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•Prior biologics exposure may hinder response to later biologics in ulcerative colitis.•Post–anti–tumor necrosis factor (TNF) discontinuation, persistence was compared in patients switching to a new biologic class versus cycling to another anti–TNF.•Patients switching had greater persistence than those cycling to another anti–TNF.•Results remained consistent when switching was restricted to ustekinumab only.•Findings may inform treatment choices for patients with loss of response to anti–TNFs. In ulcerative colitis (UC), anti–tumor necrosis factor (TNF) agents often are first-line biologic therapy. Switching to a biologic with a different mode of action (ustekinumab and vedolizumab) or cycling to another anti–TNF agent (adalimumab, infliximab, and golimumab) is necessary if an initial anti–TNF fails. This study compared real-world persistence in patients with UC who switched to a biologic with a different mode of action or cycled with another anti–TNF after nonresponse to an anti–TNF. Adults with UC treated with an anti–TNF, who switched or cycled (index date) between October 21, 2019, and March 02, 2022, were selected from the IQVIA PharMetrics® Plus database. Patients had ≥12 months of continuous insurance eligibility before the first anti–TNF without UC-indicated biologics or advanced therapies. During the 12 months before the index date (baseline period), patients had no other immune disorders and discontinued the first anti–TNF. Baseline characteristics were balanced using inverse probability of treatment weights. Persistence on the index biologic was defined as no therapy exposure gaps >120 days (ustekinumab, vedolizumab, and infliximab) or >60 days (adalimumab and golimumab) between days of supply. Composite end points were persistence while corticosteroid-free (<14 consecutive days of corticosteroid supply after day 90 post-index) and persistence while on monotherapy (no immunomodulators/nonindex biologics/advanced therapies). End points were assessed with weighted Kaplan-Meier and Cox proportional hazards models 12 months after the maintenance phase started. The switch cohort included 488 patients (mean age: 41.4 years; 44.9% female), and the cycle cohort included 129 patients (mean age: 40.7 years; 43.8% female). At 12 months after the maintenance phase started, the proportions of persistent patients (switch cohort: 79.6%; cycle cohort: 64.9%) and persistent patients on monotherapy (switch cohort: 74.6%; cycle cohort: 48.0%) were significantly higher in the switch versus cycle cohort; the proportions of persistent patients while corticosteroid-free was also higher in the switch (60.1%) versus cycle cohort (49.3%) but was not significant. In the switch cohort, the rate of persistence was 1.92 times higher (hazard ratio [HR] = 1.92; 95% CI, 1.31−2.82), the rate of persistence while on monotherapy was 2.56 times higher (HR = 2.56; 95% CI, 1.86−3.53), and the rate of persistence and being corticosteroid-free was 1.31 times higher (HR = 1.31; 95% CI, 0.98−1.77) than in the cycle cohort. Patients with UC who switched from an anti–TNF agent to a biologic with a different mode of action were more persistent on treatment than patients who cycled to another anti–TNF agent. Findings may aid physicians whose patients experience treatment failure on the first anti–TNF agent.

ObjectiveThe influence of eosinophilic oesophagitis (EoE)-associated inflammation upon oesophageal epithelial biology remains poorly understood. We investigated the functional role of autophagy in oesophageal epithelial cells (keratinocytes) exposed to the inflammatory EoE milieu.DesignFunctional consequences of genetic or pharmacological autophagy inhibition were assessed in endoscopic oesophageal biopsies, human oesophageal keratinocytes, single cell-derived ex vivo murine oesophageal organoids as well as a murine model recapitulating EoE-like inflammation and basal cell hyperplasia. Gene expression, morphological and functional characterisation of autophagy and oxidative stress were performed by transmission electron microscopy, immunostaining, immunoblotting, live cell imaging and flow cytometry.ResultsEoE-relevant inflammatory conditions promoted autophagy and basal cell hyperplasia in three independent murine EoE models and oesophageal organoids. Inhibition of autophagic flux via chloroquine treatment augmented basal cell hyperplasia in these model systems. Oesophageal keratinocytes stimulated with EoE-relevant cytokines, including tumour necrosis factor-α and interleukin-13 exhibited activation of autophagic flux in a reactive oxygen species-dependent manner. Autophagy inhibition via chloroquine treatment or depletion of Beclin-1 or ATG-7, augmented oxidative stress induced by EoE-relevant stimuli in murine EoE, oesophageal organoids and human oesophageal keratinocytes. Oesophageal epithelia of paediatric EoE patients with active inflammation displayed increased autophagic vesicle content compared with normal and EoE remission subjects. Functional flow cytometric analysis revealed autophagic flux in human oesophageal biopsies.ConclusionsOur findings reveal for the first time that autophagy may function as a cytoprotective mechanism to maintain epithelial redox balance and homeostasis under EoE inflammation-associated stress, providing mechanistic insights into the role of autophagy in EoE pathogenesis.

