The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis.

Sulfasalazine is a prodrug known to be effective for the treatment of inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA), but the mechanistic role for the gut microbiome in regulating its clinical efficacy is not well understood. Here, treatment of 22 IBD-pSpA subjects with sulfasalazine identifies clinical responders with a gut microbiome enriched in Faecalibacterium prausnitzii and the capacity for butyrate production. Sulfapyridine promotes butyrate production and transcription of the butyrate synthesis gene but in F. prausnitzii in vitro, which is suppressed by excess folate. Sulfasalazine therapy enhances fecal butyrate production and limits colitis in wild-type and gnotobiotic mice colonized with responder, but not non-responder, microbiomes. F. prausnitzii is sufficient to restore sulfasalazine protection from colitis in gnotobiotic mice colonized with non-responder microbiomes. These findings reveal a mechanistic link between the efficacy of sulfasalazine therapy and the gut microbiome with the potential to guide diagnostic and therapeutic approaches for IBD-pSpA.

Management of Primary Sclerosing Cholangitis and Extraintestinal Disorders in Patients With Ileal Pouches: A Systematic Review.

BACKGROUND: Restorative proctocolectomy with IPAA improves the quality of life in patients with ulcerative colitis by the removal of diseased large bowel and preservation of the natural route of defecation. Although the surgery may improve preexisting extraintestinal manifestations in the joints, skin, and eyes, extraintestinal manifestations, particularly primary sclerosing cholangitis, can persist after colectomy. OBJECTIVES: A systematic review of diagnosis and treatment of liver, joint, skin, and eye manifestations in patients with restorative proctocolectomy and IPAA for ulcerative colitis. DATA SOURCES: PubMed, Google Scholar, and Cochrane database. STUDY SELECTION: Relevant articles on primary sclerosing cholangitis and extraintestinal manifestations in ileal pouches published between January 2001 and July 2023 in English were included on the basis of Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. INTERVENTION: Diagnosis and treatment of primary sclerosing cholangitis and extraintestinal manifestations in patients with restorative proctocolectomy and IPAA were included. MAIN OUTCOME MEASURES: Association between primary sclerosing cholangitis, extraintestinal manifestations, and inflammatory disorders of the pouch and their management. RESULTS: Primary sclerosing cholangitis and extraintestinal manifestations are associated with pouchitis, particularly chronic pouchitis. Primary sclerosing cholangitis is associated with chronic pouchitis, enteritis, and possible pouch neoplasia. However, the disease severity and course of primary sclerosing cholangitis and pouchitis do not appear to be parallel. Despite the fact that oral vancomycin or budesonide have been used to treat primary sclerosing cholangitis-associated pouchitis, their impact on the disease course of primary sclerosing cholangitis is not known. Biological therapy for chronic inflammatory disorders of the pouch may also be beneficial for the concurrent extraintestinal manifestations of the joints, skin, and eyes. However, studies on the correlation between the severity of inflammatory pouch disorders and the severity of joint, skin, and eye diseases are lacking. LIMITATIONS: This is a qualitative, not quantitative, review of case series and case reports. CONCLUSIONS: Primary sclerosing cholangitis and extraintestinal manifestations of the joints, skin, and eyes appear to be associated with inflammatory disorders of the ileal pouch. Although the treatment of pouchitis does not seem to affect the disease course of primary sclerosing cholangitis, effective therapy of inflammatory pouch disorders, particularly with biologics, likely benefits concurrent disorders of the joints, skin, and eyes. See video from the symposium .

Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results of the UNIFI Long-Term Maintenance Study.

INTRODUCTION: Ulcerative colitis (UC) is a chronic condition that may require long-term treatment. We report the final efficacy and safety results of the UNIFI long-term extension study of ustekinumab in patients with UC through 4 years. METHODS: Ustekinumab induction responders who completed 44 weeks of maintenance treatment and agreed to enter the long-term extension continued their subcutaneous maintenance therapy (90 mg ustekinumab every 8 or 12 weeks [q8w or q12w] or placebo). Starting at week 56, randomized patients could receive dose adjustment to 90 mg q8w. Symptoms and adverse events were assessed through the study; endoscopic assessment was conducted at week 200. RESULTS: Of the 348 patients randomized to subcutaneous ustekinumab at maintenance baseline (q8w and q12w combined), 55.2% were in symptomatic remission at week 200. A greater proportion of biologic-naive patients (67.2% [117/174]) were in symptomatic remission than those with a history of biologic failure (41.6% [67/161]). Among patients in symptomatic remission at week 200, 96.4% were corticosteroid-free. Of the 171 patients with endoscopic evaluation at week 200, 81.6% (71/87) in the q12w group and 79.8% (67/84) in the q8w group had endoscopic improvement. From weeks 156 to the final safety visit (up to week 220), no deaths, major adverse cardiovascular events, or tuberculosis occurred in patients receiving ustekinumab. Nasopharyngitis, UC worsening, and upper respiratory tract infections were the most frequently reported adverse events. DISCUSSION: The long-term efficacy of ustekinumab maintenance in patients with UC was confirmed through 4 years. No new safety signals were observed. ClinicalTrials.gov number NCT02407236.

