Characterization of Biologic Discontinuation Among Pediatric Patients with Crohn's Disease.

BACKGROUND & AIMS: Biologic therapies may effectively treat Crohn's disease (CD), and pediatric patients who discontinue multiple biologics risk exhausting treatment options. The frequency and context of biologic discontinuation have not been well-characterized. We aimed to determine patterns of biologic use, discontinuation, and evaluation in pediatric patients with CD. METHODS: Pediatric patients with CD at 7 U.S. centers (2010-2020) were identified. Prospective ImproveCareNow registry data were supplemented with medical record abstraction. Biologics included monoclonal antibody and small molecule medications. Therapeutic drug monitoring (TDM) was considered induction if <14 weeks after biologic start, proactive if later during quiescent disease, and reactive during active disease. RESULTS: Of 823 patients included (median age, 13.0 years; 40% female), 86% started biologics (78% infliximab, 21% adalimumab, <1% others). Twenty-six percent used concomitant immunomodulators for ≥12 months. Most (85%) measured TDM including 47% induction, 69% proactive, and 24% reactive. Twenty-nine percent discontinued their first biologic after median 793 days because of inefficacy (34%), anti-drug antibodies (8%), adverse events (8%), or non-adherence (12%). If inefficacy, 86% underwent pre-discontinuation evaluation. If infliximab or adalimumab inefficacy and TDM was done, 62% had levels <10 µg/mL. Proactive TDM and concomitant immunomodulators were associated with 60% and 32% reduced biologic discontinuation. CONCLUSIONS: Most children with CD are treated with biologics; 25%-37% discontinue biologics, resulting in 1 in 12 using >2 biologics during pediatric care. Half of patients discontinued biologics without trial of high-dose therapy and 14% without any evaluation. Concomitant immunomodulator use and proactive TDM decreased risk of biologic discontinuation. Strategies are needed to preserve biologic efficacy and prevent biologic discontinuation.

Venous Thromboembolism Prophylaxis in Pediatric Inflammatory Bowel Disease Patients Hospitalized With a Central Line.

OBJECTIVES: Patients hospitalized with inflammatory bowel disease (IBD) have increased risk of venous thromboembolism (VTE). The aim of this study was to determine whether the adoption of a VTE protocol would change rates of medical VTE prophylaxis (low molecular weight heparin) in patients with IBD and a central venous catheter (CVC), while subsequently decreasing the incidence of VTE in this population. METHODS: A protocol for VTE prophylaxis in IBD was established in March of 2018. Every patient hospitalized with an IBD flare and central venous access from March 2013 to March 2020 was identified. Study data, including patient demographics, rates of Doppler ultrasound (US), and rates of VTE were collected using International Classification of Diseases (ICD)-10 codes, CPT codes, and chart review retrospectively. Determination of an IBD flare was based on physician global assessment. Groups were compared with independent-sample t tests and chi-squared tests. RESULTS: A total of 313 hospitalizations across 187 different patients were identified that met criteria including IBD and central venous access. VTE prophylaxis increased from 5.24% (n = 12) prior to the intervention to 63.10% (n = 53) after the intervention [chi-square (1, N = 313) = 125.0192, P < 0.001]. Rate of Doppler US increased from 9.17% (n = 21) prior to the intervention to 17.86% (n = 15) after the intervention [chi-square (1, N = 313) = 4.5562, P < 0.05]. Diagnosis of VTE increased from 0.87% (n = 2) prior to the intervention to 7.14% (n = 6) after the intervention [chi-square (1, N = 313) = 9.6992, P < 0.01]. There were no significant differences in the demographic characteristics pre- versus post-intervention. CONCLUSIONS: Rates of Doppler US and VTE prophylaxis use increased significantly after implementation of a VTE protocol. Rates of VTE diagnosis also increased, though we suspect this may be due to missed diagnoses prior to implementation of the protocol and increased risk awareness after the protocol was established.

Text Messaging Effect on Adherence in Children With Inflammatory Bowel Disease.

