity for early optimization, deeper therapeutic targets, and improved outcomes.

Dual-Targeted Therapy with Upadacitinib and Ustekinumab in Medically Complex Crohn's Disease.

BACKGROUND AND AIMS: Ongoing efforts to break the therapeutic ceiling in inflammatory bowel disease include combination therapy approaches. Dual-targeted therapy (DTT) has been reported in case reports and small case series. This report describes our experience with ustekinumab (UST) and upadacitinib (UPA) as DTT in patients with Crohn's disease (CD). METHODS: In this retrospective, observational study, we reviewed medical records of patients with CD treated with combined UST and UPA between April 2021 and July 2022. Clinical remission was defined as Harvey-Bradshaw Index (HBI) ≤ 4, and clinical response was defined as decrease in HBI ≥ 3 or physician's assessment of clinical response. RESULTS: We identified 10 CD patients treated with UST/UPA, with median follow-up period of 10 months (interquartile range (IQR) 7.3-12). Median age was 35.5 years (IQR 28.3-43.8) and median number of prior biologic treatment exposures was 4 (IQR 4-5). Indications for UST/UPA were active CD (n = 6), extraintestinal manifestations (EIM) (n = 2), and both active CD and EIM (n = 2). Five of six patients with active CD achieved clinical remission with UST/UPA. Two patients with active EIM (joint pain) achieved resolution of their symptoms. One patient exhibited improvement in both conditions. Three patients developed mild respiratory symptoms and one experienced bowel obstruction. Two patients developed nausea resulting in de-escalation of treatment interval or discontinuation altogether. CONCLUSION: Based on our case series, combination therapy with UST and UPA may be effective and appears safe in refractory Crohn's disease and for patients with co-existing extraintestinal manifestations.

Utility of the Endoscopic Healing Index in Identifying Active Inflammation in Patients with Crohn's Disease: Real World Data from a Tertiary Center.

BACKGROUND: The Endoscopic Healing Index (EHI) analyzes biomarkers in a patient's peripheral blood to assess mucosal healing. We aimed to characterize the effectiveness of the EHI as a predictor of disease activity in a real world clinical setting. METHODS: This retrospective study looked at patients treated and followed up at the University of Chicago Medicine IBD center who had EHI tests done as part of routine clinical care. The results of the EHI were compared with radiological imaging or endoscopy performed within 3 months of the EHI in order to determine accuracy at diagnosing active inflammation. RESULTS: Fifty-five patients with CD and with an available EHI were included in this study. Four (50%) patients with an EHI of < 20 (n = 8) had evidence of objective inflammation. A cutoff of ≤ 20 had a sensitivity of 89% and specificity of 23.5% for predicting no evidence of any objective inflammation with an AUROC of 0.69. This score had a negative predictive value (NPV) of 50% and positive predictive value (PPV) of 72.3%. A cutoff EHI of 30 tended to classify patients as either having objective evidence of inflammation or not more often than FCAL (Correctly classifying inflammation: 89% vs 64%, respectively; p = 0.32). CONCLUSION: In this real world analysis, the EHI showed poor predictive value for the absence of active inflammation as assessed by imaging or endoscopy, has limited utility in confirming deep remission and should be used with another objective modality.

Real World Clinical Effectiveness and Safety of Ozanimod in the Treatment of Ulcerative Colitis: 1-Year Follow-Up from a Tertiary Center.

BACKGROUND: Ozanimod is a first-in-class Sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of moderately to severely active ulcerative colitis (UC). Real world data describing use of ozanimod are limited. AIM: To provide 1-year follow-up results of our UC patient cohort treated with ozanimod. METHODS: This prospective, observational cohort study includes consecutive patients who initiated ozanimod at the University of Chicago IBD Center between 5/2021 and 12/2022. We collected demographic, clinical, and laboratory data. Clinical disease activity was prospectively assessed using the Simple Clinical Colitis Activity Index. RESULTS: Forty-five patients with UC initiated ozanimod therapy and were included in the effectiveness analysis. The median age was 35 years (interquartile range (IQR) 28-52), median disease duration of 6 years (IQR 3-13), 26 (58%) were male, 23 (51%) had extensive colitis, 34 (76%) had previous advanced therapy exposure. Thirty-four patients had clinically active UC at the time of ozanimod initiation; week 10 clinical response and remission rates were 58% and 53%, respectively. By week 52, the rates were 25% for both clinical response and remission. In the 12 (39%) patients with a > 75% reduction in absolute lymphocyte count, numerically greater induction clinical response and remission rates were observed (80% vs 54%, p = 0.4 and 75% vs 53%, p = 0.4, respectively). There were no episodes of symptomatic bradycardia and no other new safety signals. CONCLUSION: Ozanimod effectively induced clinical response and remission patients with largely treatment refractory UC, however, had modest long-term effectiveness. The safety profile was favorable with no new signals.