Maternal and Neonatal Outcomes in Vedolizumab and Ustekinumab Exposed Pregnancies: Results from the PIANO registry.

BACKGROUND: Pregnancy outcomes in inflammatory bowel disease (IBD) patients with quiescent disease are similar to the general population. Data from the Pregnancy Inflammatory bowel disease And Neonatal Outcomes (PIANO) registry have demonstrated the safety of anti-tumor necrosis factor alpha (TNFs) agents and thiopurines in pregnancy. The objective of this study was to provide information from the PIANO registry on maternal and fetal outcomes in patients exposed to the newer biologics ustekinumab (UST) and vedolizumab (VDZ). METHODS: In this multicenter prospective observational study, we included pregnant women with singleton pregnancies and a diagnosis of IBD. Questionnaires were administered to women at study intake, each subsequent trimester, delivery, and at 4, 9, and 12 months after birth. Bivariate analyses were utilized to determine the independent effects of specific drug classes on outcomes. The exposure cohorts were VDZ, UST, anti-TNFs, immunomodulators, and combination with anti-TNFs and immunomodulators. All were compared to no exposure and to biologics/immunomodulators. RESULTS: There were 1669 completed pregnancies with 1610 live births. Maternal mean age was 32.1 (SD 4.6) years at delivery with 66 VDZ and 47 UST exposed. Women on UST were more likely to have Crohn's disease. There was no increased risk of spontaneous abortion, small for gestational age, low birth weight, neonatal intensive care unit stay, congenital malformations, or intrauterine growth restriction with in utero VDZ or UST exposure. The rate of preterm birth was lower (0.0%) for UST-exposed as compared to other groups including VDZ (13.8%), anti-TNF (8.2%), combination therapy (14.2%), immunomodulator (12.3%), and unexposed (9.7%)(p = 0.03). Rates of serious infections at birth, 4 months, and within the first 12 months of life were comparable among all groups. Nonserious infections were lower at 12 months in UST exposed pregnancies. There was no increased risk signal for placental complications in the VDZ cohort. UST infant concentrations at birth were increased whereas VDZ concentrations were overall decreased compared to maternal serum drug concentration. CONCLUSION: This analysis of UST and VDZ exposure during pregnancy suggests no increase in complications compared to TNFs, immunomodulators and combination TNFs/immunomodulators. No signal was found for increased placental events with either therapy. Continuation of UST and VDZ throughout pregnancy is recommended.

Increased Primary Bile Acids with Ileocolonic Resection Impact Ileal Inflammation and Gut Microbiota in Inflammatory Bowel Disease.

BACKGROUND: Most Crohn's disease [CD] patients require surgery. Ileitis recurs after most ileocolectomies and is a critical determinant for outcomes. The impacts of ileocolectomy-induced bile acid [BA] perturbations on intestinal microbiota and inflammation are unknown. We characterized the relationships between ileocolectomy, stool BAs, microbiota and intestinal inflammation in inflammatory bowel disease [IBD]. METHODS: Validated IBD clinical and endoscopic assessments were prospectively collected. Stool primary and secondary BA concentrations were compared based on ileocolectomy and ileitis status. Primary BA thresholds for ileitis were evaluated. Metagenomic sequencing was use to profile microbial composition and function. Relationships between ileocolectomy, BAs and microbiota were assessed. RESULTS: In 166 patients, elevated primary and secondary BAs existed with ileocolectomy. With ileitis, only primary BAs [795 vs 398 nmol/g, p = 0.009] were higher compared to without ileitis. The optimal primary BA threshold [≥228 nmol/g] identified ileitis on multivariable analysis [odds ratio = 2.3, p = 0.04]. Microbial diversity, Faecalibacterium prausnitzii and O-acetylhomoserine aminocarboxypropyltransferase [MetY] were decreased with elevated primary BAs. Amongst ileocolectomy patients, only those with elevated primary BAs had diversity, F. prausnitzii and MetY reductions. Those with both ileocolectomy and intermediate [p = 0.002] or high [≥228 nmol/g, p = 9.1e-11]] primary BA concentrations had reduced F. prausnitzii compared to without ileocolectomy. Those with ileocolectomy and low [<29.2 nmol/g] primary BA concentrations had similar F. prausnitzii to those without ileocolectomy [p = 0.13]. MetY was reduced with ileitis [p = 0.02]. CONCLUSIONS: Elevated primary BAs were associated with ileitis, and reduced microbial diversity, F. prausnitzii abundance and enzymatic abundance of MetY [acetate and l-methionine-producing enzyme expressed by F. prausnitzii], and were the only factors associated with these findings after ileocolectomy.

