Tofacitinib in Pediatric Ulcerative Colitis: A Retrospective Multicenter Experience.

BACKGROUND: Tofacitinib has recently been approved for treatment of moderate-to-severe ulcerative colitis (UC) in adults, yet pediatric data are limited. This international multicenter study describes the effectiveness and safety of tofacitinib in pediatric UC. METHODS: This is a retrospective review of children diagnosed with UC treated with tofacitinib from 16 pediatric centers internationally. The primary outcome was week 8 corticosteroid-free clinical remission (Pediatric Ulcerative Colitis Activity Index <10). Secondary outcomes were clinical response (≥20-point decrease in Pediatric Ulcerative Colitis Activity Index) at week 8, corticosteroid-free clinical remission at week 24, and colectomy rate and adverse safety events through to last follow-up. The primary outcome was calculated by the intention-to-treat principle. RESULTS: We included 101 children with a mean age at diagnosis of 12.8 ±â€…2.8 years and a median disease duration of 20 months (interquartile range [IQR], 10-39 months). All had treatment failure with at least 1 biologic agent, and 36 (36%) had treatment failure with 3 agents. Median follow-up was 24 weeks (IQR, 16-54 weeks). Sixteen (16%) children achieved corticosteroid-free clinical remission at week 8, and an additional 30 (30%) demonstrated clinical response. Twenty (23%) of 88 children achieved corticosteroid-free clinical remission at week 24. A total of 25 (25%) children underwent colectomy by median 86 days (IQR, 36-130 days). No serious drug-related adverse events were reported; there was 1 case of herpes zoster and 2 cases of minor blood test perturbations. CONCLUSIONS: In this largest real-life pediatric cohort to date, tofacitinib was effective in at least 16% of patients with highly refractory UC by week 8. Adverse events were minor and largely consistent with adult data.

Tofacitinib, widely reported in adult ulcerative colitis, has very limited pediatric data. This international collaboration is the largest pediatric study on the efficacy and safety of tofacitinib to date, providing important supportive data to clinicians and regulators.

Patient and Health Care Professional Perceptions of the Experience and Impact of Symptoms of Moderate-to-Severe Crohn's Disease in US and Europe: Results from the Cross-Sectional CONFIDE Study.

BACKGROUND: Crohn's disease (CD) significantly affects patients' health-related quality of life and well-being. AIMS: Communicating Needs and Features of IBD Experiences (CONFIDE) survey explores the experience and impact of moderate-to-severe CD symptoms on patients' lives and identifies communication gaps between patients and health care professionals (HCPs). METHODS: Online, quantitative, cross-sectional surveys of patients, and HCPs were conducted in the United States (US), Europe (France, Germany, Italy, Spain, United Kingdom), and Japan. Criteria based on previous treatment, steroid use, and/or hospitalization defined moderate-to-severe CD. US and Europe data are presented as descriptive statistics. RESULTS: Surveys were completed by 215 US and 547 European patients and 200 US and 503 European HCPs. In both patient groups, top three symptoms currently (past month) experienced were diarrhea, bowel urgency, and increased stool frequency, with more than one-third patients wearing diaper/pad/protection at least once a week in past 3 months due to fear of bowel urgency-related accidents. HCPs ranked diarrhea, blood in stool, and increased stool frequency as the most common symptoms. Although 34.0% US and 27.2% European HCPs ranked bowel urgency among the top five symptoms affecting patient lives, only 12.0% US and 10.9% European HCPs ranked it among top three most impactful symptoms on treatment decisions. CONCLUSION: Bowel urgency is common and impactful among patients with CD in the US and Europe. Differences in patient and HCP perceptions of experiences and impacts of bowel urgency exist, with HCPs underestimating its burden. Proactive communication between HCPs and patients in clinical settings is crucial for improving health outcomes in patients with CD.

Forecasted infliximab concentrations during induction predict time to remission and sustained disease control of inflammatory bowel disease.

