Modern Advanced Therapies for Inflammatory Bowel Diseases: Practical Considerations and Positioning.

The therapeutic armamentarium for management of inflammatory bowel diseases has expanded dramatically in the last 5 years, with the introduction of several medications with different mechanisms of action. These include the oral small molecule drugs Janus kinase inhibitors (including upadacitinib, approved for Crohn's disease and ulcerative colitis [UC], and tofacitinib, approved for UC) and sphingosphine 1-phosphate receptor modulators (ozanimod and etrasimod, both approved for UC), and biologic agents, such as selective interleukin-23 antagonists (risankizumab approved for Crohn's disease, and mirikizumab approved for UC). The efficacy and safety of these therapies vary. In this review, we discuss practical use of these newer advanced therapies focusing on real-world effectiveness and safety data, dosing and monitoring considerations, and special situations for their use, such as pregnancy, comorbid immune-mediated disease, use in hospitalized patients with acute severe UC, and in the perioperative setting. We also propose our approach to positioning these therapies in clinical practice, relying on careful integration of the medication's comparative effectiveness and safety in the context of an individual patient's risk of disease- and treatment-related complications and preferences.

Comparative Safety of Biologic Agents in Patients With Inflammatory Bowel Disease With Active or Recent Malignancy: A Multi-Center Cohort Study.

BACKGROUND & AIMS: Safety of biologic agents is a key consideration in patients with inflammatory bowel disease (IBD) and active or recent cancer. We compared the safety of tumor necrosis factor (TNF)-α antagonists vs non-TNF biologics in patients with IBD with active or recent cancer. METHODS: We conducted a multicenter retrospective cohort study of patients with IBD and either active cancer (cohort A) or recent prior cancer (within ≤5 years; cohort B) who were treated with TNFα antagonists or non-TNF biologics after their cancer diagnosis. Primary outcomes were progression-free survival (cohort A) or recurrence-free survival (cohort B). Safety was compared using inverse probability of treatment weighting with propensity scores. RESULTS: In cohort A, of 125 patients (483.8 person-years of follow-up evaluation) with active cancer (age, 54 ± 15 y, 75% solid-organ malignancy), 10 of 55 (incidence rate [IR] per 100 py, 4.4) and 9 of 40 (IR, 10.4) patients treated with TNFα antagonists and non-TNF biologics had cancer progression, respectively. There was no difference in the risk of progression-free survival between TNFα antagonists vs non-TNF biologics (hazard ratio, 0.76; 95% CI, 0.25-2.30). In cohort B, of 170 patients (513 person-years of follow-up evaluation) with recent prior cancer (age, 53 ± 15 y, 84% solid-organ malignancy; duration of remission, 19 ± 19 mo), 8 of 78 (IR, 3.4) and 5 of 66 (IR 3.7) patients treated with TNFα antagonists and non-TNF biologics had cancer recurrence, respectively. The risk of recurrence-free survival was similar between both groups (hazard ratio, 0.94; 95% CI, 0.24-3.77). CONCLUSIONS: In patients with IBD with active or recent cancer, TNFα antagonists and non-TNF biologics have comparable safety. The choice of biologic should be dictated by IBD disease severity in collaboration with an oncologist.

Prevalence of Forceps Polypectomy of Nondiminutive Polyps Is Substantial But Modifiable.

