Baseline serum and stool microbiome biomarkers predict clinical efficacy and tissue molecular response after ritlecitinib induction therapy in ulcerative colitis.

BACKGROUND AND AIMS: Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, was well- tolerated and efficacious in the phase 2b VIBRATO study in participants with moderate-to-severe ulcerative colitis (UC). The aim of this study was to identify baseline serum and microbiome markers that predict subsequent clinical efficacy and to develop noninvasive serum signatures as potential real-time noninvasive surrogates of clinical efficacy after ritlecitinib. METHODS: Tissue and peripheral blood proteomics, transcriptomics, and fecal metagenomics were performed on samples before and after 8-week oral ritlecitinib induction therapy (20 mg, 70 mg, 200 mg, or placebo once daily, N=39, 41, 33, and 18, respectively). Linear mixed models were used to identify baseline and longitudinal protein markers associated with efficacy. The combined predictivity of these proteins was evaluated using a logistic model with permuted efficacy data. Differential expression of fecal metagenomic was used to differentiate responders and nonresponders. RESULTS: Peripheral blood serum proteomics identified 4 baseline serum markers (LTA, CCL21, HLA-E, MEGF10) predictive of modified clinical remission (MR), endoscopic improvement (EI), histologic remission (HR), and integrative score of tissue molecular improvement. In responders, 37 serum proteins significantly changed at Week 8 compared with baseline (FDR<0.05); of these, changes in 4 (IL4R, TNFRSF4, SPINK4, and LAIR-1) predicted concurrent EI and HR responses. Fecal metagenomics analysis revealed baseline and treatment response signatures that correlated with EI, MR, and tissue molecular improvement. CONCLUSIONS: Blood and microbiome biomarkers stratify endoscopic, histologic, and tissue molecular response to ritlecitinib, which may help guide future precision medicine approaches to UC treatment.

Oral Ritlecitinib and Brepocitinib for Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2b Study.

BACKGROUND & AIMS: The efficacy and safety of ritlecitinib (oral JAK3/TEC family kinase inhibitor) and brepocitinib (oral TYK2/JAK1 inhibitor) as induction therapy were assessed in patients with active, moderate-to-severe ulcerative colitis. METHODS: This phase 2b, parallel-arm, double-blind umbrella study randomized patients with moderate-to-severe ulcerative colitis to receive 8-week induction therapy with ritlecitinib (20, 70, 200 mg), brepocitinib (10, 30, 60 mg), or placebo once daily. The primary endpoint was total Mayo Score (TMS) at week 8. RESULTS: Of 319 randomized patients, 317 received ritlecitinib (n = 150), brepocitinib (n = 142), or placebo (n = 25). The placebo-adjusted mean TMSs (90% confidence interval) at week 8 were -2.0 (-3.2 to -0.9), -3.9 (-5.0 to -2.7), and -4.6 (-5.8 to -3.5) for ritlecitinib 20, 70, and 200 mg, respectively (P = .003, P < .001, P < .001), and -1.8 (-2.9 to -0.7), -2.3 (-3.4 to -1.1), and -3.2 (-4.3 to -2.1) for brepocitinib 10, 30, and 60 mg, respectively (P = .009, P = .001, P < .001). Estimates (90% confidence interval) for placebo-adjusted proportions of patients with modified clinical remission at week 8 were 13.7% (0.5%-24.2%), 32.7% (20.2%-45.3%), and 36.0% (23.6%-48.6%) for ritlecitinib 20, 70, and 200 mg, respectively, and 14.6% (1.9%-25.7%), 25.5% (11.0%-38.1%), and 25.5% (11.0%-38.1%) for brepocitinib 10, 30, and 60 mg, respectively. Adverse events were mostly mild, and there were no serious cases of herpes zoster infection. Infections were observed with brepocitinib (16.9% [12.5%-23.7%]), ritlecitinib (8.7% [5.2%-13.4%]), and placebo (4.0% [0.2%-17.6%]). One death due to myocardial infarction (ritlecitinib) and 1 thromboembolic event (brepocitinib) occurred; both were considered unrelated to study drug. CONCLUSIONS: Ritlecitinib and brepocitinib induction therapies were more effective than placebo for the treatment of moderate-to-severe active ulcerative colitis, with an acceptable short-term safety profile. CLINICALTRIALS: gov number: NCT02958865.

Deprescription of aspirin for primary prevention is uncommon at discharge in hospitalised patients with gastrointestinal bleeding.