BACKGROUND: Successful treatment of patients with inflammatory bowel disease (IBD) requires regular intake of medication. Nonadherence to treatment is associated with increased frequency of relapses, morbidity, and cost. METHODS: Pediatric patients with IBD taking oral medication and with access to text messaging (TM) services were included. Children were randomized by age, sex, medication administration responsibility (self vs parent), and disease activity (Pediatric Crohn Disease Activity Index or Pediatric Ulcerative Colitis Activity Index) into TM intervention and standard of care. Prospectively, the interventional group received 2-way TM reminders about medication administration. Failure to confirm intake by the patient resulted in a TM alert to the caregiver and weekly compliance reports were sent to patients, caregivers, and healthcare providers. Patients' medical records were reviewed and an adherence Morisky questionnaire completed at recruitment, 6 and 12 months. RESULTS: A total of 51 children were randomized (21 TM and 30 control). The age, sex, diagnosis (ulcerative colitis/Crohn), activity index, ethnicity, insurance, and Morisky score at baseline were similar in both groups. Morisky score improved by 1 and 0.8 points, respectively in the TM group at 6 and 12 months, whereas it did not change in the control group (P = 0.0131 and P = 0.1687, prospectively). CONCLUSIONS: TM may be effective in promoting adherence in children with IBD. Larger and longer multicenter studies are required to confirm this finding.

Medical management of pediatric inflammatory bowel disease.

Management of inflammatory bowel disease, both Crohn's disease (CD) and ulcerative colitis (UC), has seen a seismic shift over the past decade. Over the past five years, there has been the introduction of many new therapies with differing mechanisms of action and a goal of achieving mucosal healing, as well as clinical and biochemical remission (1,2). In addition, management is aimed at restoring normal growth and normalizing quality of life. The ultimate goal is to individualize medical management and determine the right drug for the right patient by identifying which inflammatory pathway is predominant and avoiding unwarranted lack of efficacy or side effects through biomarkers and risk prognostication. Patient's age, location of disease, behavior (inflammatory vs. penetrating/structuring), severity and growth delay all play into deciding on the best treatment approach. Ultimately, early intervention is key in preventing complications. The therapeutic approaches to management can be broken down to nutritional therapy, biologic agents, immunomodulators (including corticosteroids), aminosalicylates and antibiotics. There are numerous other therapies, such as small molecule agents recently approved in adults, which are garnering a great deal of interest.

Rescue therapy with upadacitinib in medically refractory pediatric ulcerative colitis.

Approved options for advanced therapy in pediatric inflammatory bowel disease (IBD) are limited. Although Janus kinase (JAK) inhibitors are approved in adult IBD, their benefit in pediatric populations is not yet delineated. We present a 13-year-old female patient with ulcerative colitis (UC) refractory to numerous therapies and courses of prednisone that ultimately responded to a JAK inhibitor. Initial treatment consisted of 5-aminosalicylate and azathioprine. This was changed to adalimumab due to persistent symptoms. Repeat colonoscopy revealed pancolitis, thus she was transitioned to vedolizumab. She was hospitalized twice for uncontrolled symptoms on vedolizumab and subsequent scope showed continued pancolitis. As a result, she transitioned to ustekinumab without symptomatic relief after adjusting to monthly dosing. The family declined colectomy, opting to exhaust all medical therapies. Upadacitinib was started and her symptoms resolved within 1 week, and she remains in steroid-free remission. This case illustrates the possible role of JAK inhibitors in extensively refractory pediatric UC patients before colectomy.

Diagnosis and treatment of perianal Crohn disease: NASPGHAN clinical report and consensus statement.

Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract that includes both Crohn disease (CD) and ulcerative colitis. Abdominal pain, rectal bleeding, diarrhea, and weight loss characterize both CD and ulcerative colitis. The incidence of IBD in the United States is 70 to 150 cases per 100,000 individuals and, as with other autoimmune diseases, is on the rise. CD can affect any part of the gastrointestinal tract from the mouth to the anus and frequently will include perianal disease. The first description connecting regional enteritis with perianal disease was by Bissell et al in 1934, and since that time perianal disease has become a recognized entity and an important consideration in the diagnosis and treatment of CD. Perianal Crohn disease (PCD) is defined as inflammation at or near the anus, including tags, fissures, fistulae, abscesses, or stenosis. The symptoms of PCD include pain, itching, bleeding, purulent discharge, and incontinence of stool. In this report, we review and discuss the etiology, diagnosis, evaluation, and treatment of PCD.

Drug Interaction Between Tacrolimus and Paxlovid (Nirmatrelvir/Ritonavir) in an Adolescent with Inflammatory Bowel Disease.

