Inflammatory bowel disease (IBD) causes chronic suffering from gastrointestinal inflammation and dysfunction that can progress to colon cancer1,2. The prevalence of the disease is increasing, and there is an urgent need to better understand its pathogenic mechanisms to improve treatment. We show that GPR15-a G-protein-coupled receptor expressed in immune cells and described previously as an entry co-factor for human and simian immunodeficiency viruses3-is a marker and homing receptor for a subset of intramucosal GPR15-guided regulatory CD8+ T lymphocytes (CD8+ TIGR cells). Deleterious GPR15 gene variants in humans cause defective homing of CD8+ TIGR cells and are associated with severe early-onset IBD. Moreover, CD8+ TIGR cells are reduced in the intestinal mucosa of individuals with sporadic IBD. In mice, GPR15 deficiency impairs colonic homing of CD8+ TIGR cells, leading to accumulation of inflammatory macrophages and increased susceptibility to colitis. CD8+ TIGR cells potently kill macrophages activated by intestinal damage or disease using Fas ligand and TNF-related weak inducer of apoptosis (TWEAK). The identification of CD8+ TIGR cells yields new insights into organ-specific immune regulation and potential therapeutics for IBD.

Infants and children with primary and secondary immune deficiency often present with gastrointestinal symptoms, including diarrhea, abdominal pain, failure to thrive, intestinal infection, malabsorption, and intestinal inflammation. In addition, certain immune deficiencies predispose patients to gastrointestinal and hepatic malignancy. This chapter reviews the development of the mucosal immune system, the pathogenesis of the immune response and intestinal inflammation, and the gastrointestinal manifestations of immune deficiency. In addition, monogenic defects that result in very early onset inflammatory bowel disease are discussed in detail.

Upadacitinib (UPA) is a selective JAK1 inhibitor approved for use in adult IBD, including CD and UC. Off-label use in pediatric IBD is common, but long-term outcomes data with respect to efficacy and safety are lacking. This was a single-center, retrospective study of pediatric patients with IBD, who initiated UPA at < 18 years. Primary outcome was corticosteroid-free clinical remission (CFCR) at 52 ± 16 weeks, defined by PUCAI < 10 (UC), PCDAI ≤10 (CD), or PGA = 0 (where PUCAI or PCDAI unavailable). Secondary outcomes were durability, normalization of CRP, endoscopic remission, and adverse events (AEs). Endoscopic remission was defined as Mayo score 0 (UC) or SES-CD score 0-2 (CD). Forty-eight patients, including 22 (46%) with CD and 26 (54%) with UC were included. Patients were diagnosed at mean age 10.9 ± 4.0 years and started UPA at mean age 14.1 ± 2.9 years. Prior advanced therapy failures included anti-TNF (98%), ustekinumab (56%), vedolizumab (46%), tofacitinib (15%), and risankizumab (6%). For those with CD, 18/22 (82%) had ileocolonic disease and 9/22 (41%) had perianal disease. For those with UC, 20/26 (77%) had pancolitis and 21/26 (81%) had S1 ever-severe disease. Twenty-nine patients (60%) had CRP elevations at UPA initiation and all (100%) had active disease endoscopically. More than half of patients in our cohort (25/48, 52%) had extra-intestinal manifestations (EIMs), with psoriasis (n = 7, 15%), atopic dermatitis (n = 5, 10%), and cutaneous CD (n = 4, 8%) most common. At 52-week follow-up, 39/48 (81%) remained on UPA, including 17/22 (77%) with CD and 22/26 (85%) UC, and of these, 8/17 (47%) with CD and 16/22 (73%) with UC were in CFCR. Of the 7 tofacitinib-experienced patients, 6/7 (86%, 3 CD, 3 UC) continued on UPA at 52 weeks, and 4/7 (57%, 2 CD, 2 UC) achieved CFCR at 52 weeks. Maintenance dosing at 52 weeks was 30 mg (46%), 15 mg (17%), 45 mg (15%), and 12 mg (2%). In terms of biomarker outcomes, 27/37 (73%) had normal CRP values at 52 weeks, including 12/17 (71%) with CD and 15/20 (75%) with UC. Twenty-eight patients had endoscopic re-staging at 52 weeks, and of these, 13 (46%) had confirmed endoscopic remission, including 5/12 (42%) with CD and 8/16 (50%) with UC. AEs were documented in 23/48 (48%), with acne (n = 9, 19%) and abnormal cholesterol (n = 7, 15%) most common. Two patients (4.2%) discontinued UPA due to AEs, including leukopenia (n = 1) and drug reaction (n = 1). There was one reported serious infection occurring on UPA (MRSA cellulitis); there were no thrombotic events, malignancies, or deaths. In this single-center cohort of pediatric IBD patients using UPA, we report high durability and high rates of CFCR at 52 weeks, especially in UC. Most patients used 30 mg or higher maintenance dosing. AEs were common, but AEs leading to medication discontinuation were rare.