BACKGROUND: Guidelines recommend against aspirin for primary prevention of cardiovascular events in individuals with a history of gastrointestinal bleeding (GIB). It is unknown how often patients on primary prevention aspirin hospitalised with GIB have aspirin discontinued at discharge. AIMS: To determine the rate of aspirin deprescription and explore long-term outcomes in patients taking aspirin for primary prevention of cardiovascular events. METHODS: We evaluated all patients hospitalised at Yale-New Haven Hospital between January 2014 and October 2021 with GIB who were on aspirin for primary prevention. Our primary endpoint was the frequency of aspirin deprescription at discharge. Our secondary endpoints were post-discharge hospitalisations for major adverse cardiovascular events (MACE) or GIB. Time-to-event analysis was performed using Kaplan-Meier curves and the log-rank test. RESULTS: We identified 320 patients with GIB on aspirin for primary prevention: median age was 72 (interquartile range [IQR] 61-81) years and 297 (92.8%) were on aspirin 81 mg daily. Only 25 (9.0%) patients surviving their hospitalisation were deprescribed aspirin at discharge. Among 260 patients with follow-up (median 1103 days; IQR 367-1670), MACE developed post-discharge in 2/25 (8.0%) with aspirin deprescription versus 37/235 (15.7%) with aspirin continuation (log-rank p = 0.28). 0/25 patients with aspirin deprescription had subsequent hospitalisation for GIB versus 17/235 (7.2%) who continued aspirin (log-rank p = 0.13). CONCLUSIONS: Aspirin for primary cardiovascular prevention was rarely deprescribed at discharge in patients hospitalised with GIB. Processes designed to ensure appropriate deprescription of aspirin are crucial to improve adherence to guidelines, thereby improving the risk-benefit ratio in patients at high risk of subsequent GIB hospitalisations with minimal increased risk of MACE.

A shared tissue transcriptome signature and pathways in psoriasis and ulcerative colitis.

Despite multiple efficacious therapies in common between psoriasis (PS) and Ulcerative Colitis (UC), mechanisms underlying their common pathophysiology remain largely unclear. Here we sought to establish a link by evaluating expression differences and pathway alterations in diseased tissues. We identified two sets of differentially expressed genes (DEGs) between lesional and nonlesional tissues in meta-analyses of data collected from baseline samples in 3 UC and then 3 PS available clinical studies from Pfizer. A shared gene signature was defined by 190 DEGs common to both diseases. Commonly dysregulated pathways identified via enrichment analysis include interferon signaling, partly driven by genes IFI6, CXCL9, CXCL10 and CXCL11, which may attract chemotaxis of Th1 cells to inflammatory sites; IL-23 pathway (IL-23A, CCL20, PI3, CXCL1, LCN2); and Th17 pathway except IL-17A. Elevated expression of costimulatory molecules ICOS and CTLA4 suggests ongoing T-cell activation in both diseases. The clinical value of the shared signature is demonstrated by a gene set improvement score reflecting post-treatment molecular improvement for each disease. This is the first study using transcriptomic meta-analysis to define a tissue gene signature and pathways dysregulated in both PS and UC. These findings suggest immune mechanisms may initiate and sustain inflammation similarly in the two diseases.

Increased Mortality in Patients Undergoing Inpatient Endoscopy During the Early COVID-19 Pandemic.

BACKGROUND AND AIMS: The Coronavirus disease 2019 (COVID-19) pandemic led to the restructuring of most healthcare systems, but the impact on patients undergoing inpatient endoscopic procedures is unknown. We sought to identify factors associated with 30-day mortality among patients undergoing inpatient endoscopy before and during the first wave of the pandemic within an academic tertiary care center. METHODS: We studied patients who underwent inpatient endoscopic procedures from March 1-May 31 in 2020 (COVID-19 era), the peak of the pandemic's first wave across the care center studied, and in March 1-May 31, 2018 and 2019 (control). Patient demographics and hospitalization/procedure data were compared between groups. Cox regression analyses were conducted to identify factors associated with 30-day mortality. RESULTS: Inpatient endoscopy volume decreased in 2020 with a higher proportion of urgent procedures, increased proportion of patients receiving blood transfusions, and a 10.1% mortality rate. In 2020, male gender, further distance from hospital, need for intensive care unit (ICU) admission, and procedures conducted outside the endoscopy suite were associated with increased risk of 30-day mortality. CONCLUSIONS: Patients undergoing endoscopy during the pandemic had higher proportions of ICU admission, more urgent indications, and higher rates of 30-day mortality. Greater proportions of urgent endoscopy cases may be due to hospital restructuring or patient reluctance to seek hospital care during a pandemic. Demographic and procedural characteristics associated with higher mortality risk may be potential areas to improve outcomes during future pandemic hospital restructuring efforts.

Antitumor Necrosis Factor-like Ligand 1A Therapy Targets Tissue Inflammation and Fibrosis Pathways and Reduces Gut Pathobionts in Ulcerative Colitis.

BACKGROUND: The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. METHODS: Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. RESULTS: Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. CONCLUSIONS: The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.