The Real-World Effectiveness and Safety of Ustekinumab in the Treatment of Crohn's Disease: Results From the SUCCESS Consortium.

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.

Prevalence and factors associated with vitamin C deficiency in inflammatory bowel disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are prone to several nutritional deficiencies. However, data are lacking on vitamin C deficiency in Crohn's disease (CD) and ulcerative colitis (UC) patients, as well as the impact of clinical, biomarker and endoscopic disease severity on the development of vitamin C deficiency. AIM: To determine proportions and factors associated with vitamin C deficiency in CD and UC patients. METHODS: In this retrospective study, we obtained clinical, laboratory and endoscopic data from CD and UC patients presenting to the IBD clinic at a single tertiary care center from 2014 to 2019. All patients had an available plasma vitamin C level. Of 353 subjects who met initial search criteria using a cohort discovery tool, 301 ultimately met criteria for inclusion in the study. The primary aim described vitamin C deficiency (≤ 11.4 µmol/L) rates in IBD. Secondary analyses compared proportions with deficiency between active and inactive IBD. Multivariate logistic regression analysis evaluated factors associated with deficiency. RESULTS: Of 301 IBD patients, 21.6% had deficiency, including 24.4% of CD patients and 16.0% of UC patients. Patients with elevated C-reactive protein (CRP) (39.1% vs 16.9%, P < 0.001) and fecal calprotectin (50.0% vs 20.0%, P = 0.009) had significantly higher proportions of deficiency compared to those without. Penetrating disease (P = 0.03), obesity (P = 0.02) and current biologic use (P = 0.006) were also associated with deficiency on univariate analysis. On multivariate analysis, the objective inflammatory marker utilized for analysis (elevated CRP) was the only factor associated with deficiency (odds ratio = 3.1, 95% confidence interval: 1.5-6.6, P = 0.003). There was no difference in the presence of clinical symptoms of scurvy in those with vitamin C deficiency and those without. CONCLUSION: Vitamin C deficiency was common in IBD. Patients with elevated inflammatory markers and penetrating disease had higher rates of vitamin C deficiency.

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.

Management of pouch neoplasia: consensus guidelines from the International Ileal Pouch Consortium.

Surveillance pouchoscopy is recommended for patients with restorative proctocolectomy with ileal pouch-anal anastomosis in ulcerative colitis or familial adenomatous polyposis, with the surveillance interval depending on the risk of neoplasia. Neoplasia in patients with ileal pouches mainly have a glandular source and less often are of squamous cell origin. Various grades of neoplasia can occur in the prepouch ileum, pouch body, rectal cuff, anal transition zone, anus, or perianal skin. The main treatment modalities are endoscopic polypectomy, endoscopic ablation, endoscopic mucosal resection, endoscopic submucosal dissection, surgical local excision, surgical circumferential resection and re-anastomosis, and pouch excision. The choice of the treatment modality is determined by the grade, location, size, and features of neoplastic lesions, along with patients' risk of neoplasia and comorbidities, and local endoscopic and surgical expertise.

Mucosal metabolites fuel the growth and virulence of E. coli linked to Crohn's disease.