Patient and Health Care Professional Perceptions of the Experience and Impact of Symptoms of Moderate-to-Severe Crohn's Disease in US and Europe: Results from the Cross-Sectional CONFIDE Study.

BACKGROUND: Crohn's disease (CD) significantly affects patients' health-related quality of life and well-being. AIMS: Communicating Needs and Features of IBD Experiences (CONFIDE) survey explores the experience and impact of moderate-to-severe CD symptoms on patients' lives and identifies communication gaps between patients and health care professionals (HCPs). METHODS: Online, quantitative, cross-sectional surveys of patients, and HCPs were conducted in the United States (US), Europe (France, Germany, Italy, Spain, United Kingdom), and Japan. Criteria based on previous treatment, steroid use, and/or hospitalization defined moderate-to-severe CD. US and Europe data are presented as descriptive statistics. RESULTS: Surveys were completed by 215 US and 547 European patients and 200 US and 503 European HCPs. In both patient groups, top three symptoms currently (past month) experienced were diarrhea, bowel urgency, and increased stool frequency, with more than one-third patients wearing diaper/pad/protection at least once a week in past 3 months due to fear of bowel urgency-related accidents. HCPs ranked diarrhea, blood in stool, and increased stool frequency as the most common symptoms. Although 34.0% US and 27.2% European HCPs ranked bowel urgency among the top five symptoms affecting patient lives, only 12.0% US and 10.9% European HCPs ranked it among top three most impactful symptoms on treatment decisions. CONCLUSION: Bowel urgency is common and impactful among patients with CD in the US and Europe. Differences in patient and HCP perceptions of experiences and impacts of bowel urgency exist, with HCPs underestimating its burden. Proactive communication between HCPs and patients in clinical settings is crucial for improving health outcomes in patients with CD.

Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial.

BACKGROUND: There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy. METHODS: FORTIFY is a phase 3, multicentre, randomised, double-blind, placebo-controlled, maintenance withdrawal study across 273 clinical centres in 44 countries across North and South America, Europe, Oceania, Africa, and the Asia-Pacific region that enrolled participants with clinical response to risankizumab in the ADVANCE or MOTIVATE induction studies. Patients in ADVANCE or MOTIVATE were aged 16-80 years with moderately to severely active Crohn's disease. Patients in the FORTIFY substudy 1 were randomly assigned again (1:1:1) to receive either subcutaneous risankizumab 180 mg, subcutaneous risankizumab 360 mg, or withdrawal from risankizumab to receive subcutaneous placebo (herein referred to as withdrawal [subcutaneous placebo]). Treatment was given every 8 weeks. Patients were stratified by induction dose, post-induction endoscopic response, and clinical remission status. Patients, investigators, and study personnel were masked to treatment assignments. Week 52 co-primary endpoints were clinical remission (Crohn's disease activity index [CDAI] in the US protocol, or stool frequency and abdominal pain score in the non-US protocol) and endoscopic response in patients who received at least one dose of study drug during the 52-week maintenance period. Safety was assessed in patients receiving at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03105102. FINDINGS: 712 patients were initially assessed and, between April 9, 2018, and April 24, 2020, 542 patients were randomly assigned to either the risankizumab 180 mg group (n=179), the risankizumab 360 mg group (n=179), or the placebo group (n=184). Greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (CDAI clinical remission was reached in 74 (52%) of 141 patients vs 67 (41%) of 164 patients, adjusted difference 15% [95% CI 5-24]; stool frequency and abdominal pain score clinical remission was reached in 73 (52%) of 141 vs 65 (40%) of 164, adjusted difference 15% [5-25]; endoscopic response 66 (47%) of 141 patients vs 36 (22%) of 164 patients, adjusted difference 28% [19-37]). Higher rates of CDAI clinical remission and endoscopic response (but not stool frequency and abdominal pain score clinical remission [p=0·124]) were also reached with risankizumab 180 mg versus withdrawal (subcutaneous placebo; CDAI clinical remission reached in 87 [55%] of 157 patients, adjusted difference 15% [95% CI 5-24]; endoscopic response 74 [47%] of 157, adjusted difference 26% [17-35]). Results for more stringent endoscopic and composite endpoints and inflammatory biomarkers were consistent with a dose-response relationship. Maintenance treatment was well tolerated. Adverse event rates were similar among groups, and the most frequently reported adverse events in all treatment groups were worsening Crohn's disease, arthralgia, and headache. INTERPRETATION: Subcutaneous risankizumab is a safe and efficacious treatment for maintenance of remission in patients with moderately to severely active Crohn's disease and offers a new therapeutic option for a broad range of patients by meeting endpoints that might change the future course of disease. FUNDING: AbbVie.