A Qualitative Investigation Into Faith and LGBTQ Identities in a Nonclinical Sample of Readers of the Dear Abby Column: The Dear Abby Project.

ABSTRACT: To better understand the relationship between faith and LGBTQ+ identity, we conducted a qualitative analysis of 86 respondents to a general question posed through the Dear Abby column. Responses were anonymized and analyzed using a grounded theory approach. Analysis revealed six themes, reflecting a diversity of lived experience from community rejection to acceptance, and self-rejection to feelings of acceptance by God. Despite frequent media portrayals of conflict between faith and LGBTQ+ identity, the reality is more complex, and faith and LGBTQ+ identity development can be complementary.

Impact of COVID-19 on gastroenterology fellowship training: a multicenter analysis of endoscopy volumes.

Background and study aims The COVID-19 pandemic has had a profound impact on gastroenterology training programs. We aimed to objectively evaluate procedural training volume and impact of COVID-19 on gastroenterology fellowship programs in the United States. Methods This was a retrospective, multicenter study. Procedure volume data on upper and lower endoscopies performed by gastroenterology fellows was abstracted directly from the electronic medical record. The study period was stratified into 2 time periods: Study Period 1, SP1 (03/15/2020 to 06/30/2020) and Study Period 2, SP2 (07/01/2020 to 12/15/2020). Procedure volumes during SP1 and SP2 were compared to Historic Period 1 (HP1) (03/15/2019 to 06/30/2019) and Historic Period 2 (HP2) (07/01/2019 to 12/15/2019) as historical reference. Results Data from 23 gastroenterology fellowship programs (total procedures = 127,958) with a median of 284 fellows (range 273-289; representing 17.8 % of all trainees in the United States) were collected. Compared to HP1, fellows performed 53.6 % less procedures in SP1 (total volume: 28,808 vs 13,378; mean 105.52 ±â€Š71.94 vs 47.61 ±â€Š41.43 per fellow; P  < 0.0001). This reduction was significant across all three training years and for both lower and upper endoscopies ( P  < 0.0001). However, the reduction in volume was more pronounced for lower endoscopy compared to upper endoscopy [59.03 % (95 % CI: 58.2-59.86) vs 48.75 % (95 % CI: 47.96-49.54); P  < 0.0001]. The procedure volume in SP2 returned to near baseline of HP2 (total volume: 42,497 vs 43,275; mean 147.05 ±â€Š96.36 vs 150.78 ±â€Š99.67; P  = 0.65). Conclusions Although there was a significant reduction in fellows' endoscopy volume in the initial stages of the pandemic, adaptive mechanisms have resulted in a return of procedure volume to near baseline without ongoing impact on endoscopy training.

Immune Checkpoint Inhibitor-associated Diarrhea and Colitis: A Systematic Review and Meta-analysis of Observational Studies.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed the management of advanced malignancies but are associated with diarrhea and colitis. The objective of our systematic review and meta-analysis was to determine the incidence and outcomes of ICI-associated diarrhea and colitis. Bibliographic databases were searched through August 13, 2019, for observational studies of ICI therapy reporting the incidence and/or treatment of diarrhea or colitis. The primary outcome was ICI-associated diarrhea and colitis. Meta-analyses were performed with random-effects models. Twenty-five studies (N=12,661) were included. All studies had a high risk of bias in at least 1 domain. The overall incidence of diarrhea/colitis was 12.8% [95% confidence interval (CI), 8.8-18.2, I2=96.5]. The incidence was lower in patients treated with anti-programmed cell death 1/programmed death-ligand 1 (4.1%, 95% CI, 2.6-6.5) than in those treated with anti-cytotoxic T-cell lymphocyte-associated antigen 4 (20.1%, 95% CI, 15.9-25.1). The remission of diarrhea and/or colitis was higher in patients treated with corticosteroids plus biologics (88.4%, 95% CI, 79.4-93.8) than in those treated with corticosteroids alone (58.3%, 95% CI, 49.3-66.7, Q=18.7, P<0.001). ICI were permanently discontinued in 48.1% of patients (95% CI, 17.8-79.1). ICI were restarted after temporary interruption in 48.6% of patients (95% CI, 18.2-79.4) of whom 17.0% (95% CI, 6.4-30.0) experienced recurrence. Real-world incidence of ICI-associated diarrhea/colitis exceeds 10%. These events lead to permanent ICI discontinuation in just over 50% of patients, while <20% have recurrence of symptoms if ICI are resumed. Further studies are needed to identify patients who would benefit from early treatment with biologics as well as appropriate patients to resume ICI therapy.

Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study.