BACKGROUND: Infliximab (IFX) exposure is established as a predictive factor of pharmacokinetic (PK) origin in inflammatory bowel disease (IBD), and expert consensus is to achieve adequate exposure during induction to achieve and sustain remission. METHODS: We retrospectively evaluated the performance of a Bayesian PK tool in IBD patients starting IFX. Trough IFX serum levels collected immediately before the third (at week 6) and fourth (at week 14) infusions were evaluated from 307 IBD patients (median age=17 years, 50 % females, 83 % with Crohn's disease). Forecasted IFX concentration at the fourth infusion were estimated using serum IFX, antibodies to IFX, albumin and weight determined immediately before the third infusion using population PK calculator with Bayesian prior. The outcome variable was a clinical & biochemical remission status achieved (CRP levels below 3 mg/L in presence of clinical remission). Statistics consisted of Kaplan Meier analysis with calculation of Hazard ratio (HR), and logistic regression. RESULTS: IFX concentration above 15 µg/mL immediately before the third infusion associated with shorter time to clinical & biochemical remission than concentration below 15 µg/mL without reaching significance (163±14 days vs 200±16 days, respectively; p=0.052). However, using PK parameters at the third infusion, forecasted IFX concentrations above 10 µg/mL immediately before the fourth infusion were significantly associated with a higher rate (HR=1.6 95 %CI: 1.1 to 2.1 p<0.01) and shorter time to remission (148±18 days vs 200±13 days p<0.01). In the presence of IFX concentration above 15 µg/mL at the third infusion, there was a significant 2.5-fold higher likelihood of sustained clinical & biochemical remission status during maintenance as compared to IFX concentrations below 15 µg/mL (p<0.01). Forecasted IFX level above 10 µg/mL at fourth infusion associated with significantly 3.9-fold higher likelihood of clinical & biochemical remission as compared to forecasted IFX concentrations below 10 µg/mL (p<0.01). CONCLUSIONS: These data further support that optimized IFX concentrations during induction are associated with enhanced disease control in IBD.

Preventing and managing cardiovascular events in patients with inflammatory bowel diseases treated with small-molecule drugs, an international Delphi consensus.

Janus kinase (JAK) inhibitors and sphingosine 1 phosphate (S1P) receptor modulators are small molecule drugs (SMDs) approved for IBD treatment. Their use in clinical practice might be limited due to cardiovascular concerns. We aimed to provide guidance on risk assessment, monitoring, and management strategies, aiming to minimize potential cardiovascular risks of SMDs and to facilitate an adequate shared decision-making. A systematic literature search was conducted, and proposed statements were prepared. A virtual consensus meeting was held, in which eleven IBD physicians and two cardiovascular specialists from ten countries attended. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75 % of participants voting as 'agree' with each statement. Consensus was reached for eighteen statements. Available evidence does not show a higher risk of cardiovascular events with JAK inhibitors in the overall IBD population, although it might be increased in patients with an unfavorable cardiovascular profile. S1P receptor modulators may be associated with a risk of bradycardia, atrioventricular blocks, and hypertension. Cardiovascular risk stratification should be done before initiation of SMDs. Although the risk of cardiovascular events in patients with IBD on SMDs appears to be low overall, caution should still be taken in certain scenarios.

Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme.

BACKGROUND AND AIMS: Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, oncedaily, selective sphingosine 1phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. METHODS: Patients, including those with isolated proctitis (<10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. RESULTS: We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p<0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. CONCLUSIONS: Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52.

Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.11) [corrected] higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD.

Extensive Disease and Exposure to Multiple Biologics Precolectomy Is Associated with Endoscopic Cuffitis Post-Ileal Pouch-Anal Anastomosis in Patients With Ulcerative Colitis.

INTRODUCTION: To better inform the risk of cuffitis in patients with ulcerative colitis (UC), we aimed to identify its occurrence and associated precolectomy factors in a large multicenter cohort of patients who underwent restorative proctocolectomy (RPC) with stapled ileal pouch-anal anastomosis (IPAA). METHODS: This study was a retrospective cohort analysis of individuals diagnosed with UC or indeterminate colitis who underwent RPC with IPAA for refractory disease or dysplasia at Mount Sinai Hospital or the University of Chicago followed by at least 1 pouchoscopy with report of the pouch-anal anastomosis. The primary outcome was cuffitis defined as ulceration of the cuff as reported in each pouchoscopy report. RESULTS: The pouch-anal anastomosis was mentioned in the pouchoscopy reports of 674 patients, of whom 525 (77.9%) had a stapled anastomosis. Among these, cuffitis occurred in 313 (59.6%) patients a median of 1.51 (interquartile range 0.59-4.17) years after final surgical stage. On multivariable analysis, older age (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.01-1.02), extensive disease (HR, 1.34; 95% CI, 1.01-1.78), exposure to biologics before colectomy (HR, 2.51; 95% CI, 1.93-3.27), and exposure to at least 2 or more biologics before colectomy (HR, 2.18; 95% CI, 1.40-3.39) were significantly associated with subsequent cuffitis. CONCLUSIONS: In this multicenter study of patients who underwent RPC with stapled IPAA and at least 1 follow-up pouchoscopy, cuffitis occurred in approximately 60% and was significantly associated with extensive disease and exposure to multiple biologics precolectomy.