The coronavirus disease of 2019 (COVID-19) led to a worldwide pandemic. The emergency use of a combination of nirmatrelvir/ritonavir (paxlovid) was approved for high-risk individuals (such as immunocompromised) testing positive for the disease. We present a patient with ulcerative colitis being treated with tacrolimus, as well as ustekinumab, who was diagnosed with COVID-19 and placed on paxlovid due to her immunosuppressed state. She stopped her tacrolimus while on paxlovid and did well clinically. Tacrolimus was restarted 12 hours after completion of paxlovid, but she became symptomatic with vomiting, headache, and malaise and was found to have a toxic tacrolimus level. Tacrolimus was stopped and symptoms resolved, but levels remained elevated for a prolonged period. There is a paucity of literature on this drug-drug interaction, and with the resurgence of COVID-19, it is important to be cognizant of the potential for adverse effects and toxicity.

Endoscopy in a Pediatric Patient After Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a gastrointestinal condition usually found in premature neonates. Our case involves a full-term, 3-month-old male who was found to have pneumatosis after surgical repair of congenital cardiac defects. After cessation of enteral feeds, nasogastric tube decompression, and broad-spectrum antibiotics, breast milk was reintroduced 8 days after his procedure. Hematochezia developed, but repeat abdominal X-rays were normal with benign abdominal examinations, stable vital signs, and improved laboratory findings. Although feeds were slowly restarted with an amino acid-based formula, hematochezia persisted. Meckel's scan was negative, and Computerized Tomography revealed diffuse bowel inflammation. Esophagogastroduodenoscopy and flexible sigmoidoscopy were performed for further evaluation which showed stricture and ulceration at the descending colon. This procedure was complicated by perforation with subsequent resection of this segment and diverting ileostomy. Due to the risk of complications, it is suggested to wait at least 6 weeks from acute events such as NEC before performing an endoscopy.

Anatomic and histologic variability of epithelial apoptosis in small bowel transplants.

Surveillance ileoscopies are performed regularly immediately post-transplantation to prevent allograft rejection. We investigated whether variability in apoptosis exists between proximal and distal intestinal limbs of double-barreled ileostomies, and if detection varies according to number of biopsies taken and sections prepared for evaluation. We retrospectively analyzed endoscopy/pathology reports of patients who underwent simultaneous proximal and distal ileoscopies during surveillance. We re-reviewed three sections of selected biopsies for the presence of apoptotic bodies and viral inclusions. Seven patients underwent 26 endoscopies in which both distal and proximal limbs were investigated simultaneously. Apoptosis was identified in each limb simultaneously in 21/26 cases (81%). Of the discrepant results, 3/5 (60%) revealed apoptosis in the proximal limb with normal distal limb and 2/5 (40%) had apoptotic bodies identified in the distal limb and normal proximal biopsies. Re-reviewing discrepant biopsies, two patients had at least one piece of mucosa without apoptosis and apoptotic bodies were seen in only 47% of sections. Histologic variability exists between proximal and distal limbs of double-barreled ileostomies and detection of apoptosis increases with number of pieces obtained and sections examined. Investigating both limbs with adequate sample size and rigorous processing may have clinical implications.

Lipopolysaccharide exposure is linked to activation of the acute phase response and growth failure in pediatric Crohn's disease and murine colitis.

BACKGROUND: Systemic exposure to lipopolysaccharide (LPS) has been linked to clinical disease activity in adults with inflammatory bowel disease (IBD). We hypothesized that markers of LPS exposure and the acute phase response (APR) would be increased in pediatric IBD patients with growth failure, and that LPS signaling would be required for induction of the APR in murine colitis. METHODS: Serum markers of LPS exposure, endotoxin core IgA antibody (EndoCAb), and the APR, LPS binding protein (LBP) were quantified in pediatric IBD patients and controls. LBP and cytokine production were determined after administration of trinitrobenzene sulfonic acid (TNBS) enemas to mice with genetic deletion of Toll-Like receptor 4 (TLR4), and wildtype (WT) controls. RESULTS: Serum EndoCAb and LBP were significantly elevated in patients with Crohn's disease (CD), compared to disease controls with ulcerative colitis (UC) and healthy controls (P < 0.001). This was independent of disease activity or location. CD patients with elevated serum EndoCAb and LBP exhibited linear growth failure which persisted during therapy. Serum LBP increased in WT mice following TNBS administration, in conjunction with increased serum TNF-alpha, IL-6, and IL-10, and expansion of regulatory T-cell numbers. Both the APR and expansion of foxp3+ T cells were abrogated in TLR4-deficient mice, in conjunction with a reduction in acute weight loss. CONCLUSIONS: LPS exposure and a persistent APR are associated with growth failure in pediatric CD. LPS signaling is required for the APR in murine colitis. Therapies targeting this pathway may benefit the subset of patients with refractory growth failure.