BACKGROUND & AIMS: An immune component of inflammatory bowel disease is up-regulated tumor necrosis factor-like ligand 1A (TL1A). Anti-TL1A antibodies such as PF-06480605, a fully human immunoglobulin G1 monoclonal antibody, may have therapeutic potential. METHODS: This Phase 2a, multicenter, single-arm, open-label study (TUSCANY) evaluated safety, tolerability, efficacy, pharmacokinetics, and immunogenicity in PF-06480605-treated participants with moderate to severe ulcerative colitis (UC). Participants received 500 mg intravenous PF-06480605 every 2 weeks, 7 doses total, with a 3-month follow-up period. Primary safety and efficacy endpoints were the incidence of adverse events (AEs) and week 14 endoscopic improvement (EI) (Mayo endoscopic subscore = 0 or 1), respectively. Secondary endpoints included total soluble TL1A (free/drug-bound) (sTL1A), incidence of anti-drug and neutralizing antibodies, PF-06480605 concentrations, and changes in fecal calprotectin and high-sensitivity C-reactive protein. Histology was assessed at week 14. RESULTS: The study enrolled 50 participants; 42 completed. Of 109 treatment-emergent AEs, 18 were treatment-related. The most common AEs were UC disease exacerbation and arthralgia (6 participants each). Four serious AEs, no deaths, and no malignancies were reported. Week 14 EI was observed in a statistically significant proportion of participants (38.2% [uniformly minimum-variance unbiased estimator, per protocol population]). Minimal histologic disease was observed after treatment (Robarts Histopathology Index ≤5: 33.3%; Geboes Index ≤3.2: 47.6%). sTL1A increase over time from baseline indicated sustained target engagement. Forty-one participants (82%) tested positive for anti-drug antibodies and 5 (10%) for neutralizing antibodies. CONCLUSIONS: PF-06480605 demonstrated an acceptable safety profile and statistically significant EI in participants with moderate to severe UC, warranting further study in a larger participant cohort. Tissue histopathology analyses support this conclusion. TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/NCT02840721.

Distinct clinical phenotypes for Crohn's disease derived from patient surveys.

BACKGROUND: Defining clinical phenotypes provides opportunities for new diagnostics and may provide insights into early intervention and disease prevention. There is increasing evidence that patient-derived health data may contain information that complements traditional methods of clinical phenotyping. The utility of these data for defining meaningful phenotypic groups is of great interest because social media and online resources make it possible to query large cohorts of patients with health conditions. METHODS: We evaluated the degree to which patient-reported categorical data is useful for discovering subclinical phenotypes and evaluated its utility for discovering new measures of disease severity, treatment response and genetic architecture. Specifically, we examined the responses of 1961 patients with inflammatory bowel disease to questionnaires in search of sub-phenotypes. We applied machine learning methods to identify novel subtypes of Crohn's disease and studied their associations with drug responses. RESULTS: Using the patients' self-reported information, we identified two subpopulations of Crohn's disease; these subpopulations differ in disease severity, associations with smoking, and genetic transmission patterns. We also identified distinct features of drug response for the two Crohn's disease subtypes. These subtypes show a trend towards differential genotype signatures. CONCLUSION: Our findings suggest that patient-defined data can have unplanned utility for defining disease subtypes and may be useful for guiding treatment approaches.

The Impact of Vedolizumab on Pre-Existing Extraintestinal Manifestations of Inflammatory Bowel Disease: A Multicenter Study.

BACKGROUND: There are limited data on how vedolizumab (VDZ) impacts extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD). The aim of this study was to determine the clinical outcomes of EIMs after initiation of VDZ for patients with IBD. METHODS: A multicenter retrospective study of patients with IBD who received at least 1 dose of VDZ between January 1, 2014 and August 1, 2019 was conducted. The primary outcome was the rate of worsening EIMs after VDZ. Secondary outcomes were factors associated with worsening EIMs and peripheral arthritis (PA) specifically after VDZ. RESULTS: A total of 201 patients with IBD (72.6% with Crohn disease; median age 38.4 years (interquartile range, 29-52.4 years); 62.2% female) with EIMs before VDZ treatment were included. The most common type of EIM before VDZ was peripheral arthritis (PA) (68.2%). Worsening of EIMs after VDZ occurred in 34.8% of patients. There were no statistically significant differences between the worsened EIM (n = 70) and the stable EIM (n = 131) groups in term of age, IBD subtype, or previous and current medical therapy. We found that PA was significantly more common in the worsening EIM group (84.3% vs 59.6%; P < 0.01). Worsening of EIMs was associated with a higher rate of discontinuation of VDZ during study follow-up when compared with the stable EIM group (61.4% vs 44%; P = 0.02). Treatment using VDZ was discontinued specifically because of EIMs in 9.5% of patients. CONCLUSIONS: Almost one-third of patients had worsening EIMs after VDZ, which resulted in VDZ discontinuation in approximately 10% of patients. Previous biologic use or concurrent immunosuppressant or corticosteroid therapy did not predict EIM course after VDZ.