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.

BACKGROUND: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. METHODS: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. FINDINGS: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. INTERPRETATION: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. FUNDING: AbbVie.

What Does Disease Progression Look Like in Ulcerative Colitis, and How Might It Be Prevented?

Ulcerative colitis (UC) has been characterized by inflammation limited to the mucosa. Although sustained and durable remission has been associated with mucosal healing, the recurrent phenomenon of persistent clinical disease activity despite mucosal healing has been observed in clinical practice and across pivotal trials. Over time, UC appears to confer an increased risk of progression, defined as changes of disease phenotype; adverse transmural effects on the bowel wall; increased risk of neoplasia development; worsening colorectal function; and increased risk of colectomy, hospitalizations, and other extraintestinal comorbidities. Although the treatment paradigm for Crohn's disease has shifted toward early aggressive intervention to prevent disease progression and irreversible bowel damage, such urgency in efforts to halt disease progression in UC have been largely overlooked. This review summarizes the multiple facets of UC contributing to a modified perception of the disease as a progressive one. We propose further study of the natural history and priorities for further treatment goals that include these considerations.

Common Instances of Low-value Care in Inflammatory Bowel Diseases.

Value-based care focuses on improving the quality, effectiveness, and efficiency of health care while controlling costs. Low-value care implies services or interventions that provide little or no benefit to patients, have the potential to cause harm, incur unnecessary cost to patients, or waste limited health care resources. In this review, we discuss common instances of low-value care along the spectrum of management in inflammatory bowel diseases (IBD). These include low value care in: (1) diagnosis and monitoring of IBD: utilization of serological markers to screen and diagnose IBD, over-reliance on symptoms for monitoring disease, failure to employ treat-to-target strategies in symptomatic patients with IBD, and annual surveillance colonoscopies in patients at low risk of developing dysplasia; (2) treatment of IBD: use of 5-aminosalicylates in Crohn's disease, continuation of 5-aminosalicylates after escalation to immunosuppressive therapy, chronic corticosteroid use without steroid-sparing strategies, step therapy for Crohn's disease, failure to optimize tumor necrosis factor antagonists in patients with active disease and subsequently de-intensification of therapies in those who have achieved stable remission; and (3) management of hospitalized patients with IBD: routine cross-sectional imaging for patients with IBD presenting to the emergency department, withholding pharmacological prophylaxis for venous thromboembolism in patients hospitalized with IBD flare, and prolonged use of high-dose intravenous corticosteroids in patients with acute severe ulcerative colitis. This review is meant to bring attention to value-based care in IBD and provide guidance to treating practitioners. Future studies on systematic evaluation of high- and low-value care in patients with IBD are warranted.

Risankizumab Effectiveness and Safety in Crohn's Disease: Real-world Data From a Large Tertiary Center.

L23 is a recognized cytokine involved in the pathogenesis of inflammatory bowel diseases (IBDs).1 The first IL23-targeting agent that became available for clinical use in IBD was Ustekinumab, a monoclonal antibody that targets p40, a shared subunit of both IL23 and IL12.2,3 Risankizumab (Skyrizi; Abbvie) is a humanized IgG1 monoclonal antibody which binds to the p19 subunit and therefore selectively inhibits IL23.4 In June 2022, it was approved by the United States Food and Drug Administration for the treatment of moderately to severely active Crohn's disease (CD). Here, we describe the effectiveness and safety of risankizumab throughout the induction period in a real-world setting of a large tertiary center.