In this multicenter study of patients who underwent restorative proctocolectomy with stapled ileal pouch­anal anastomosis and at least 1 subsequent pouchoscopy, endoscopic cuffitis occurred in 60% and was significantly associated with extensive disease and exposure to multiple biologics.

Two-Year Efficacy and Safety of Mirikizumab Following 104 Weeks of Continuous Treatment for Ulcerative Colitis: Results From the LUCENT-3 Open-Label Extension Study.

BACKGROUND: Mirikizumab, a p19-directed interleukin-23 monoclonal antibody, is efficacious in inducing clinical remission at week 12 (W12) and maintaining clinical remission at W52 in patients with moderately to severely active ulcerative colitis. Results are presented from the open-label extension study through W104. METHODS: Clinical, symptomatic, quality-of-life, and adverse event outcomes are reported for mirikizumab induction responders and extended induction responders, including biologic-failed patients, who entered LUCENT-3, with data shown for W52 maintenance responders or remitters. Discontinuations or missing data were handled by nonresponder imputation (NRI), modified NRI (mNRI), and observed case (OC). RESULTS: Among W52 mirikizumab responders, clinical response at W104 was 74.5%, 87.2%, and 96.7% and clinical remission was 76.6%, 89.0%, and 98.3% for NRI, mNRI, and OC, respectively. Among W52 mirikizumab remitters, clinical response at W104 was 54.0%, 62.8%, and 70.1% and clinical remission was 65.6%, 76.1%, and 84.2%. Using mNRI, remission rates at W104 for W52 clinical remitters were 74.7% corticosteroid-free, 79.5% endoscopic, 63.9% histologic-endoscopic mucosal remission, 85.9% symptomatic, 59.8% bowel urgency, 80.5% Inflammatory Bowel Disease Questionnaire (using NRI), 71.2% histologic-endoscopic mucosal improvement, and 77.5% bowel urgency improvement. Previous biologic-failed vs not-biologic-failed patient data were generally similar. Extended induction mNRI clinical response was 81.9%. Serious adverse events were reported in 5.2% of patients; 2.8% discontinued treatment due to adverse events. CONCLUSIONS: Endoscopic, histologic, symptomatic, and quality-of-life outcomes support the long-term benefit of mirikizumab treatment up to 104 weeks in patients with ulcerative colitis, including biologic-failed patients, with no new safety concerns.

Long-term clinical response/remission, endoscopic, histologic, and symptomatic data from an open-label study in patients with moderately to severely active ulcerative colitis demonstrate that 2-year continuous mirikizumab treatment maintained clinical remission in a majority of induction clinical responders, regardless of previous biologic failure status.

Real-World Outcomes of Dual Advanced Therapy in Children and Young Adults with Inflammatory Bowel Disease.

BACKGROUND: Data are limited on the safety and efficacy of combining advanced therapies for refractory patients with IBD. AIM: To evaluate the real-world efficacy and safety of dual advanced therapy (DAT), combining 2 biologics or a biologic with a small molecule, in children and young adults with refractory IBD. METHODS: Primary outcome of this single IBD center cohort was DAT remission (clinical and biomarker remission) at first assessment (T1). Secondary outcomes included remission at T2, if DAT de-intensification (De-I) occurred and T3, if T2 DAT re-intensification (Re-I) occurred. Efficacy and safety outcomes were described. RESULTS: Of the 30 patients [43% female, 30% CD, median age of 18.3 [15.1-19.8] years], all 11 UST + TOFA achieved T1 remission; 6/10 De-I failed at T2; and 4/4 Re-I achieved T3 remission. Of 9 VDZ + TOFA, 6 achieved T1 remission; 5/6 De-I failed at T2; and 1/1 failed T3 Re-I. Of 4 UST + VDZ, 3 achieved T1 remission; 2/3 De-I failed at T2; and 0 had Re-I. Of 5 UST + UPA, 4 achieved T1 remission; 1/5 De-I failed at T2 but recaptured T3 remission post-Re-I. One VDZ + OZA achieved T1 remission and maintained T2 remission post-De-I to OZA monotherapy. At last follow-up, 43% were on original DAT, 17% on one of original DAT, and 40% neither. One UST + TOFA patient developed mild leukopenia and another developed septic arthritis and venous thromboembolism on VDZ + TOFA and prednisone. CONCLUSION: Most children and young adults treated with DAT achieved remission with minimal safety events; however, de-intensification had limited success.