BACKGROUND AND AIMS: The use of forceps for removal of nondiminutive polyps is associated with incomplete resection compared with snare polypectomy. However, few studies have characterized the frequency of forceps polypectomy for nondiminutive polyps or identified strategies to improve this practice. To address this gap, we estimated the prevalence and predictors of forceps polypectomy in clinical practice and examined the effectiveness of a multicomponent intervention to reduce inappropriate forceps polypectomy. METHODS: We retrospectively reviewed all colonoscopies with polypectomies performed at 2 U.S. health systems between October 1, 2017, and September 30, 2019. We used a mixed-effects logistic regression model to examine the effect of a multicomponent intervention, including provider education and a financial incentive, to reduce inappropriate forceps polypectomy, defined as use of forceps polypectomy for polyps ≥5 mm. RESULTS: A total of 9968 colonoscopies with 25,534 polypectomies were performed by 42 gastroenterologists during the study period. Overall, 8.5% (n = 2176) of polyps were removed with inappropriate forceps polypectomy. Inappropriate forceps polypectomy significantly decreased after the intervention (odds ratio [OR], 0.34, 95% confidence interval [CI], 0.30-0.39), from 11.4% (n = 1539) to 5.3% (n = 637). Predictors of inappropriate forceps polypectomy included inadequate bowel prep (OR, 1.25; 95% CI, 1.06-1.47), polyps in the right colon (vs left: OR, 1.29; 95% CI, 1.09-1.51), and number of polyps removed (OR, 0.96; 95% CI, 0.94-0.97). Inappropriate forceps polypectomy also varied by gastroenterologist (median OR, 3.43). In a post hoc analysis, the proportion of polyps >2 mm removed with forceps decreased from 50.0% before the intervention to 43.0% after it (OR, 0.62; 95% CI, 0.58-0.68). CONCLUSIONS: Inappropriate forceps polypectomy is common but modifiable. The proportion of nondiminutive polyps removed with forceps polypectomy should be considered as a quality measure.

Interventions to Decrease Unplanned Healthcare Utilization and Improve Quality of Care in Adults With Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) care and outcomes exhibit substantial variability, suggesting quality gaps. We aimed to identify interventions to narrow these gaps. METHODS: We performed a systematic review of Medline, Embase, and Web of Science through May 2021 to find manuscripts and abstracts reporting quality improvement (QI) interventions in IBD. We included studies with interventions that addressed acute care utilization, vaccination, or Crohn's and Colitis Foundation quality indicators for care processes, including pre-therapy testing, tobacco cessation, colorectal cancer surveillance, Clostridium difficile infection screening in flares, sigmoidoscopy in patients hospitalized with ulcerative colitis, and use of steroid-sparing therapy. The primary objective was to identify successful QI interventions. Risk of bias assessment was conducted using the Joanna Briggs Institute critical appraisal checklist. RESULTS: Twenty-three manuscripts and 23 meeting abstracts met inclusion criteria. Influenza and pneumococcal vaccination were the most studied indicators (24 references), followed by emergency room and/or hospital utilization, tobacco cessation, and pre-therapy testing (17, 11, and 10 references, respectively). Electronic medical record-based interventions were the most frequent, whereas other initiatives used strategies that included changes to care structure or delivery, vaccination protocols, or physician and patient education. Successful interventions matched the complexity of the metric to the intervention including making changes to care structure or delivery, empowered non-physician staff, and used electronic medical record changes to prompt clinicians. CONCLUSIONS: The quality of IBD care can be improved with diverse interventions that range from simple to complex. However, these interventions are not universally successful. Clinicians should emulate successful interventions and design new initiatives to narrow gaps in care quality.

Effect of Consent and Educational Adjuncts to Consent on Patient Perceptions About Colonoscopy.

BACKGROUND AND AIMS: Informed consent is a vital preprocedural step for endoscopy but there are substantial variations in its delivery. We therefore sought to assess a multifaceted intervention to improve the consent process. METHODS: Gastroenterologists at a tertiary center were educated on the recommended components of informed consent. Following this, 3 cohorts of patients undergoing colonoscopy were surveyed before and after consent. In one cohort, the effect of optimized verbal consent alone was assessed. In the second and third groups, the effects of the addition of either a handout or a video describing colonoscopy and its risks were evaluated. The primary outcomes were the changes between preconsent and postconsent survey responses regarding confidence in understanding the procedure's purpose, likelihood of adverse events, and levels of anxiety. RESULTS: In total, 240 patients were included with 79 to 81 patients per group. There were no significant differences among the groups' survey responses. Compared with patients receiving verbal consent alone, fewer patients in the handout and video groups increased their perceived risk of adverse events following consent, but this difference did not reach significance (P=0.08). Examining all groups together, anxiety levels changed significantly after consent (P=0.003), with 31% of patients reducing their anxiety level, 8% increasing it, and 62% having no change. CONCLUSIONS: The consent process appears to decrease patient anxiety about colonoscopy. When used in conjunction with a high-quality verbal consent, written or video educational adjuncts provided on the day of colonoscopy likely have no effect on patient perceptions.

Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett's esophagus: results from a US Multicenter Consortium.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) is an established treatment for dysplastic Barrett's esophagus (BE). Although short-term end points of ablation have been ascertained, there have been concerns about recurrence of intestinal metaplasia (IM) after ablation. We aimed to estimate the incidence and identify factors that predicted the recurrence of IM after successful RFA. METHODS: We analyzed data from 592 patients with BE treated with RFA from 2003 through 2011 at 3 tertiary referral centers. Complete remission of intestinal metaplasia (CRIM) was defined as eradication of IM (in esophageal and gastroesophageal junction biopsy specimens), documented by 2 consecutive endoscopies. Recurrence was defined as the presence of IM or dysplasia after CRIM in surveillance biopsies. Two experienced gastrointestinal pathologists confirmed pathology findings. RESULTS: Based on histology analysis, before RFA, 71% of patients had high-grade dysplasia or esophageal adenocarcinoma, 15% had low-grade dysplasia, and 14% had nondysplastic BE. Of patients treated, 448 (76%) were assessed after RFA. Fifty-five percent of patients underwent endoscopic mucosal resection before RFA. The median time to CRIM was 22 months, with 56% of patients in CRIM by 24 months. Increasing age and length of BE segment were associated with longer times to CRIM. Twenty-four months after CRIM, the incidence of recurrence was 33%; 22% of all recurrences observed were dysplastic BE. There were no demographic or endoscopic factors associated with recurrence. Complications developed in 6.5% of subjects treated with RFA; strictures were the most common complication. CONCLUSIONS: Of patients with BE treated by RFA, 56% were in complete remission after 24 months. However, 33% of these patients had disease recurrence within the next 2 years. Most recurrences were nondysplastic and endoscopically manageable, but continued surveillance after RFA is essential.

Positive correlation between endoscopist radiofrequency ablation volume and response rates in Barrett's esophagus.

BACKGROUND: Radiofrequency ablation (RFA) has become an accepted form of endoscopic treatment for Barrett's esophagus (BE), yet reported response rates are variable. There are no accepted quality measures for performing RFA, and provider-level characteristics may influence RFA outcomes. OBJECTIVE: To determine whether endoscopist RFA volume is associated with rates of complete remission of intestinal metaplasia (CRIM) after RFA in patients with BE. DESIGN: Retrospective analysis of longitudinal data. SETTING: Three tertiary-care medical centers. PATIENTS: Patients with BE treated with RFA. INTERVENTION RFA MAIN OUTCOME MEASUREMENTS: For each endoscopist, we recorded RFA volume, defined as the number of unique patients treated as well as corresponding CRIM rates. We calculated a Spearman correlation coefficient relating these 2 measures. RESULTS: We identified 417 patients with BE treated with RFA who had at least 1 post-RFA endoscopy with biopsies. A total of 73% of the cases had pretreatment histology of high-grade dysplasia or adenocarcinoma. The procedures were performed by 7 endoscopists, who had a median RFA volume of 62 patients (range 20-188). The overall CRIM rate was 75.3% (provider range 62%-88%). The correlation between endoscopist RFA volume and CRIM rate was strong and significant (rho = 0.85; P = .014). In multivariable analysis, higher RFA volume was significantly associated with CRIM (P for trend .04). LIMITATIONS: Referral setting may limit generalizability. Limited number of endoscopists analyzed. CONCLUSION: Endoscopist RFA volume correlates with rates of successful BE eradication. Further studies are required to confirm these findings and to determine whether RFA volume is a valid predictor of treatment outcomes in BE.

