BACKGROUND: A treat-to-target strategy for inflammatory bowel disease (IBD) recommends iterative treatment adjustments to achieve clinical and endoscopic remission. In asymptomatic patients with ongoing endoscopic activity, the risk/benefit balance of this approach is unclear, particularly with prior exposure to advanced therapies. METHODS: Using the RAND/University of California Los Angeles Appropriateness Method, 9 IBD specialists rated appropriateness of changing therapy in 126 scenarios of asymptomatic patients with ulcerative colitis and Crohn's disease and active endoscopic disease. Disease extent and behavior, prior treatment, prior complications, and recent disease progression were considered, as were factors that might influence decision-making, including age and pregnancy. Ratings were collected through anonymous survey, discussed at an in-person meeting, and finalized in a second anonymous survey. RESULTS: Panelists rated change in therapy as appropriate (i.e., expected benefit sufficiently outweighs potential harms from continuing therapy) in 96/126 scenarios, generally in patients with progressive, complicated, and/or extensive disease, while changing therapy was rated uncertain in 27 scenarios of mild and/or stable disease. Changing therapy was rated inappropriate in ulcerative colitis patients with mild and stable disease previously exposed to ≥3 therapies or with improved endoscopic activity, and in Crohn's disease patients with only scattered aphthous ulcers. The validated threshold for disagreement was not crossed for any scenario. Patient age older than 65 years and a plan for pregnancy in the next year might influence decision-making in some settings. DISCUSSION: Appropriateness ratings can help guide clinical decision-making about changing therapy to achieve endoscopic remission in asymptomatic patients with IBD until data from ongoing randomized studies are available.

Lay Summary The use of digital behavioral interventions was tested among patients with inflammatory bowel disease with a predominately low-income, Black/Hispanic background who had elevated symptoms of anxiety/depression. Both mood-tracking and cognitive behavioral self-management applications were feasible and acceptable to use, with opportunities for improvement identified.

Abstract Background The treat-to-target strategy for inflammatory bowel disease (IBD) recommends optimising or changing therapy in patients who have not achieved clinical remission and endoscopic healing. In asymptomatic patients, the potential benefit of changing therapy to achieve endoscopic healing is less clear, particularly since <40% typically achieve endoscopic healing with current therapy. We sought to define appropriateness of changing therapy in asymptomatic IBD patients with active endoscopic inflammation. Methods Using the RAND/UCLA Appropriateness Method, a panel of 9 IBD specialists considered appropriateness of changing therapy in 16 scenarios of patients with ulcerative colitis (UC) and 96 scenarios of Crohn’s disease (CD), rated on a 9-point Likert scale as inappropriate (1-3), uncertain (4-6), or appropriate (7-9). Patients in all scenarios were asymptomatic with active endoscopic disease; variables included disease extent, behaviour, prior treatment, recent disease progression, and prior disease complications. Current therapy was assumed to be optimised, so the only options were changing therapy or continuing current therapy. An additional 14 scenarios explored patient factors that might influence treatment decision-making. Ratings were collected via online anonymous survey, discussed at an in-person meeting, then finalised in a second anonymous survey using a modified Delphi approach. Disagreement was assessed using a validated index. Results Panelists rated it appropriate to change therapy (i.e., expected benefit sufficiently exceeds expected negative consequences) in 96/126 scenarios, generally those with progressive, complicated, and/or extensive disease; 27 scenarios of mild and/or stable disease were rated uncertain, particularly with prior exposure to ≥3 drug classes. Changing therapy in asymptomatic patients was rated inappropriate in 3 scenarios: in Mayo 1 UC previously treated with ≥3 therapy classes with no endoscopic progression in the last year; in any patient who showed endoscopic improvement over the last year; and in any patient with CD who had only scattered aphthous ulcers. Patient age >65 years influenced a decision to change therapy specifically for anti-TNFs and JAK inhibitors; the possibility of pregnancy also influenced decision-making. Despite variability in ratings, the threshold for disagreement was not crossed for any scenario. Conclusion Our panel of IBD specialists rated appropriateness of changing therapy to achieve endoscopic healing in asymptomatic patients with UC and CD in a variety of scenarios. Our findings can be used to help guide clinical decision-making in this population until data from ongoing randomised studies are available (NCT05230173).