Elucidating how resident enteric bacteria interact with their hosts to promote health or inflammation is of central importance to diarrheal and inflammatory bowel diseases across species. Here, we integrated the microbial and chemical microenvironment of a patient's ileal mucosa with their clinical phenotype and genotype to identify factors favoring the growth and virulence of adherent and invasive E. coli (AIEC) linked to Crohn's disease. We determined that the ileal niche of AIEC was characterized by inflammation, dysbiosis, coculture of Enterococcus, and oxidative stress. We discovered that mucosal metabolites supported general growth of ileal E. coli, with a selective effect of ethanolamine on AIEC that was augmented by cometabolism of ileitis-associated amino acids and glutathione and by symbiosis-associated fucose. This metabolic plasticity was facilitated by the eut and pdu microcompartments, amino acid metabolism, γ-glutamyl-cycle, and pleiotropic stress responses. We linked metabolism to virulence and found that ethanolamine and glutamine enhanced AIEC motility, infectivity, and proinflammatory responses in vitro. We connected use of ethanolamine to intestinal inflammation and L-fuculose phosphate aldolase (fucA) to symbiosis in AIEC monoassociated IL10-/- mice. Collectively, we established that AIEC were pathoadapted to utilize mucosal metabolites associated with health and inflammation for growth and virulence, enabling the transition from symbiont to pathogen in a susceptible host.

Immune regulation by fungal strain diversity in inflammatory bowel disease.

The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation1-6. Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease3-9, it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR-Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host-fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1ß-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (TH17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans-secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host-fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin.

Efficacy and Safety of Maintenance Ustekinumab for Ulcerative Colitis Through 3 Years: UNIFI Long-term Extension.

BACKGROUND AND AIMS: The UNIFI long-term extension [LTE] study reports the efficacy and safety of subcutaneous 90 mg ustekinumab through 3 years of maintenance therapy. METHODS: Patients randomised to ustekinumab every 12 weeks [q12w] or every 8 weeks [q8w] at maintenance baseline [N = 348] and randomised ustekinumab-treated patients in the LTE [N = 284] were evaluated. Symptomatic remission [Mayo stool frequency = 0/1, rectal bleeding = 0] was assessed. Safety included all LTE patients [N = 188 placebo and N = 457 ustekinumab]. RESULTS: Among patients randomised to the ustekinumab q12w and q8w groups at maintenance baseline, 54.1% and 56.3% achieved symptomatic remission at Week 152, respectively. Overall, 20% of patients discontinued ustekinumab, 10% of biologic-naïve and 30% of biologic-exposed patients. Among patients in symptomatic remission at Year 3, 94.6% and 98.0% of patients were also corticosteroid free, respectively. Corticosteroid-free symptomatic remission rates in the ustekinumab q12w and q8w groups were 51.2% and 55.1% at Week 152, respectively. Remission rates were higher for biologic-naïve patients than for those with a history of biologic failure. Biochemical evidence of response was demonstrated by stable, decreased C-reactive protein and faecal calprotectin measurements over 3 years. From Weeks 96 to 156, no deaths, major adverse cardiovascular events, or tuberculosis occurred. Nasopharyngitis, ulcerative colitis, and upper respiratory tract infection were most frequently reported. One ustekinumab-treated patient with a history of basal cell carcinoma [BCC] reported two BCCs. One patient in the q8w ustekinumab group, who was receiving concomitant 6-mercaptopurine, experienced serious adverse events of neutropenic sepsis and oral herpes. CONCLUSIONS: Efficacy of ustekinumab in patients with ulcerative colitis was confirmed through 3 years. No new safety signals were observed.

Utility of Therapeutic Drug Monitoring for Tumor Necrosis Factor Antagonists and Ustekinumab in Postoperative Crohn's Disease.

BACKGROUND: In postoperative Crohn's disease (POCD), data are lacking on relationships between serum biologic concentrations and treatment outcomes. We assessed if established threshold concentrations of infliximab (IFX), adalimumab (ADA), and ustekinumab (UST) impact outcomes in POCD. METHODS: Data were extracted from POCD patients with serum biologic concentration measurements using Weill Cornell Medicine biobanks. The primary outcome compared rates of deep remission (achieving both objective [endoscopic or biomarker] and clinical [Harvey-Bradshaw index or Crohn's Disease Patient Reported Outcome-2] remission), using established serum drug level cutoffs of IFX ≥3 µg/mL, ADA ≥7.5 µg/mL, and UST ≥4.5 µg/mL. RESULTS: In 130 patients, median IFX, ADA, and UST concentrations were 10 (interquartile range [IQR], 2.9-26.9) µg/mL, 10.5 (IQR, 4.9-14.9) µg/mL, and 6.9 (IQR, 5.1-10.2) µg/mL, respectively. In patients with IFX ≥3 µg/mL, higher rates of deep remission (39% vs 0%; P = .02) existed compared with those with IFX <3 µg/mL. Similar differences existed for clinical (44% vs 9%; P = .04) and objective (83% vs 62%; P = .1) remission. In patients with ADA ≥7.5 µg/mL, rates of deep (42% vs 0%; P = .02), clinical (42% vs 0%; P = .02), and objective (88% vs 40%; P = .007) remission were higher than patients with lower concentrations. For UST, rates of deep (28% vs 17%; P = 1.0), clinical (33% vs 33%; P = 1.0), and objective (70% vs 67%; P = 1.0) remission were similar between patients regardless of drug concentration. CONCLUSIONS: In POCD, established anti-tumor necrosis factor concentrations were associated with improved outcomes. No relationship between UST concentrations and postoperative outcomes existed.