Nonresponse to an anti–tumor necrosis factor (TNF) agent in patients with Crohn disease (CD) is often managed by either a switch to a different class of biologic (ie, ustekinumab, vedolizumab) or by cycling to another anti-TNF agent (ie, adalimumab, infliximab, certolizumab pegol). Persistence after a switch to a different biologic class or after cycling within the anti-TNF class was assessed in patients with nonresponse to an anti-TNF agent. Adults with CD who discontinued from an anti-TNF agent and either switched to a different class of biologic (ie, anti-interleukin/integrin; the switching cohort) or cycled within the anti-TNF class (the cycling cohort) between September 23, 2016, and August 1, 2019, were selected from a commercial database. The index date was defined as the date of the first claim of the subsequent-line biologic (index biologic) after an anti-TNF. The switching and cycling cohorts were balanced with regard to baseline characteristics, using inverse probability of treatment weights–average treatment effect (IPTW-ATE). Persistence with the index biologic was defined as consistent use with no gaps of >120 days (ustekinumab, vedolizumab, infliximab) or of >60 days (adalimumab, certolizumab pegol) in biologic supply. Composite end points were persistence while being corticosteroid-free (defined as no use of corticosteroids with ≥14 days of supply after day 90 post-index) and persistence while on monotherapy (no immunomodulators/nonindex biologics). Weighted Kaplan-Meier and Cox models were used to assess outcomes at 12 months post-index. There were 444 patients in the weighted switching cohort (mean age, 40.4 years; 56.3% female) and 441 in the weighted cycling cohort (mean age, 39.5 years; 58.4% female). At 12 months post-index, the rate of persistence with the index biologic was 75.7% in the switching cohort compared to 67.5% in the cycling cohort (log-rank P = 0.023); the rate of persistence while on monotherapy was 58.2% compared to 44.2%, respectively (log-rank P < 0.001). The rate of persistence was 44% greater in the switching compared to that in the cycling cohort (hazard ratio [HR] = 1.44; 95% CI, 1.11–1.88; P = 0.007); the rate of persistence while on monotherapy was 56% greater in the switching cohort (HR = 1.56; 95% CI, 1.28–1.90; P < 0.001). The between-cohort difference in persistence while being corticosteroid-free was not statistically significant (HR = 1.08; 95% CI, 0.89–1.32; P = 0.426). Patients with CD who switched to a different biologic class were more persistent than were patients who cycled to another anti-TNF agent. These findings may be useful for physicians when considering the treatment of patients who have experienced nonresponse or loss of response to the first-line anti-TNF agent.

Crohn disease is a systemic illness that may include a variety of extraintestinal manifestations, but respiratory tract involvement is rare. Primary involvement of the airway, pleura, and lung parenchyma can be seen, as well as secondary involvement from medications commonly used to treat IBD.MethodsWe present the cases of a 16 year old male with new-onset Crohn disease found incidentally to have multiple pulmonary nodules on CT imaging, a 12 year old male with known Crohn disease with progressive dyspnea, and a 15 year old male with odynophagia found to have Crohn disease of the upper airway.ResultsCase 1: A previously healthy 16 year old male presented with 3 weeks of abdominal pain, bloody diarrhea, and weight loss. CT imaging showed diffuse colonic wall thickening, and multiple, small, bilateral pulmonary nodules, as large as 9 mm. The patient reported no respiratory symptoms. The diagnosis of Crohn disease was confirmed by endoscopy. Bronchoscopy and pulmonary function testing were normal. Complete infectious disease and rheumatological evaluations were also unremarkable, suggesting the nodules were a manifestation of Crohn disease. The patient began treatment with a 5-ASA and systemic corticosteroids with clinical improvement. Repeat CT imaging performed 2 months later showed resolution of the nodules. Case 2: A 12 year old male with known Crohn disease presented to the office with progressive stridor, croup-like cough, snoring, and dyspnea on exertion for several weeks. The patient had experienced similar symptoms in the past, including in the years prior to his Crohn disease diagnosis, although less severe. His Crohn disease had been complicated by oral lesions and scrotal swelling with a relatively quiescent intestinal course. The patient was referred to ENT. On laryngoscopy, swollen, erythematous, aryepiglottic folds were seen. Aryepiglottic biopsies showed chronic inflammatory infiltrates and a granuloma, consistent with airway Crohn disease. The patient was treated with several steroid injections to the supraglottis, with partial clinical improvement. He soon developed progression of his intestinal symptoms, including perianal disease. His therapy was escalated from 6-MP to infliximab. Within several months the patient had complete resolution of both his respiratory and gastrointestinal symptoms. Case 3: A 15 year old male presented with a 2 year history of sore throat, severe odynophagia, and significant weight loss. He had previously been diagnosed with Crohn disease based on esophagitis and mild ileocecal inflammation on endoscopy. His current symptoms had not responded to ileocecectomy or dual therapy with infliximab and methotrexate. On laryngoscopy, the epiglottis and aryepiglottic folds were edematous and friable with extensive, deep ulcerations. Biopsies were consistent with airway Crohn disease and showed chronic inflammatory infiltrates. The patient was nutritionally rehabilitated with parental nutrition and gastro-jejunal feedings for several weeks. He was started on systemic corticosteroids and was treated with several steroid injections to the supraglottis with clinical improvement.ConclusionsRespiratory system involvement can occur with Crohn disease. The presentation is varied with a range of clinical presentations. A high level of clinical suspicion is needed to correctly identify cases of Crohn disease with respiratory system involvement.