Abstract INTRODUCTION Social determinants of health (SDOH) factors such as insurance status, race, ethnicity, and socioeconomic status have been associated with clinical outcomes in ulcerative colitis (UC). We assessed the impact of demographic, clinical, and SDOH factors on advanced therapy medication adherence and persistence in patients (pts) with UC. METHODS Pts with UC who initiated an advanced therapy (Janus kinase inhibitor, sphingosine-1-phosphate receptor agonist, or biologic) were identified using Commercial and Medicaid Managed Care (MMC) claims data from the MORE2 Registry (2017–2022) and Medicare Fee-for-Service (FFS) (2017–2021) claims. Community-level SDOH variables were linked using pt ZIP codes at index date (first advanced UC therapy prescription date from May 01, 2018 up to Jun 30, 2021). Adherence (proportion of days covered [PDC]) and persistence (duration) of treatment were assessed for 1 year post-index. Logistic regression analyses evaluated the associations between demographic, clinical, and SDOH factors and adherence/persistence. RESULTS The number of pts included in the Medicare FFS, Commercial, and MMC plan types were 9,158, 6,706, and 3,170, respectively. Mean PDC were 69%, 72%, and 64% (Fig. a), respectively, and the corresponding proportions of pts with 1-year persistence were 53%, 43%, and 31%, respectively (Fig. b). PDC by percentile is shown in Fig. c. Female pts had lower odds of adherence vs male pts in the Medicare FFS plan only (odds ratio [OR] 0.89; Table). A higher Charlson Comorbidity Index Score was associated with lower odds of adherence in the Medicare FFS and Commercial plans only (OR for both: 0.94; Table). In the 1 year post-index period, a corticosteroid prescription was associated with lower odds of adherence across plan types (OR 0.57–0.66; Table); a 5-aminosalicylic acid prescription was associated with higher odds of adherence in the Medicare FFS and Commercial plans only (OR 1.12–1.15; Table). A mental health condition diagnosis in the 1 year prior to and post-index was associated with lower adherence vs those without among pts with Medicare FFS and Commercial coverage (OR 0.85–0.87; Table). Community-level SDOH variables assessed had no association with adherence (Table); persistence model results were similar (data not shown). CONCLUSION For pts initiating an advanced therapy, there are still unmet treatment needs as demonstrated by mean PDC <80% and full persistence ≤53% across plan types. Adherence and persistence were lower among pts on MMC vs Medicare FFS or Commercial plans. The impact of demographic variables on adherence varied depending on plan type. Higher comorbidity burden, mental health diagnosis, and concomitant steroid use were generally associated with lower adherence to advanced UC therapies. Community-level SDOH variables were not associated with adherence in these populations.

BACKGROUND:Patients with ulcerative colitis (UC) often report impaired health-related quality of life (HRQoL). Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of UC. In addition to previous demonstrations of improved clinical measures (e.g., Mayo score), tofacitinib has been shown to improve HRQoL in patients with UC. This analysis explored the interrelationships among tofacitinib treatment, HRQoL, and disease activity (measured using Mayo subscores) using mediation modeling.METHODS:Data were collected from two 8-week induction studies (OCTAVE Induction 1 and 2) in patients with moderate to severe UC treated with tofacitinib or placebo. Two mediation models were specified. First, Mayo subscores were mediators between the binary treatment variable (tofacitinib vs. placebo) and the eight Short Form-36 Health Survey (SF-36) domain scores as outcomes. Second, the four Inflammatory Bowel Disease Questionnaire (IBDQ) domain scores served as outcomes. Both models used data collected at week 8.RESULTS:Overall, 1,073 and 1,079 patients were included in the SF-36- and IBDQ-based models, respectively. For all SF-36 domains, improvements in Mayo subscores were estimated to explain 65.6% (bodily pain) to 92.9% (mental health) of the total treatment effect on SF-36 domain scores (all p < 0.05). For all IBDQ domains, improvements in Mayo subscores explained 71.6% (systemic symptoms) to 84.7% (emotional function) of the total treatment effect (all p < 0.05).CONCLUSION:Mayo scores and Mayo subscores are significant but incomplete contributors to tofacitinib's effect on HRQoL in patients with moderate to severe UC.CLINICALTRIALS:gov: NCT01465763; NCT01458951.