Low-Dose Aspirin Use Does Not Increase Disease Activity in Pregnant Patients with Inflammatory Bowel Disease.

BACKGROUND: The adverse effects of non-steroidal anti-inflammatory (NSAID) drugs on the gastrointestinal system are well recognized, but the effect of NSAID use on disease activity patients with inflammatory bowel disease (IBD) remains unresolved. Low-dose aspirin (LDA) is recommended for all pregnant patients with risk factors for developing preeclampsia, including autoimmune conditions. As recognition of risk factors for preeclampsia improves, the preventative use of LDA is likely to increase. AIMS: To investigate if LDA use for prevention of preeclampsia increases the risk of disease activity in pregnant women with IBD. METHODS: Single-center retrospective cohort study of pregnant patients with IBD who delivered from 2012 to 2020, comparing those with and without LDA use. Primary outcome was odds of clinical IBD activity in patients in remission at time of conception. Secondary outcomes were rate of elevated inflammatory biomarkers, defined as C-reactive protein > 5 ug/mL or fecal calprotectin > 250 ug/g, and rate of preeclampsia. Univariate analyses tested for associations. RESULTS: Patients taking LDA were older (p = 0.003) and more likely to have chronic hypertension (p = 0.002), to have undergone in vitro fertilization (p < 0.001), and to be on biologics (p = 0.03). Among patients in remission at conception, there was no difference in clinical disease activity or biomarker elevation during pregnancy based on LDA use (OR 1.27, 95% CI [0.55-2.94], p = 0.6). Rates of preeclampsia were similar between groups. CONCLUSION: LDA use for preeclampsia prevention did not increase the incidence of disease activity in pregnant patients with IBD.

Corrigendum: Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

[This corrects the article DOI: 10.3389/fimmu.2024.1342477.].

Cytomegalovirus Colitis in a Patient with Severe Treatment Refractory Ulcerative Colitis.

Background: Cytomegalovirus (CMV) can be reactivated in ulcerative colitis (UC), but its role in progression of inflammation is unclear. Risk factors include severe colitis and treatment with immunosuppressive medications, particularly corticosteroids and immunomodulators. Methods: We report a case of cytomegalovirus colitis in a pediatric patient with pancolitis who had been refractory to aminosalicylate, infliximab, and ustekinumab and was in clinical remission and with transmural response on upadacitinib. Results: This is a case of a 13-year-old male with UC refractory to multiple therapies who were in clinical remission on upadacitinib 30 mg daily. He developed an acute increase in symptoms and did not respond to therapy escalation with increased upadacitinib 45 mg daily for 2 weeks and prednisone for 1 week. He was diagnosed with cytomegalovirus colitis on flexible sigmoidoscopy biopsy. He was treated with intravenous ganciclovir with tapering of immunosuppressive regimen. Despite initial response, he underwent subtotal colectomy and subsequent restorative proctocolectomy with ileal pouch anal-anastomosis. Conclusions: Despite our patient having multiple risk factors for developing CMV colitis, upadacitinib may have played a role when considering its known impact on the herpes family of viruses. CMV colitis should be evaluated for in any patient who presents with worsening symptoms without evidence of other infection or response to increase in therapy.

Humoral immune response and safety of SARS-CoV-2 vaccination in very early onset inflammatory bowel disease.

Children with very early onset inflammatory bowel disease (VEO-IBD) may respond differently to coronavirus disease 2019 (COVID-19) immunization compared to healthy children or other patients with IBD. We recruited children with VEO-IBD <6 years of age and younger following receipt of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Demographics, IBD characteristics, medication use, adverse events (AEs) and IBD exacerbations were collected. Blood draws (optional) were obtained for measurement of antireceptor binding domain (RBD) IgG antibodies following vaccination. Of 41 participants, none required emergency department visit or hospitalization due to AE, and only one experienced IBD exacerbation. Detectable antibody was present in 19/19 participants who provided blood sample; 6/7 participants (86%) had durable humoral response 12 months postvaccination. Children with VEO-IBD experience robust humoral immune response to COVID-19 immunization. Severe AEs were rare. These findings provide reassurance that children with VEO-IBD respond well and safely to SARS-CoV-2 vaccination.