Data are lacking on therapeutic drug monitoring in postoperative Crohn's disease. The current study found that tumor necrosis factor antagonist concentrations above established drug thresholds were associated with improved outcomes. In contrast, for ustekinumab, no relationship between drug thresholds and outcomes existed.

A Quality Improvement Initiative Is Associated With Reduced Time to Administer Biologics and Small Molecules and Emergency Room Visits in Inflammatory Bowel Disease.

BACKGROUND: Delays in biologic or small molecule medication administration are associated with increased adverse events, hospitalization, and surgery in inflammatory bowel disease (IBD). We evaluated the impact of a quality improvement (QI) intervention on the time to administration of biologics or small molecules (TABS) in IBD. METHODS: Data were retrospectively extracted for IBD patients prescribed biologics or small molecules from a convenience sample of providers participating in an accredited QI educational intervention (baseline cohort). Subsequent to the intervention, data were prospectively collected from patients prescribed these medications (postintervention cohort). Dates related to steps between a treatment decision to medication administration were collected. The primary outcome compared TABS in baseline and postintervention cohorts. RESULTS: Eighteen physicians provided survey and patient data for 200 patients in each cohort (n=400). The median time to medication administration (TABS) decreased from baseline to postintervention cohorts (30 vs. 26 d, P=0.04). Emergency room visits before medication administration also decreased (25.5% vs. 12.5%, P=0.001). Similar numerical TABS reductions were observed in subgroups limited to physicians providing patients to both cohorts and for individual medications prescribed. Primary contributors to delays included filling prescriptions subsequent to insurance approval and dispensation subsequent to this. CONCLUSIONS: A QI intervention successfully reduced medication administration times (TABS) by accelerating provider-dependent steps. This intervention was associated with reduced emergency room visits. We propose TABS as a quality metric to assess the effective delivery of therapies in IBD. Further evaluation of QI interventions, patient education on prescription drug insurance, and quality metrics are warranted.

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.

Impact of Inflammatory Bowel Disease Therapies on Durability of Humoral Response to SARS-CoV-2 Vaccination.

Immunization against the spike protein of SARS-CoV-2 reduces transmission1,2 and severe outcomes. However, little is known regarding the impact of immune-mediated diseases and immunosuppressive medications on the efficacy of vaccination. Vaccination immunity is transient, with breakthrough cases increasing at longer time intervals since the last dose.3,4 Although there are data on SARS-CoV-2 vaccine on early seroconversion in patients with inflammatory bowel disease (IBD),5 no data in the same cohort exist describing the durability of these antibodies over time. We sought to investigate the impact of IBD and its therapies on postvaccination antibody response and kinetics of immunogenicity decline, because these findings may better inform clinical guidelines and recommendations on precautions and booster vaccination.

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.

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Adherent-invasive E. coli metabolism of propanediol in Crohn's disease regulates phagocytes to drive intestinal inflammation.

Adherent-invasive E. coli (AIEC) are enriched in the intestinal microbiota of patients with Crohn's disease (CD) and promote intestinal inflammation. Yet, how AIEC metabolism of nutrients impacts intestinal homeostasis is poorly defined. Here, we show that AIEC encoding the large subunit of propanediol dehydratase (PduC), which facilitates the utilization of fucose fermentation product 1,2-propanediol, are increased in the microbiome of CD patients and drive AIEC-induced intestinal T cell inflammation. In murine models, CX3CR1+ mononuclear phagocytes (MNP) are required for PduC-dependent induction of T helper 17 (Th17) cells and interleukin-1ß (IL-1ß) production that leads to AIEC-induced inflammatory colitis. Activation of this inflammatory cascade requires the catalytic activity of PduC to generate propionate, which synergizes with lipopolysaccharide (LPS) to induce IL-1ß by MNPs. Disrupting fucose availability limits AIEC-induced propionate production and intestinal inflammation. These findings identify MNPs as metabolic sensors linking AIEC metabolism with intestinal inflammation and identify microbial metabolism as a potential therapeutic target in Crohn's disease treatment.