Visceral Adipose Tissue Volumetrics Inform Odds of Treatment Response and Risk of Subsequent Surgery in IBD Patients Starting Antitumor Necrosis Factor Therapy.

BACKGROUND: Data describing the effect of obesity on antitumor necrosis factor (anti-TNF) treatment response are inconsistent. Visceral adipose tissue (VAT) is a superior marker of adiposity to body mass index. However, its effect on treatment response is unclear. We aimed to evaluate the effect of VAT on anti-TNF treatment response. METHODS: Inflammatory bowel disease (IBD) patients starting anti-TNF agents between January 1, 2009, and July 31, 2019, were included. 3-dimensional measurements of VAT volume and visceral fat index (visceral:subcutaneous adipose tissue ratio; VFI) were obtained from computed tomography (CT) scans. Subjects were categorized by predefined volume cutoffs (<1500cm3, 1500-2999cm3, ≥3000cm3) and VFI (<0.33, 0.33-0.66, ≥0.67). Primary outcomes included a composite treatment response end point at 6 and 12 months. Secondary outcomes were surgery at 6 and 12 months. Multivariable logistic regression was used to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). RESULTS: The final cohort included 176 patients. No significant differences in treatment response at 6 months was observed. At 12 months, compared with volume <1500cm3, patients with volume 1500-2999cm3 had higher odds of response (aOR, 3.52; 95% CI, 1.16-10.71; P = .023), whereas volume ≥3000cm3 did not. Compared with VFI<0.33, VFI ≥0.67 had higher odds of surgery at 6 (aOR, 48.22; 95% CI, 4.73-491.57; P = .023) and 12 months (aOR, 20.94; 95% CI, 3.14-139.67; P = .004). Post hoc analysis suggested VAT may affect drug pharmacokinetics. CONCLUSIONS: We found VAT volume is associated with anti-TNF treatment response in a nondose dependent manner, and VFI may inform risk of surgery after anti-TNF initiation. If confirmed by prospective studies, VAT volumetrics are potentially useful biomarkers to inform IBD treatment decisions.

Visceral adipose tissue volume is associated with anti-TNF treatment response in a nondose response manner. Additionally, high visceral fat index is associated with significantly increased risk of early surgery after anti-TNF initiation.

Improved Healthcare Access Reduces Requirements for Surgery in Indigent IBD Patients Using Biologic Therapy: A 'Safety-Net' Hospital Experience.

Low socioeconomic status (SES) is associated with greater morbidity and increased healthcare resource utilization (HRU) in IBD. We examined whether a financial assistance program (FAP) to improve healthcare access affected outcomes and HRU in a cohort of indigent IBD patients requiring biologics. IBD patients (>18 years) receiving care at a 'safety-net' hospital who initiated biologics as outpatients between 1 January 2010 and 1 January 2019 were included. Patients were divided by FAP status. Patients without FAP had Medicare, Medicaid, or commercial insurance. Primary outcomes were steroid-free clinical remission at 6 and 12 months. Secondary outcomes were surgery, hospitalization, and ED utilization. Multivariate logistic regression was used to calculate odds ratio (OR) and 95% confidence interval (CI). Decision tree analysis (DTA) was also performed. We included 204 patients with 258 new biologic prescriptions. FAP patients had less complex Crohn's disease (50.7% vs. 70%, p = 0.033) than non-FAP patients. FAP records indicated fewer prior surgeries (19.6% vs. 38.4% p = 0.003). There were no statistically significant differences in remission rates, disease duration, or days between prescription and receipt of biologics. In multivariable logistic regression, adjusting for baseline demographics and disease severity variables, FAP patients were less likely to undergo surgery (OR: 0.28, 95% CI [0.08−0.91], p = 0.034). DTA suggests that imaging utilization may shed light on surgical differences. We found FAP enrollment was associated with fewer surgeries in a cohort of indigent IBD patients requiring biologics. Further studies are needed to identify interventions to address healthcare disparities in IBD.