Long-Term Effectiveness and Durability of COVID-19 Vaccination Among Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: COVID-19 vaccination prevents severe disease in most patients with inflammatory bowel disease (IBD), but immunosuppressive medications can blunt serologic response. We followed adults with IBD for >1 year post-COVID-19 vaccination to describe factors associated with SARS-CoV-2 infection after vaccination, evaluate for a protective SARS-CoV-2 antibody level, characterize SARS-CoV-2 antibody persistence, and identify factors associated with humoral immune response durability. METHODS: Using a prospective cohort of COVID-19 immunized adults with IBD, we analyzed factors associated with SARS-CoV-2 infection after vaccination. We evaluated for an association between SARS-CoV-2 antibody level 12 weeks postvaccination and subsequent SARS-CoV-2 infection and assessed for a threshold of protection using receiver-operating characteristic curve analysis. We then conducted a separate analysis evaluating factors associated with persistence of SARS-CoV-2 antibodies 52 weeks postimmunization. RESULTS: Almost half (43%) of 1869 participants developed COVID-19 after vaccination, but most infections were mild, and <1% required hospitalization. Older age and corticosteroid use were associated with a decreased risk of SARS-CoV-2 infection postvaccination (50-59 years of age vs 18-29 years of age: adjusted hazard ratio, 0.57; 95% confidence interval, 0.44-0.74; steroid users vs nonusers: adjusted hazard ratio, 0.58; 95% confidence interval, 0.39-0.87). Most (98%) participants had detectable antibody levels at 52 weeks postvaccination. Antibody levels at 12 weeks and number of vaccine doses were positively associated with higher antibody levels at 52 weeks, while anti-tumor necrosis factor α therapy was negatively associated. CONCLUSIONS: COVID-19 vaccination generates an effective and durable protective response for the vast majority of adults with IBD, including vulnerable populations such as corticosteroid users and older individuals. Patients with IBD benefit from COVID-19 booster vaccination.

Pregnancy Outcomes in the Ozanimod Clinical Development Program in Patients With Ulcerative Colitis, Crohn's Disease, and Relapsing Multiple Sclerosis.

This study evaluated pregnancy outcomes in patients with ulcerative colitis, Crohn's disease, or multiple sclerosis and in healthy volunteers treated with ozanimod. There was no increased incidence of fetal abnormalities or adverse pregnancy outcomes with ozanimod exposure during early pregnancy.

Determining the Accuracy of Intestinal Ultrasound Scores as a Prescreening Tool in Crohn's Disease Clinical Trials.

INTRODUCTION: High rates of screen failure for the minimum Simple Endoscopic Score for Crohn's Disease (SES-CD) plague Crohn's disease (CD) clinical trials. We aimed to determine the accuracy of segmental intestinal ultrasound (IUS) parameters and scores to detect segmental SES-CD activity. METHODS: A single-center, blinded, cross-sectional cohort study of children and young adult patients with CD undergoing IUS and ileocolonoscopy, comparing segmental IUS bowel wall thickness (BWT), hyperemia (modified Limberg score [MLS]), and scores to detect segmental SES-CD activity: (i) SES-CD ≤2, (ii) SES-CD ≥6, and (iii) SES-CD ≥4 in the terminal ileum (TI) only. Primary outcome was accuracy of BWT, MLS, and IUS scores to detect SES-CD ≤2 and SES-CD ≥6. Secondary outcomes were accuracy of TI BWT, MLS, and IUS scores to detect SES-CD ≥4 and correlation with the SES-CD. RESULTS: Eighty-two patients (median [interquartile range] age 16.5 [12.9-20.0] years) underwent IUS and ileocolonoscopy of 323 bowel segments. Segmental BWT ≤3.1 mm had a similar high accuracy to detect SES-CD ≤2 as IUS scores (area under the receiver operating curve [AUROC] 0.833 [95% confidence interval 0.76-0.91], 94% sensitivity, and 73% specificity). Segmental BWT ≥3.6 mm and ≥4.3 mm had similar high accuracy to detect SES-CD ≥6 (AUROC 0.950 [95% confidence interval 0.92-0.98], 89% sensitivity, 93% specificity) in the colon and an SES-CD ≥4 in the TI (AUROC 0.874 [0.79-0.96], 80% sensitivity, and 91% specificity) as IUS scores. Segmental IUS scores strongly correlated with the SES-CD. DISCUSSION: Segmental IUS BWT is highly accurate to detect moderate-to-severe endoscopic inflammation. IUS may be the ideal prescreening tool to reduce unnecessary trial screen failures.