Background: Waning levels of anti-SARS-CoV-2 Spike (S) antibodies, particularly neutralizing, are associated with the risk of breakthrough infections.The impact of immunosuppression on antibody decay kinetics is unclear.We have previously reported a strong correlation between total anti-S antibodies and neutralization titers.Here, we report the decay kinetics in anti-S IgG antibodies across various immunosuppressive medications used in patients with CID.Methods: We recruited a volunteer sample of adults with confirmed CID eligible for SARS-CoV-2 vaccination in a prospective observational cohort study at two United States CID referral centers.All study participants received two doses of mRNA vaccine to SARS-CoV-2.To assess the durability of immunogenicity, anti-S IgG were measured at 7 (visit 3), 90 (visit 5), and 120 (visit 6) days after the 2nd dose of mRNA vaccine.The impact of various medications was assessed in repeated measures mixed model with the patient as a random effect, adjusting for gender and age, and using the group of patients on sulfasalazine, NSAIDs, or on no medications as a reference, using STATA.The half-life of anti-S IgG for a 50 percent reduction in titers at visit 3 was calculated for each medication class.Results: A total of 316 CID patients were recruited of which 148 (46.8%) had inflammatory bowel disease (IBD).Durability was assessed in 495 samples obtained in 293 patients.The arithmetic mean of anti-S IgG antibodies for each medication class at visits 3, 5, and 6 is shown in Figure 1.Overall, a 2-fold reduction in titers was observed from 7 to 90 days and 90 to 120 days (Table 1).The strongest decline was observed among patients on B cell depleting/ modulating therapies followed by those on combinations of biologics and/or small molecules and antimetabolites (methotrexate, leflunomide, thiopurines, mycophenolate mofetil, and teriflunomide).There was modest decline seen with TNFi (half-life 430.5 days, -2.15, 95% CI -4.31 to -1.07, p = 0.03).There was also a modest, but not significant, decline seen with Janus Kinase inhibitor (JAKi).No decline was seen with anti-IL-23 or anti-integrin medication classes.Conclusions: Antibody decay in patients with CID is not observed in patients on anti-integrins or anti-IL-23 while it is seen among patients on TNFi, JAKi, antimetabolites, and combinations of biologics and/or small molecules.Our data and those from other cohorts may be used to prioritize medication classes for boosting immunogenicity with additional doses of vaccination against SARS-CoV-2.Collection of antibody titers after booster doses is currently ongoing.

Background: Several SARS-CoV-2 vaccines are highly effective in preventing most infections, serious disease, hospitalization, and death from COVID-19 in the general population, but data regarding their use and efficacy in patients with inflammatory bowel disease (IBD) are limited.In this study we assessed the use patterns and efficacy of SARS-CoV-2 vaccines in patients with IBD.Methods: We established a multicenter matched case-control cohort of patients with IBD [Crohn's disease (CD), ulcerative colitis (UC)] and COVID-19 between February 2020 and December 2020 for the Surveillance of COVID-19 Impact on Long-Term Outcomes in IBD (SCOUT IBD) study.Cases were defined by the presence of COVID-19-related symptoms and confirmatory SARS-CoV-2 PCR or IgG testing and non-COVID controls were defined as absence of symptoms and both a negative PCR and IgG in 2020.Cases were matched 1:1 to controls based on age, sex and IBD type.Data were collected on vaccine administration in 2021 and incidence of interval COVID-19 (defined as above) between January and September 2021.Results: The total cohort included 502 patients with IBD [UC (n=222, 44%), CD (n=278, 55%), IBD-undefined (n=2, 1%)] of whom 251 had a history of COVID-19 in 2020.The overall vaccination rate was 61% (n=306) with 189

Background Observational studies have described racial differences in inflammatory bowel disease (IBD) genetics, clinical manifestations, and outcomes. Whether race impacts response to biologics in IBD is unclear. We conducted a post hoc analysis of phase 2 and 3 randomized clinical trials in ulcerative colitis to evaluate the effect of race on response to golimumab. Methods We analyzed pooled individual-level data from induction and maintenance trials of golimumab through the Yale Open Data Access Project. The primary outcome was clinical response. Secondary outcomes were clinical remission and endoscopic healing. Multivariable logistic regression was performed comparing White vs racial minority groups (Asian, Black, or other race), adjusting for potential confounders. Results There were 1006 participants in the induction (18% racial minority) and 783 participants in the maintenance (17% racial minority) trials. Compared with White participants, participants from racial minority groups had significantly lower clinical response (adjusted odds ratio [aOR], 0.43; 95% confidence interval [CI], 0.28-0.66), clinical remission (aOR, 0.41; 95% CI, 0.22-0.77), and endoscopic healing (aOR, 0.48; 95% CI, 0.31-0.74) at week 6. Participants from racial minority groups also had significantly lower clinical remission (aOR, 0.46; 95% CI, 0.28-0.74) and endoscopic healing (aOR, 0.63; 95% CI, 0.41-0.96) at week 30. There were no racial differences in placebo response rates. Conclusions Ulcerative colitis participants from racial minority groups were less likely to achieve clinical response, clinical remission, and endoscopic healing with golimumab compared with White participants in induction and maintenance trials. Further studies are needed to understand the impact of race on therapeutic response in IBD.

