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Gleeson D, Bornand R, Brownlee A, Dhaliwal H, Dyson JK, Hails J, Henderson P, Kelly D, Mells GF, Miquel R, Oo YH, Sutton A, Yeoman A, Heneghan MA. British Society of Gastroenterology guidelines for diagnosis and management of autoimmune hepatitis. Gut 2025:gutjnl-2024-333171. [PMID: 40169244 DOI: 10.1136/gutjnl-2024-333171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 10/22/2024] [Indexed: 04/03/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.
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Affiliation(s)
- Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Science, University of Sheffield, Sheffield, UK
| | | | | | - Harpreet Dhaliwal
- Department of Gastroenterology, Manchester Royal Infirmary, Manchester, UK
| | - Jessica K Dyson
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Janeane Hails
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
| | - Paul Henderson
- Royal Hospital for Children and Young People, Edinburgh, UK
| | - Deirdre Kelly
- Birmingham Women's & Children's Hospital, Birmingham, UK
- University of Birmingham, Birmingham, UK
| | - George F Mells
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Rosa Miquel
- Liver Histopathology Laboratory, Institute of Liver Studies, King's College London, London, UK
| | - Ye H Oo
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- NIHR Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) centre, Birmingham, UK
| | - Anthea Sutton
- Sheffield Centre for Health and Related Research, The University of Sheffield, Sheffield, UK
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Samanta A, Srivastava A. Biologics in the management of pediatric inflammatory bowel disease: When and what to choose. World J Clin Pediatr 2025; 14:100938. [DOI: 10.5409/wjcp.v14.i1.100938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/14/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024] Open
Abstract
Pediatric inflammatory bowel disease (PIBD) is a chronic inflammatory disorder of the gastrointestinal tract, with rising global incidence and prevalence. Over the past two decades, biologics have added to the therapeutic armamentarium and revolutionized the approach to treatment of inflammatory bowel disease. The available biologics include monoclonal antibodies which target inflammatory cytokines (anti-tumor necrosis factor alpha, anti-interleukin 12/23) or recruitment of leucocytes to the gastrointestinal tract (anti-alpha4beta7 integrin) and small molecules (Janus kinase inhibitors, sphingosine 1-phosphate-inhibitors) which modify the proinflammatory signaling. Considering their potential disease-modifying ability, recent pediatric guidelines from the West have advocated upfront use of biologics in appropriate clinical scenarios as a top-down approach rather than the conventional step-up approach. Although real-world studies are available regarding the clinical efficacy of biologics in PIBD, there is paucity of long-term outcome and safety data in children. Also, little information is available about the best approach in the newly industrialized - developing countries where PIBD is rising but at the same time, infections are prevalent and resources are limited. In this review, we summarize the efficacy and safety profile of biologics and small molecule drugs and discuss the challenges in the management of PIBD, especially in the developing world, and future directions.
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Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Adler J, Gadepalli S, Rahman M, Kim S. Early tumour necrosis factor antagonist treatment prevents perianal fistula development in children with Crohn's disease: post hoc analysis of the RISK study. Gut 2025; 74:539-546. [PMID: 39667905 DOI: 10.1136/gutjnl-2024-333280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 11/24/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND One in three children with Crohn's disease develop perianal fistula complications (PFCs), among the most disturbing and difficult-to-treat disease-related complications. Retrospective evidence suggests PFCs may be preventable. OBJECTIVE We aimed to determine if early antitumour necrosis factor-alpha (anti-TNF⍺) therapy prevents PFC development in a well-characterised prospective cohort of paediatric patients with Crohn's disease who were free from PFC at enrolment. DESIGN RISK was a multicentre inception cohort of children newly diagnosed with Crohn's disease. We included all patients who had never experienced PFCs 30 days after study enrolment. We conducted nearest-neighbour propensity score-matched triad analyses. Matching was performed to balance patient characteristics across three mutually exclusive treatment groups based on therapy prior to either PFC development or the end of the observation period. RESULTS Among 873 patients without perianal fistula, 447 matched patients were included (149 per treatment group). The presence of non-penetrating perianal lesions (large skin tags, ulcers and/or fissures) was significantly associated with PFC development, with 4-fold greater odds of PFC (OR 4.08, 95% CI (95% CI) 1.70 to 9.78; p=0.0016). Early anti-TNF⍺ therapy was associated with an 82% decrease in the odds of PFC (OR 0.18, 95% CI 0.05 to 0.66; p=0.01). Among those with perianal lesions, anti-TNF⍺ therapy was associated with 94% reduced odds of PFC development (OR 0.055, 95% CI 0.006 to 0.50; p=0.010). No other treatment group was associated with reduced risk of PFC. CONCLUSION Early anti-TNF therapy prevents perianal fistula development, especially among patients at increased risk.