BACKGROUND:Mirikizumab, a humanised immunoglobulin G4 monoclonal antibody, targets the p19 subunit of IL-23, with demonstrated efficacy and safety in adults with ulcerative colitis and Crohn's disease. This study evaluated the pharmacokinetics, efficacy, and safety of mirikizumab in paediatric participants with moderately-to-severely active ulcerative colitis. METHODS:This 52-week, multicentre, open-label, non-randomised, phase 2 study enrolled paediatric participants (2 to <18 years) with moderately-to-severely active ulcerative colitis with inadequate or loss of response or intolerance to corticosteroids, immunomodulators, biologics, or JAK inhibitors from 19 centres in Canada, Israel, Japan, South Korea, and the USA. Participants received induction doses of intravenous mirikizumab 5 mg/kg or 10 mg/kg (for bodyweight ≤40 kg) or 300 mg (bodyweight >40 kg) at weeks 0, 4, and 8. Clinical response was determined by the modified Mayo score (mMS). Responders at week 12 entered the maintenance period and received subcutaneous doses of mirikizumab 50 mg (bodyweight ≤20 kg), 100 mg (bodyweight >20 to ≤40 kg), or 200 mg (bodyweight >40 kg) every 4 weeks through week 48. Non-responders at week 12 received three additional intravenous induction doses (10 mg/kg [bodyweight ≤40 kg] or 300 mg [bodyweight >40 kg] every 4 weeks), before continuing to subcutaneous maintenance dosing. Here we present the secondary outcomes of safety and efficacy; pharmacokinetics (primary endpoint) data have been reported previously. The modified intention-to-treat and safety populations included participants who received at least one dose of treatment, regardless of adherence to the protocol or treatment. This study is registered with ClinicalTrials.gov, NCT04004611. FINDINGS:26 participants were enrolled between May 18, 2020, and March 15, 2023; mean age was 11·8 years (SD 3·4) and mean weight was 40·5 kg (SD 16·0). 15 (58%) participants were female and 11 (42%) were male. At week 12, 18 (69·2%, 95% CI 50·0-83·5) participants had a clinical response by mMS, ten (38·5%, 95% CI 22·4-57·5) achieved clinical remission by mMS, 14 (53·8%, 95% CI 35·5-71·2) achieved endoscopic remission, four (15·4%, 6·2-33·5) had histologic-endoscopic mucosal improvement (HEMI), one (3·8%, 0·7-18·9) had histologic-endoscopic mucosal remission (HEMR), and 12 (46·2%, 28·8-64·5) achieved symptomatic remission. When assessed by Pediatric Ulcerative Colitis Activity Index (PUCAI), 20 (76·9%, 57·9-89·0) of the 26 participants had a clinical response, and ten (38·5%, 22·4-57·5) achieved clinical remission at week 12. At week 52, 14 (53·8%, 35·5-71·2) of 26 participants achieved mMS-based clinical response, ten (38·5%, 22·4-57·5) were in mMS-based clinical remission, 14 (53·8%, 35·5-71·2) had a PUCAI-based clinical response and 13 (50·0%, 32·1-67·9) were in PUCAI-based clinical remission. At week 52, ten (38·5%, 95% CI 22·4-57·5) of 26 patients were in endoscopic remission, nine (34·6%, 19·4-53·8) had HEMI, nine (34·6%, 19·4-53·8) had HEMR, and 12 (46·2%, 28·8-64·5) were in symptomatic remission. At week 52, ten (38·5%, 95% CI 22·4-57·5) of the 26 participants had achieved clinical remission without corticosteroid use or ulcerative colitis-related surgery for at least 12 weeks leading up to week 52. Three (12%) participants experienced serious adverse events across induction and maintenance periods (non-infective appendicitis, worsening of ulcerative colitis, and pseudarthrosis), of which one (4%; worsening of ulcerative colitis) led to study discontinuation. The most common adverse events were COVID-19 (in six [23%] of 26 participants); injection site pain (six [23%]); headache (five [19%]); pyrexia (four [15%]); and viral upper respiratory tract infection (four [15%]). INTERPRETATION:Mirikizumab exhibited safety and efficacy in paediatric participants with moderately-to-severely active ulcerative colitis. These results support further evaluation of mirikizumab in the paediatric population. FUNDING:Eli Lilly and Company.