BACKGROUNDIndividuals with inflammatory bowel disease (IBD) have elevated symptoms of anxiety and depression. The burden of such symptoms, accompanied by functional impairment in IBD, is not well documented, nor is utilization of mental health care in this population.METHODSAdults ≥18 years were identified in the cross-sectional 2015-2016 National Health Interview Survey. Responses from the Kessler Index were used to estimate the national prevalence of psychological distress with impairment and mental health-care use in IBD. Factors associated with psychological distress with impairment in IBD were analyzed using logistic regression.RESULTSThe prevalence of psychological distress with impairment was significantly higher in IBD than non-IBD adults (7.69% vs. 3.50%, respectively; P < .01). Among those with IBD and psychological distress with impairment, only a third (36.29%) had seen or talked to a mental health provider in the preceding 12 months. About half of these found the cost of mental health care unaffordable. On multivariable analysis, factors associated with psychological distress in IBD included increasing emergency room visits and trouble finding a health provider.CONCLUSIONSA significant number of adults with IBD in the United States have psychological distress accompanied by functional impairment. However, mental health care is underutilized in this population. Many of these individuals find the cost of mental health care unaffordable, struggle to find a health provider, and experience repeated emergency room visits. Ongoing efforts to improve mental health care in IBD should address issues of access and cost. Additionally, these efforts should seek to understand other barriers to mental health-care use.

Tumor suppressor p53 is a transcription factor that transactivates a wide range of genes, including those in DNA repair, cell cycle arrest, apoptosis and its own degradation. To estimate the role of selectivity in binding to its promoters, we measured the binding affinities of a tetrameric p53 construct (p53CT) in vitro with 20 of its recognition elements from a variety of representative genes. The binding of full length p53 to four representative sequences exactly paralleled the affinities to p53CT. The binding of p53 to different recognition elements was co-operative and the affinities varied by up to 50-fold. p53 bound with high affinity to the recognition elements of all the genes involved in cell cycle arrest and some of the genes in apoptosis. All of the lower affinity-binding sites were in genes involved in apoptosis. Our quantitative-binding data were in agreement with published cell-based assays. The regulation of p53 activity is in part determined through the specificity of its DNA-binding interactions.

Background and Aims The treatment of chronic pouchitis remains a challenge due to the paucity of high-quality studies. We aimed to provide guidance for clinicians on the appropriateness of medical and surgical treatments in chronic pouchitis. Methods Appropriateness of medical and surgical treatments in patients with chronic pouchitis was considered in 16 scenarios incorporating presence/absence of four variables: pouchitis symptoms, response to antibiotics, significant prepouch ileitis, and Crohn's disease (CD)-like complications (i.e., stricture or fistula). Appropriateness of permanent ileostomy in patients refractory to medical treatments was considered in eight additional scenarios. Using the RAND/UCLA appropriateness method, international IBD expert panelists rated appropriateness of treatments in each scenario on a 1-9 scale. Results Chronic antibiotic therapy was rated appropriate only in asymptomatic antibiotic-dependent patients with no CD-like complications and inappropriate in all other scenarios. Ileal-release budesonide was rated appropriate in 6/16 scenarios including patients with significant prepouch ileitis but no CD-like complications. Probiotics were considered either inappropriate (14/16) or uncertain (2/16). Biologic therapy was considered appropriate in most scenarios (14/16) and uncertain in situations where significant prepouch ileitis or CD-like complications were absent (2/16). In patients who are refractory to all medications, permanent ileostomy was considered appropriate in all scenarios (7/8) except in asymptomatic patients with no CD-like complications. Conclusions In the presence of significant prepouch ileitis or CD-like complications, chronic antibiotics and probiotics are inappropriate. Biologics are appropriate in all patients except in asymptomatic patients with no evidence of complications. Permanent ileostomy is appropriate in most medically refractory patients.

INTRODUCTION: We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD). METHODS: This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation. RESULTS: A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49–0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48–0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients. DISCUSSION: UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response.