Systematic Review With Meta-analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Disease.

Background: Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis to assess the safety and effectiveness of dual biologic therapy (DBT), or small molecule combined with a biologic therapy (SBT) in IBD patients. Methods: We searched MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and Clinical trials.gov until November 3, 2020, including studies with 2 or more IBD patients on DBT or SBT. Main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination. Effectiveness was reported as pooled rates of clinical, endoscopic, and/or radiographic response and remission. The certainty of evidence was rated according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Results: Of the 3688 publications identified, 13 studies (1 clinical trial, 12 observational studies) involving 266 patients on 7 different combinations were included. Median number of prior biologics ranged from 0 to 4, and median duration of follow-up was 16-68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-tumor necrosis factor (aTNF, n = 56) or tofacitinib (Tofa, n = 57), respectively. Pooled rates of SAE for these were 9.6% (95% confidence interval [CI], 1.5-21.4) for VDZ-aTNF and 1.0% (95% CI, 0.0-7.6) for Tofa-VDZ. The overall certainty of evidence was very low due to the observational nature of the studies, and very serious imprecision and inconsistency. Conclusions: DBT or SBT appears to be generally safe and may be effective in IBD patients, but the evidence is very uncertain.

Favorable Outcomes Combining Vedolizumab With Other Biologics or Tofacitinib for Treatment of Inflammatory Bowel Disease.

Background: Combining advanced therapies may improve outcomes in inflammatory bowel disease (IBD), but there are little data on the effectiveness and safety of this approach. Methods: We examined outcomes of patients who received vedolizumab in combination with another biologic or tofacitinib between 2016 and 2020. Results: Fourteen patients (10 ulcerative colitis [UC], 3 Crohn disease, 1 indeterminate colitis) received a combination of advanced therapies. Vedolizumab was combined with tofacitinib in 9 patients, ustekinumab in 3, and adalimumab in 2. Median follow-up on combination therapy was 31 weeks. Normalization of C-reactive protein (CRP) or fecal calprotectin (<5 mg/L and <150 µg/g, respectively) was achieved in 56% (5/9) and 50% (4/8) of patients. Paired median CRP decreased from 14 mg/L to <5 mg/L with combination therapy (n = 9, P = 0.02), and paired median calprotectin from 594 µg/g to 113 µg/g (n = 8, P = 0.12). Among patients with UC, paired median Lichtiger score decreased from 9 to 3 (n = 7, P = 0.02). Prednisone discontinuation was achieved in 67% (4/6) of prednisone-dependent patients. There were 4 infections: 2 required hospitalization (rotavirus, Clostridium difficile), and 2 did not (pneumonia, sinusitis). During follow-up, 5/14 patients discontinued combination therapy (2 nonresponse; 1 improvement and de-escalation; 1 noninfectious adverse effect; 1 loss of coverage). Conclusions: In this retrospective case series of a cohort with refractory IBD, combining vedolizumab with other biologics or tofacitinib improved inflammatory markers, reduced clinical disease activity and steroid use, and was well tolerated.

Inpatient Management of Acute Severe Ulcerative Colitis.

Acute severe ulcerative colitis (ASUC) is a potentially life-threatening presentation of ulcerative colitis that in nearly all cases requires inpatient management and coordinated care from hospitalists, gastroenterologists, and surgeons. Even with ideal care, a substantial proportion of patients will ultimately require colectomy, but most patients can avoid surgery with intravenous corticosteroid treatment and if needed, appropriate rescue therapy with infliximab or cyclosporine. In-hospital management requires not only therapies to reduce the inflammation at the heart of the disease process, but also to avoid complications of the disease and its treatment. Care for ASUC must be anticipatory, with patient education and evaluation starting at the time of admission in advance of the possible need for urgent medical or surgical rescue therapy. Here we outline a general approach to the treatment of patients hospitalized with ASUC, highlighting the common pitfalls and critical points in management.