Helicobacter pylori (HP) clinical guidelines encourage obtaining gastric biopsy culture and antimicrobial susceptibilities to guide therapy. Susceptibility-guided treatment (SGT) reduces unnecessary exposure to ineffective antibiotics, minimizes adverse events, and promotes antimicrobial stewardship. However, real-world data on its effectiveness remains limited. We aim to compare the efficacy of SGT to empirical therapy (ET). Retrospective cohort study, single pediatric tertiary care center, Boston Children's Hospital, January/2019 to June/2024. First-time H. pylori-histological diagnosis and subsequent treatment. Data extracted: demographic variables, endoscopy indications, endoscopic and histological findings, prior antimicrobial use, treatment regimen, eradication, and antimicrobial susceptibility. We compared eradication rates on patients who received ET versus those who received SGT and among SGT recipients. Two hundred and eighteen study subjects (95 ET, 123 SGT) were included. Mean age:13.6 ± 4.8 years, 50.9% male, 59.6% White, 38.1% Hispanic. Endoscopic findings: gastritis (92.7%), duodenitis (11.5%), gastric ulcer/erosion (5.0%), duodenal ulcer/erosion (13.3%). Eradication success was significantly higher in the SGT group (89.4%,110/121) compared to the ET group (70.2%, 66/94) (p < 0.001). Resistance rates: clarithromycin (26.8%), metronidazole (18.7%), fluoroquinolones (9.8%), amoxicillin (3.3%), rifampin (8.9%), no tetracycline resistance. Amoxicillin resistance was strongly associated with failure (27.3% vs. 0.9%, p = 0.002), as was dual clarithromycin-metronidazole resistance (36.4% vs. 8.2%, p = 0.018). In univariate analysis, amoxicillin resistance had the strongest association with failure (odds ratio [OR] 40.9, p < 0.001), followed by dual clarithromycin-metronidazole resistance (OR 6.41, p = 0.016), and metronidazole resistance (OR 4.26, p = 0.034). SGT resulted in higher eradication rates than ET. Clarithromycin and metronidazole resistance rates were >15%. Antibiotic resistance, especially to amoxicillin, is a major driver of eradication failure.

Background: Children with inflammatory bowel disease (IBD) may have diminished serologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and increased risk for subsequent severe coronavirus disease 2019 (COVID-19) infection. We sought to describe outcomes among those who developed SARS-CoV-2 infection following vaccination, characterize SARS-CoV-2 antibodies 1 year post-vaccination, and identify factors associated with durable serologic response. Methods: We recruited children with IBD who received >= 2 doses of SARS-CoV-2 vaccine and prospectively collected data on (1) demographics, IBD characteristics, and therapy and (2) SARS-CoV-2 vaccination, testing, and infection symptoms. Serum was obtained for measurement of anti-receptor-binding domain IgG antibodies following a 2-part immunization at 12 and 52 weeks. Results: We enrolled 298 participants (mean age 11.9 +/- 3.82, 50% female, 67% Crohn's disease). Symptomatic COVID-19 infection after vaccination occurred in half of the participants, although only 2 (1%) required hospitalization. Anti-tumor necrosis factor alpha (TNF-alpha) was associated with higher likelihood of symptomatic COVID-19 infection, with an adjusted hazard ratio of 2.7 (95% CI, 1.5-5.0; P = .001). Nearly all participants (99%) had detectable antibody at Week 52. Children aged 1-5 years had lower 52-week antibody level compared to older children (P = .04), as did those on anti-TNF-alpha therapy (P = .007) and those who received only 2 vaccine doses prior to Week 52 (P < .001). Conclusions: SARS-CoV-2 vaccination provides lasting serologic response and protection against severe COVID-19 for most children with IBD, despite the use of lower vaccine doses in younger children and wide-ranging classes of immunosuppressive therapies.