Abstract BACKGROUND Primary treatment goals for ulcerative colitis (UC) are to induce and maintain long-term disease remission and reduce the prevalence of symptoms such as bowel urgency and abdominal pain. Ustekinumab (UST) is a biologic approved for treating adult patients with moderate-severe UC, but real-world effectiveness data remain limited. OBJECTIVE We aimed to assess real-world effectiveness of UST in patients with UC. METHODS Data were drawn from the Adelphi Real World UC Disease Specific Programme™, a cross-sectional survey with retrospective data collection of gastroenterologists and their patients in the United States of America (USA) from December 2022–September 2023. Two samples were utilised; a sample where physicians provided data for their next six consecutive patients with UC, and an oversample where physicians provided data for their next four consulting patients with UC receiving UST. Patients receiving UST for >1 day at time of consultation (assumed to have received ≥1 UST dose) from either sample were included in the analysis. Data collected included clinical status, disease duration and location, symptoms and treatment profiles. Remission defined by Mayo score was reported separately for advanced therapy (AT)-naïve (UST received as first AT) and AT-experienced (UST received as second or later line of AT) patients. Descriptive statistics for each variable were reported for patients with known data. McNemar’s test was used for symptom prevalence and disease severity comparisons. RESULTS Data for 160 patients were included in this study from 50 physicians. Patients had been diagnosed with UC for median (interquartile range; IQR) of 2.2 (0.5, 4.5) years; mean (standard deviation) age was 39.7 (13.0) years and 50.0% of patients were male. UST was received as first AT for 68.1% of patients, second AT for 18.1% and third AT for 11.3%. Median (IQR) time on UST was 8.7 (4.1, 18.6) months, with 83.9% of patients receiving UST for ≥3 months. For patients in maintenance phase of treatment, 65.8% were on UST USA label dose, 17.9% were receiving an increased and 16.3% decreased dose. According to Mayo scores, 53.6% of AT-naïve and 58.3% of AT-experienced patients were in remission at consultation (Table 1). Improvement in disease severity was evidenced by a reduced proportion of patients with moderate/severe disease at consultation (34.4%) compared to prior to initiation of UST (90.9%; p<0.01). Similarly, there was a significantly lower prevalence of all symptoms between UST initiation and consultation, including abdominal pain (72.1% vs 30.2%), bowel urgency (55.1% vs 22.0%) and bloody diarrhea (54.4% vs 17.6%) (all p<0.01; Figure 1). CONCLUSION Our study showed real-world effectiveness of UST in patients with UC in the USA; most patients receiving UST achieved remission and demonstrated reduced prevalence of symptoms following UST initiation. Table 1 Physician-reported characteristics of patients receiving ustekinumab at the time of consultation. Figure 1 Physician-reported prevalence of (A) symptoms and (B) moderate/severe disease severity prior to initiation of ustekinumab and at time of consultation.