Complication rates of trainee- versus attending-performed upper gastrointestinal endoscopy.

BACKGROUND: Although esophagogastroduodenoscopy (EGD) is usually the first procedure trainees learn, it is not known whether the involvement of a trainee affects the procedure's complication rate, a key quality and safety indicator. The purpose of this study was to determine whether the complication rate of fellow-performed upper endoscopy differs from that of attending gastroenterologists, and whether that difference varies with the level of training. METHODS: Emergency room visits within 14 days of an outpatient EGD deemed to be probably or definitely related to the EGD were categorized as complications. Complication rates were calculated for attending- and trainee-performed gastrointestinal endoscopies, the latter stratified by level of training. RESULTS: Forty-five attendings and 43 fellows performed 21,899 EGDs during the study period. There were 43 complications (1.96 per 1000 EGDs). Procedures performed by any fellow were more likely to have a complication than those performed by an attending (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.17-4.6). This difference was driven by a higher rate of complications among fellows who had completed general gastroenterology training and were in advanced training (OR 3.8, 95%CI 1.76-8.04); all of these complications involved trainees in interventional endoscopy. Fellows in any year of general gastroenterology training were not more likely to cause complications than attendings. CONCLUSIONS: The rate of complications from EGDs performed by fellows in their general gastroenterology training does not differ from that of attending endoscopists. The complication rate of advanced trainees exceeded that of attendings, but this is likely to be attributable to the higher-risk interventions undertaken by fellows in interventional endoscopy.

Short-Term Use of Upadacitinib in Combination With Biologic Therapy for Inducing Clinical Remission in Patients With Active Inflammatory Bowel Disease.

We report that upadacitinib intended for short-term use in combination with biologic therapy appeared to be effective in inducing steroid-free clinical remission in patients with active inflammatory bowel disease, but a substantial proportion of patients required extended use.

Automated Clinical Pathway Utilizing Custom Risk Stratification Identifies Substantial Rates of Overdue Follow-up Among Patients With Inflammatory Bowel Disease and Facilitates Population Health Interventions.

We describe the development and implementation of a dynamic clinical pathway, the IBD CarePath, integrated into the electronic health record that applies custom risk stratification to identify patients with IBD who are overdue for clinical follow-up.

Predictors Of Treatment Failure After Radiofrequency Ablation For Intramucosal Adenocarcinoma in Barrett Esophagus: A Multi-institutional Retrospective Cohort Study.

Radiofrequency ablation (RFA), with or without endoscopic mucosal resection (EMR), is a safe, effective, and durable treatment option for Barrett esophagus (BE)-associated dysplasia (DYS), but few studies have identified predictors of treatment failure in BE-associated intramucosal adenocarcinoma (IMC). The aim of this study was to determine the rate of IMC eradication when using RFA±EMR and to identify clinical and pathologic predictors of treatment failure. A retrospective review of medical records and a central review of index histologic parameters were performed for 78 patients who underwent RFA±EMR as the primary treatment for biopsy-proven IMC at 4 academic tertiary medical centers. Complete eradication (CE) (absence of IMC/DYS on first follow-up endoscopy) was achieved in 86% of patients, and durable eradication (DE) (CE with no recurrence of IMC/DYS until last follow-up) was achieved in 78% of patients, with significant variation between the 4 study sites (P=0.03 and 0.09 by analysis of variance for DE and CE, respectively). Use of EMR before RFA significantly reduced the risk for treatment failure for IMC/DYS (hazard ratio, 0.15; 95% confidence interval, 0.05-0.48; P=0.001), whereas IMC involving ≥50% of the columnar metaplastic area on index examination significantly increased the risk for treatment failure (hazard ratio, 4.24; 95% confidence interval, 1.53-11.7; P=0.005). Endoscopic and pathologic factors associated with treatment failure in BE-associated IMC treated with RFA±EMR may help identify the subset of IMC patients for whom a more aggressive initial approach may be justified.