OBJECTIVES:Sulfasalazine (SZ) and 5-aminosalicylates (5-ASA) have been widely used treatments for ulcerative colitis (UC). Although some studies suggest SZ may be superior, limited data exists comparing the two in children. This study aimed to describe real-world data on their comparative safety and efficacy in children and the impact of switching between SZ and 5-ASA before treatment escalation. METHODS:We retrospectively reviewed the electronic medical records of children diagnosed with UC between June 1999 and December 2019 at Boston Children's Hospital. We described outcomes at 1 year and long-term in patients treated with SZ or 5-ASA as a first-line maintenance agent. RESULTS:Among 433 patients (age 0-19 years), 124 started on SZ and 309 on 5-ASA. Forty-eight patients switched between the two drugs within the first year, and 74 switched during long-term follow-up. The main reason for switching from SZ to 5-ASA was adverse reactions. At 1 year, 54%, 44.3%, and 36.6% of patients on SZ, 5-ASA, and those who switched, respectively, were in steroid-free remission (p = 0.13). Patients who switched due to lack of efficacy or adverse reactions were four times more likely to escalate treatment compared to nonmedical reasons. Patients with Pediatric Ulcerative Colitis Activity Index >65 at the diagnosis are more likely to require treatment escalation (p = 0.0043). CONCLUSIONS:SZ and 5-ASA are effective first-line treatments for mild to moderate pediatric UC. SZ tends to have more minor adverse reactions. Switching between SZ and 5-ASA does not offer therapeutic benefits, and disease severity at diagnosis predicts early treatment escalation.

Background and AimsCOVID-19 vaccination prevents severe disease in most patients with 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.MethodsUsing 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 post-vaccination and subsequent SARS-CoV-2 infection and assessed for a threshold of protection using receiver operating curve analysis. We then conducted a separate analysis evaluating factors associated with persistence of SARS-CoV-2 antibodies 52 weeks post-immunization.ResultsAlmost half (43%) of 1,869 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 post-vaccination (ages 50-59 vs 18-29: adjusted hazard ratio [aHR] 0.57; 95% confidence interval [CI] 0.44-0.74; steroid users vs non-users: aHR 0.58; 95% CI 0.39-0.87). Most (98%) participants had detectable antibody levels at 52 weeks post-vaccination. 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 (TNF) alpha therapy was negatively associated.ConclusionsCOVID-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.

Background: Infliximab (IFX) use is limited by loss of response often due to the development of anti-IFX antibodies and low drug levels. Methods: We performed a single center prospective observational cohort study of pediatric and young adult subjects with inflammatory bowel disease (IBD) on IFX with over 3 years of follow-up. Infliximab levels (IFXL) and antibodies to infliximab (ATI) were measured throughout the study. Subjects were followed until IFX was discontinued. Results: We enrolled 219 subjects with IBD (184: Crohn's disease; 33: Ulcerative colitis; and 2 Indeterminant colitis; 84 female, median age 14.4 years, 37% on concomitant immunomodulator). Nine hundred and nineteen serum samples (mean 4.2 +/- 2.1 per patient) were tested for IFXL and ATI. During the study, 31 (14%) subjects discontinued IFX. Sixty patients had ATI. Twenty-two of those 60 patients with ATI discontinued IFX; 14 of 31 patients who discontinued IFX had detectable ATI at study onset. The combination of ATI and IFXL < 5 g/mL at study entry was associated with the highest risk of drug discontinuation (hazard ratios [HR] ATI 4.27 [p < 0.001] and IFXL < 5 mu g/mL [HR]: 3.2 p = 0.001). Patients with IFXL 5-10 mu g/mL had the lowest rate of discontinuation (6%). IFX dose escalation eliminated ATI in 21 of 60 subjects. Conclusions: ATI is a strong predictor of needing to stop IFX use and inversely correlates with IFXL. Detection of ATI during therapeutic drug monitoring postinduction but also periodically during maintenance therapy identifies individuals who may benefit from IFX dose escalation and/or the addition of an immunomodulator, as these interventions may reduce or eliminate ATI.

