Pediatric Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBDs) are chronic, immune-mediated disorders that include Crohn's disease and ulcerative colitis. A pediatric onset of disease occurs in about 10% of all cases. Clinical presentation of IBD with rectal bleeding or perianal disease warrants direct referral for endoscopic evaluation. In the absence of red-flag symptoms, a combination of patient history and blood and fecal biomarkers can help to distinguish suspected IBD from other causes of abdominal pain or diarrhea. The therapeutic management of pediatric IBD has evolved by taking into account predictors of poor outcome, which justifies the upfront use of anti-tumor necrosis factor therapy for patients at high risk for complicated disease. In treating patients with IBD, biochemical or endoscopic remission, rather than clinical remission, is the therapeutic goal because intestinal inflammation often persists despite resolution of abdominal symptoms. Pediatric IBD comes with unique additional challenges, such as growth impairment, pubertal delay, the psychology of adolescence, and development of body image. Even after remission has been achieved, many patients with IBD continue to experience nonspecific symptoms like abdominal pain and fatigue. Transfer to adult care is a well-recognized risk for disease relapse, which highlights patient vulnerability and the need for a transition program that is continued by the adult-oriented IBD team. The general pediatrician is an invaluable link in integrating these challenges in the clinical care of patients with IBD and optimizing their outcomes. This state-of-the-art review aims to provide general pediatricians with an update on pediatric IBD to facilitate interactions with pediatric gastrointestinal specialists.

Ustekinumab trough levels in children with Crohn's disease refractory to anti-tumor necrosis factor agents: a prospective case series of off-label use.

Background: Ustekinumab is used off-label in pediatric Crohn's disease refractory to anti-tumor necrosis factor. Data on optimal dosing, target trough levels, and potential benefit of therapeutic drug monitoring in children treated with ustekinumab are limited. Materials and Methods: We describe a series of six adolescents who consented to be treated with ustekinumab. We measured their trough levels, C-reactive protein, and fecal calprotectin before every administration. Results: Standard adult dosing was effective to achieve biochemical remission (fecal calprotectin < 250 mg/kg) in one patient and clinical remission (resolution of symptoms) in another. The other four patients failed to respond on standard dosing and underwent intravenous re-induction and interval shortening to increase ustekinumab trough levels. This resulted in biochemical remission in one patient and clinical remission in another, suggesting an exposure-response relationship. The remaining two patients had no therapeutic benefit, and ustekinumab was discontinued. Conclusion: In this report, we show that ustekinumab can induce remission in pediatric patients with anti-tumor necrosis factor refractory Crohn's disease. It is worth escalating the dose before abandoning the drug as ineffective. Prospective studies in children are needed to determine long-term efficacy of ustekinumab, usefulness of therapeutic drug monitoring strategies, and, if applicable, optimal target trough levels.

De-Escalation of Anti-Tumor Necrosis Factor Alpha Agents and Reduction in Adverse Effects: A Systematic Review.

BACKGROUND: The long-term use of anti-TNF-α agents can lead to adverse effects, such as infections and immune-mediated cutaneous reactions. Whether de-escalation by dose reduction or interval lengthening reduces these adverse effects is uncertain. This systematic review aims to compare the incidence of infections and skin manifestations after anti-TNF-α dose de-escalation with standard dosing. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to 14 January 2022. Randomized controlled trials (RCTs) and observational studies comparing anti-TNF-α de-escalation strategies with standard dosing among patients with inflammatory conditions, that report on infections, skin manifestations, or both, were included. The risk of bias was assessed with the revised Cochrane risk-of bias tool (RCTs) or the Newcastle-Ottawa scale (non-RCTs). RESULTS: Fourteen RCTs and six observational studies (or 2706 patients) were included. Eight RCTs had low risk of bias or some concerns. Four non-RCTs were of good methodological quality. The studies described patients with axial spondyloarthritis (8 studies, 780 patients), rheumatoid arthritis (7 studies, 1458 patients), psoriasis (3 studies, 332 patients), or inflammatory bowel disease (2 studies, 136 patients). De-escalation strategies included interval lengthening (12 studies, 1317 patients), dose reduction (6 studies, 1130 patients), or both (2 studies, 259 patients). Overall, the occurrence of infections and skin manifestations did not differ between standard treatment and de-escalation. The disappearance of infections or skin manifestations after de-escalation was only reported in two studies. The majority of studies focused on etanercept and adalimumab. Heterogeneity in reporting of infections and skin manifestations precluded meta-analysis. CONCLUSION: We found that anti-TNF-α de-escalation does not reduce infections or skin reactions. A de-escalation strategy should not be recommended for the sole purpose of reducing drug-related adverse effects. The meticulous documentation of adverse effects is recommended to further address this question. REGISTRATION: PROSPERO CRD42021252977.

Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.

Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.

Efficacy of anti-TNF dosing interval lengthening in adolescents and young adults with inflammatory bowel disease in sustained remission (FREE-study): protocol for a partially randomised patient preference trial.

INTRODUCTION: Anti-tumour necrosis factor (TNF) therapy has greatly improved treatment outcomes in patients with inflammatory bowel disease (IBD), but long-term use is associated with cutaneous reactions, susceptibility to infections and frequent injections or hospital visits. Several non-controlled studies have demonstrated that dose reduction is feasible for a subset of patients, provided that early detection of a disease flare is possible. Here, we aim to compare the effectiveness of interval lengthening with standard dosing in maintaining remission in young patients with IBD. METHODS AND ANALYSIS: In this international, prospective, non-inferiority, partially randomised patient preference trial, we aim to recruit 148 patients aged 12-25 years with luminal Crohn's disease or ulcerative colitis in sustained remission (ie, three consecutive in-range faecal calprotectin (FC) results or recently confirmed endoscopic remission). In the interventional arm, the dosing interval will be lengthened from 8 to 12 weeks for infliximab users and from 2 to 3 weeks for adalimumab users. In the control group, standard dosing will be continued. Rapid tests will be performed for FC every 4 weeks and for anti-TNF trough levels every 12 weeks. The primary outcome is the cumulative incidence of out-of-range FC results at 48-week follow-up. Secondary endpoints include time to get out-of-range FC results, cumulative incidence of adverse effects, proportion of patients progressing to loss of response and identification of predictors of successful interval lengthening. ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Ethics Review Committee of the University Medical Centre Groningen and is pending at the other participating centres. Results will be disseminated in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT number: 2020-001811-26; ClinicalTrials.gov Identifier: NCT04646187. Protocol version 4, date 17 September 2021.