Ozanimod in the Treatment of Ulcerative Colitis: Initial Real-World Data From a Large Tertiary Center.

Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon and rectum. Long-term therapy is generally required to achieve and maintain disease control.1 In May 2021 the US Food and Drug Administration approved the use of ozanimod in patients with moderate to severe UC. We describe the first report of the use of ozanimod in real-world clinical practice.

Upadacitinib Is Effective and Safe in Both Ulcerative Colitis and Crohn's Disease: Prospective Real-World Experience.

BACKGROUND & AIMS: Upadacitinib is a novel selective Janus kinase 1 inhibitor that has shown efficacy in the treatment of moderate to severe ulcerative colitis (UC) and Crohn's disease (CD), and has received Food and Drug Administration approval for UC. We report a large real-world experience with upadacitinib in UC and CD. METHODS: We performed a prospective analysis of clinical outcomes on upadacitinib in patients with UC and CD using predetermined intervals at weeks 0, 2, 4, and 8 as part of a formalized treatment protocol at our institution. We used the Simple Clinical Colitis Activity Index and the Harvey-Bradshaw index, as well as C-reactive protein and fecal calprotectin to assess efficacy, and also recorded treatment-related adverse events and serious adverse events. RESULTS: A total of 105 patients were followed up for 8 weeks on upadacitinib, 84 of whom (44 UC patients, 40 CD patients) were initiated because of active luminal or perianal disease and included in the analysis. One hundred percent previously received anti-tumor necrosis factor therapy, and 89.3% had received 2 or more advanced therapies. At 4 and 8 weeks of treatment for UC, 19 of 25 (76.0%) and 23 of 27 (85.2%) achieved clinical response and 18 of 26 (69.2%) and 22 of 27 (81.5%) achieved clinical remission, respectively. Of those who previously were tofacitinib-exposed, 7 of 9 (77.8%) achieved clinical remission by 8 weeks. In CD, 13 of 17 (76.5.%) achieved clinical response and 12 of 17 (70.6%) achieved clinical remission by 8 weeks. Of those with increased fecal calprotectin and C-reactive protein levels, 62% and 64% normalized by week 8, respectively. Results were seen as early as week 2 in both UC and CD, with clinical remission rates of 36% and 56.3.%, respectively. Acne was the most commonly reported adverse event, occurring in 24 of 105 patients (22.9%). CONCLUSIONS: In this large real-world experience in medically resistant patients with UC or CD, we report that upadacitinib is rapidly effective and safe, including in those who had prior tofacitinib exposure. This study was approved by the Institutional Review Board at the University of Chicago (IRB20-1979).

Guselkumab for the Treatment of Crohn's Disease: Induction Results From the Phase 2 GALAXI-1 Study.

BACKGROUND & AIMS: Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis. This study evaluated the efficacy and safety of guselkumab in patients with moderately to severely active Crohn's disease with inadequate response or intolerance to conventional or biologic therapy. METHODS: GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. Change from baseline in Crohn's Disease Activity Index score (primary end point), clinical remission, clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, endoscopic response (major secondary end points), and safety in guselkumab-treated patients vs placebo were evaluated through week 12. Ustekinumab was a reference arm. RESULTS: Of 309 patients evaluated, approximately 50% had disease refractory to prior biologic therapy. At week 12, significantly greater reductions in Crohn's Disease Activity Index from baseline (least squares means: 200 mg: -160.4, 600 mg: -138.9, and 1200 mg: -144.9 vs placebo: -36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo (Crohn's Disease Activity Index <150; 57.4%, 55.6%, and 45.9% vs 16.4%; all, P < .05). Greater proportions of patients receiving guselkumab achieved clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, and endoscopic response at week 12 vs placebo. Efficacy of ustekinumab vs placebo was also demonstrated. Safety event rates were generally similar across treatment groups. CONCLUSIONS: At week 12, all 3 dose regimens of guselkumab induced greater clinical and endoscopic improvements vs placebo, with a favorable safety profile. CLINICALTRIALS: gov, Number: NCT03466411.

Efficacy and Safety of Ivarmacitinib in Patients With Moderate-to-Severe, Active, Ulcerative Colitis: A Phase II Study.