Abstract BACKGROUND Anti-tumor necrosis factor inhibitors (anti-TNFs) are biologics commonly used for the treatment of Crohn’s disease (CD). Over time, patients may require adjustment to anti-TNF therapy, including cycling to a different anti-TNF or switching to a biologic with an alternate mechanism of action. Choice of a treatment strategy could be key to managing symptoms on a sustained basis. This study aimed to compare real-world persistence among patients with CD who cycled to another anti-TNF agent or switched to ustekinumab. METHODS Adults with CD treated with an anti-TNF, whose first switching to ustekinumab or cycling to a new anti-TNF (index date) occurred between 09/23/2016 and 08/01/2019 were selected from the IBM® MarketScan® Commercial Database. Patients had ≥12 months of continuous insurance eligibility before the initiation of the first anti-TNF, discontinued the first anti-TNF within 12 months before the index date (baseline), and had no other immune disorders during baseline. Cohorts were balanced on baseline characteristics using inverse probability of treatment weights. Persistence on index biologic (ustekinumab or a new anti-TNF) was defined as absence of therapy exposure gaps >120 days (ustekinumab, infliximab) or >60 days (adalimumab, certolizumab) between days of supply. Composite endpoints were persistence while on monotherapy (no immunomodulators/non-index biologics), and persistence and being corticosteroid-free (no corticosteroids with ≥14 days of supply after day 90 post-index). Weighted Kaplan-Meier and Cox models were used to assess outcomes at 12 months post-index. RESULTS The weighted sample included 325 patients in the ustekinumab cohort and 328 in the cycling cohort (Fig. 1). At 12 months post-index, 76.6% versus 67.5% persisted on the index biologic in the ustekinumab versus the cycling cohort (Fig. 2a); the rate of persistence was 47% higher in the ustekinumab cohort (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.08-2.01; p-value 0.0158). Moreover, 61.6% versus 44.1% persisted on the index biologic while on monotherapy, respectively (Fig. 2b); the rate of persistence while on monotherapy was 68% higher in the ustekinumab cohort (HR: 1.68; 95% CI: 1.33-2.13; p-value <0.001). Finally, 54.8% vs 50.2% were persistent and corticosteroid-free, respectively (Fig. 2c); the rate of being persistent and corticosteroid free numerically trended 9% higher in the ustekinumab cohort but statistical significance was not reached (HR: 1.09; 95% CI: 0.87-1.38; p-value 0.4527). Figure 1. Baseline characteristics in weighted cohorts Figure 2. Kaplan-Meier for (a) persistent, (b) persistent while on monotherapy, and (c) persistent while corticosteroid-free patients in weighted cohorts CONCLUSIONS After discontinuation of the first anti-TNF, persistence on therapy was better among patients with CD who switched to ustekinumab compared to those who cycled to a new anti-TNF. These findings may inform treatment strategies for patients on the first anti-TNF agent who require treatment adjustment.

Abstract Background The POWER study (NCT03782376) evaluated efficacy and safety of a single ustekinumab intravenous (IV) reinduction dose versus placebo under continued ustekinumab subcutaneous (SC) treatment in adult patients with moderately to severely active Crohn’s disease who demonstrated a secondary loss of response to ustekinumab every 8 weeks (q8w) maintenance therapy. Methods Patients were randomly assigned 1:1 at Week 0 to ustekinumab IV reinduction (ustekinumab ∼6 mg/kg and SC placebo) or continuous maintenance (IV placebo and SC ustekinumab 90 mg q8w). Clinical and biomarker assessments occurred at Weeks 0, 8, 16, and 24 with optional ileocolonoscopy at Weeks 0 and16. The primary endpoint was clinical response (≥100-point decrease from baseline Crohn’s Disease Activity Index [CDAI] score or CDAI <150) at Week 16. Safety events were analyzed through Week 36 and serum samples were collected for pharmacokinetic analyses and anti-ustekinumab antibody detection. Results Overall, 215 patients were randomized: 108 to the IV reinduction group and 107 to the SC group. In the IV reinduction group, 49.1% achieved clinical response at Week 16 versus 37.4% in the SC group (adjusted treatment difference 11.5% [95% CI: −1.5%, 24.5%; P = .089]). Proportions of patients with endoscopic remission and improvement, normalization of inflammatory biomarkers, and improvement in IBDQ score were greater in the IV reinduction group vs the SC group. No new safety signals were identified. Conclusions Although the primary endpoint of clinical response was not met at Week 16, ustekinumab IV reinduction showed numerical improvements in objective endpoints including inflammatory biomarkers and endoscopic outcomes compared with SC maintenance therapy. Safety and immunogenicity results were consistent with the established profile of ustekinumab. Lay Summary Some patients with Crohn’s disease who respond to biologic treatment may lose response over time. The POWER study evaluated the efficacy and safety of receiving an additional intravenous dose of ustekinumab in patients who initially lost response to ustekinumab. Graphical abstract Graphical Abstract