Background: Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 mu g/mL for infliximab and >7.5 mu g/mL for adalimumab). Methods: We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. Results: Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 mu g/mL [P = .49]; adalimumab: 11.1 vs 10.5 mu g/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 mu g/mL [P < .01]; adalimumab: 9.1 vs 12.3 mu g/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). Conclusions: LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

OBJECTIVES:HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS:We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs. combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. RESULTS:A trend towards increased treatment failure among HLA DQA1*05 positive participants was not significant (HR 1.58, 95% CI 0.95-2.62; p=0.08). After stratification by HLA DQA1*05 and by methotrexate vs. placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05 positive patients on placebo (HR 0.31, 95% CI 0.13-0.70; p=0.005).A trend toward increased ADA development among HLA DQA1*05 positive participants was not significant (odds ratio [OR] 1.96, 95% CI 0.90-4.31, p=0.09). After further stratification, HLA DQA1*05 negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05 positive patients on placebo (OR 0.12, 95% CI 0.03-0.55; p=0.008). CONCLUSIONS:In a randomized trial of children with CD initiating anti-TNF, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

INTRODUCTION:Human leukocyte antigen (HLA) DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNFα) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS:We analyzed banked serum from patients with CD aged <21 years enrolled in clinical outcomes of Methotrexate Binary Therapy in practice, a multicenter, prospective randomized trial of anti-TNFα monotherapy vs combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. RESULTS:A trend toward increased treatment failure among HLA DQA1*05-positive participants was not significant (hazard ratio 1.58, 95% confidence interval [CI] 0.95-2.62; P = 0.08). After stratification by HLA DQA1*05 and by methotrexate vs placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05-positive patients on placebo (hazard ratio 0.31, 95% CI 0.13-0.70; P = 0.005). A trend toward increased ADA development among HLA DQA1*05-positive participants was not significant (odds ratio 1.96, 95% CI 0.90-4.31, P = 0.09). After further stratification, HLA DQA1*05-negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05-positive patients on placebo (odds ratio 0.12, 95% CI 0.03-0.55; P = 0.008). DISCUSSION:In a randomized trial of children with CD initiating anti-TNFα, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

Fecal Microbiota Transplant (FMT) has shown some success in treating inflammatory bowel diseases (IBD). There is emerging evidence that host engraftment of donor taxa is a tenet of successful FMT. We undertook a double-blind, randomized, placebo-controlled pilot study to characterize the response to FMT in children and young adults with mild to moderate active Crohn's disease (CD) and ulcerative colitis (UC). Subjects with CD or UC were randomized to receive antibiotics and weekly FMT or placebo in addition to baseline medications. We enrolled 15 subjects aged 14-29 years. Four subjects had CD, and 11 had UC. Subjects exhibited a wide range of microbial diversity and donor engraftment. Specifically, engraftment ranged from 26 to 90% at week 2 and 3-92% at 2 months. Consistent with the current literature, increases over time of both alpha diversity (p < 0.05) and donor engraftment (p < 0.05) correlated with improved clinical response. We discovered that the post-antibiotic but pre-FMT time point was rich in microbial correlates of eventual engraftment. Greater residual alpha diversity after antibiotic treatment was positively correlated with engraftment and subsequent clinical response. Interestingly, a transient rise in the relative abundance of Lactobacillus was also positively correlated with engraftment, a finding that we recapitulated with our analysis of another FMT trial.