BACKGROUND & AIMS: Current therapies for ulcerative colitis (UC) fail to achieve satisfactory disease control. Selective inhibition of Janus kinase (JAK) type 1 may improve clinical outcomes in patients with UC while avoiding the side effects associated with pan-JAK inhibition. The safety and efficacy of the selective JAK1 inhibitor ivarmacitinib (formerly SHR0302) were evaluated in patients with moderate-to-severe, active UC. METHODS: AMBER2 was a double-blind, placebo-controlled, phase II trial conducted at 63 clinical centers in China, the United States, and Europe. Patients (N = 164) were randomized 1:1:1:1 to receive oral ivarmacitinib 8 mg once daily (QD), 4 mg twice daily (BID), or 4 mg QD, or placebo for 8 weeks, followed by an 8-week extension period. The primary endpoint was clinical response rate at week 8. Hochberg's procedure was used to control the study-wise type 1 error at alpha=0.1. RESULTS: A total of 146 (89.0%) patients completed 8 weeks of treatment. Week 8 clinical response rates were significantly higher in the 8 mg QD (46.3%; P = .066), 4 mg BID (46.3%; P = .059), and 4 mg QD (43.9%; P = .095) groups vs placebo (26.8%). Week 8 rates of clinical remission were 22.0% (P = .020), 24.4% (P = .013), and 24.4% (P = .011) in the 3 ivarmacitinib treatment groups, respectively, vs 4.9% for placebo. During the initial 8-week period, treatment-emergent adverse events occurred in 43.9% to 48.8% of ivarmacitinib-treated patients and in 39.0% of the placebo group, and were predominantly mild. There were no deaths, or major adverse cardiovascular or thromboembolic events. CONCLUSION: Ivarmacitinib demonstrated clinical efficacy and was well tolerated in patients with moderate-to-severe, active, UC. Ivarmacitinib represents a promising new treatment for moderate-to-severe UC. CLINICALTRIALS: gov number, NCT03675477.

CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease.

BACKGROUND & AIMS: End points to determine the efficacy and safety of medical therapies for Crohn's disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in inflammatory bowel disease. METHODS: Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists. RESULTS: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for UC. In CD, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In UC, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. CONCLUSIONS: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of CD and UC.

Global Hospitalization Trends for Crohn's Disease and Ulcerative Colitis in the 21st Century: A Systematic Review With Temporal Analyses.

BACKGROUND & AIMS: The evolving epidemiologic patterns of inflammatory bowel disease (IBD) throughout the world, in conjunction with advances in therapeutic treatments, may influence hospitalization rates of IBD. We performed a systematic review with temporal analysis of hospitalization rates for IBD across the world in the 21st century. METHODS: We systematically reviewed Medline and Embase for population-based studies reporting hospitalization rates for IBD, Crohn's disease (CD), or ulcerative colitis (UC) in the 21st century. Log-linear models were used to calculate the average annual percentage change (AAPC) with associated 95% confidence intervals (95% CIs). Random-effects meta-analysis pooled country-level AAPCs. Data were stratified by the epidemiologic stage of a region: compounding prevalence (stage 3) in North America, Western Europe, and Oceania vs acceleration of incidence (stage 2) in Asia, Eastern Europe, and Latin America vs emergence (stage 1) in developing countries. RESULTS: Hospitalization rates for a primary diagnosis of IBD were stable in countries in stage 3 (AAPC, -0.13%; 95% CI, -0.72 to 0.97), CD (AAPC, 0.20%; 95% CI, -1.78 to 2.17), and UC (AAPC, 0.02%; 95% CI, -0.91 to 0.94). In contrast, hospitalization rates for a primary diagnosis were increasing in countries in stage 2 for IBD (AAPC, 4.44%; 95% CI, 2.75 to 6.14), CD (AAPC, 8.34%; 95% CI, 4.38 to 12.29), and UC (AAPC, 3.90; 95% CI, 1.29 to 6.52). No population-based studies were available for developing regions in stage 1 (emergence). CONCLUSIONS: Hospitalization rates for IBD are stabilizing in countries in stage 3, whereas newly industrialized countries in stage 2 have rapidly increasing hospitalization rates, contributing to an increasing burden on global health care systems.