Early Intestinal Ultrasound Response to Biologic Therapy Predicts Endoscopic Remission in Children with Ileal Crohn's Disease: Results from the Prospective Super Sonic Study.

BACKGROUND AND AIMS: STRIDE-II recommends early biomarker targets for treatment optimization to achieve treat-to-target (T2T) endoscopic remission (ER) in Crohn's disease (CD). Predictive capabilities of intestinal ultrasound (IUS) for T2T ER remains unknown. We aimed to evaluate IUS response to predict ER in children with CD. METHODS: Prospective longitudinal cohort study of children with ileal (TI) CD initiating biologic therapy undergoing IUS, clinical disease activity, and C-reactive protein (CRP) assessments at baseline, week 8, 6 months, and T2T within 1 year. Primary outcome was the accuracy of optimal cut-points to predict TI ER (SES-CD < 2) for change in bowel wall thickness (BWT) on IUS from baseline to week 8, and BWT at week 8. Area under the receiver operating curve analysis was performed and univariate analysis tested associations. RESULTS: 44 children (median age 13 [IQR 12-17] years, 29 (66%) biologic naïve) were included, 29 (66%) achieved ER. A > 18% decrease in TI BWT at week 8 predicted ER with an AUROC of 0.99 [95% CI 0.98-1.00], 100% sensitivity, 93% specificity, 97% PPV, and 100% NPV, superior to a > 46% decrease in PCDAI (AUROC 0.67 [95% CI 0.49-0.84]) and > 84% decrease in CRP (AUROC 0.49 [95% CI 0.31-0.67]) at week 8. CONCLUSIONS: Early change in TI BWT on IUS is highly predictive of ER in children with CD and superior to symptoms and CRP. Our findings suggest that IUS could be used for treatment optimization and tight control to guide T2T strategy.

Single-center Experience With Upadacitinib for Adolescents With Refractory Inflammatory Bowel Disease.

BACKGROUND: Upadacitinib (UPA) is a novel selective JAK inhibitor approved for adults with ulcerative colitis (UC) and with positive phase 3 data for Crohn's disease (CD). Pediatric off-label use is common due to delays in pediatric approvals; real-world data on UPA are needed to understand the safety and effectiveness in pediatric IBD. METHODS: This is a single-center retrospective case series study of adolescents (12-17 years) with inflammatory bowel disease IBD on UPA. The primary outcome was postinduction steroid-free clinical remission (SF-CR) defined as Pediatric UC Activity Index (PUCAI) or Pediatric CD Activity Index (PCDAI) ≤10. Secondary outcomes include postinduction clinical response (decrease ≥12.5 in PUCAI/PCDAI), postinduction C-reactive protein (CRP) normalization, 6-month SF-CR, and intestinal ultrasound response and remission. Adverse events were recorded through last follow-up. RESULTS: Twenty patients (9 CD, 10 UC, 1 IBD-U; 55% female; median age 15 years, 90% ≥2 biologics) were treated with UPA for ≥12 weeks (median 51 [43-63] weeks). Upadacitinib was used as monotherapy in 55% and as combination with ustekinumab and vedolizumab in 35% and 10%, respectively. Week 12 SF-CR was achieved in 75% (15/20) and 80% (16/20) with CRP normalization. About 3/4 (14/19) achieved SF-CR at 6 months. Adverse event occurred in 2 patients (10%): Cytomegalovirus colitis requiring hospitalization and hyperlipidemia requiring no treatment. In the 75% with ultrasound monitoring, response and remission were achieved in 77% and 60%, respectively. CONCLUSION: While awaiting pediatric registration trials, our data suggest that UPA is effective in inducing and maintaining SF-CR in adolescents with highly-refractory IBD with an acceptable safety profile.

This case series presents novel data on the effectiveness and safety of upadacitinib in adolescent patients with IBD.