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Affiliation(s)
- Jeremy Adler
- Pediatric Gastroenterology, University of Michigan, Michigan Medicine, Ann Arbor, Michigan, USA
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Samir Gadepalli
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Michigan Medicine, Ann Arbor, Michigan, USA
- Pediatric Surgery, University of Michigan, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Moshiur Rahman
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Sandra Kim
- Pediatric Gastroenterology, Cleveland Clinic, Cleveland, Ohio, USA
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Cananzi M, Jørgensen MH, Buescher G, De Bruyne R, Samyn M. Current practice in the management of paediatric autoimmune liver disease in Europe. J Pediatr Gastroenterol Nutr 2025; 80:260-270. [PMID: 39618087 DOI: 10.1002/jpn3.12424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 11/10/2024] [Accepted: 11/13/2024] [Indexed: 02/04/2025]
Abstract
OBJECTIVE Paediatric autoimmune liver disease (pAILD) is a rare condition with serious health implications. Notwithstanding treatment advancements, areas of uncertainty and knowledge gaps still exist. We here investigated the real-life approach to pAILD management in Europe. METHODS A survey was distributed to members of the European Rare Liver Disease Reference Network (ERN RARE-LIVER) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Hepatology Interest Group. Information was gathered regarding clinical activity, medications used, and access to paediatric drug formulations at each site. RESULTS Thirty-six centres from 22 European countries responded to the survey. The majority are exclusively paediatric units (86%). Among participants, 80% follow <50 children with pAILD, of which 25%-50% are <10 years old in 44% of centres. All centres use predniso(lo)ne as first-line therapy, alone (15/36) or with azathioprine (21/36). Azathioprine and mycophenolate are the preferred second-line options in centres using first-line steroid monotherapy (11/15) or combined steroid-azathioprine (19/21), respectively. Tacrolimus is used as third-line agent in 15/36 centres. Proactive measurement of drug metabolites and target levels vary widely among centres. Paediatric predniso(lo)ne formulations are commercially available in 7/22 European countries, azathioprine in 3, mycophenolate in 14, tacrolimus in 15 and ursodeoxycholic acid in 14. When paediatric formulations are unavailable, children are treated with magisterial preparations or 'solid' formulations (crushed or intact). CONCLUSIONS Treatment of pAILD in Europe varies widely in terms of medications used and treatment monitoring. Availability of paediatric drug formulations across Europe is limited. Collaborative initiatives are needed to define evidence-based strategies for management of pAILD and to promote an equal, age-appropriate treatment for affected children.
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Affiliation(s)
- Mara Cananzi
- Unit of Paediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
| | | | - Gustav Buescher
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ruth De Bruyne
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Belgium
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition Centre, King's College Hospital NHS Trust, London, UK
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Isoldi S, Mallardo S, Quitadamo P, Leter B, Cucchiara S. Review on Advances in Pediatric Endoscopy in the Management of Inflammatory Bowel Disease. Curr Pediatr Rev 2025; 21:154-165. [PMID: 38265388 DOI: 10.2174/0115733963268547231128101929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/26/2023] [Accepted: 10/19/2023] [Indexed: 01/25/2024]
Abstract
Over the past decades, an increased importance has been given to gastrointestinal (GI) endoscopy in the management of children with inflammatory bowel diseases (IBD), considering that mucosal healing has been recognized as the optimal endpoint in the treat-to-target paradigm. The recent advances in technology and anesthesia have facilitated the comprehensive evaluation of the GI tract. In this review, we will discuss the role of ileocolonoscopy, upper GI endoscopy, and device-assisted enteroscopy in the work-up and management of pediatric Crohn's disease (CD) and ulcerative colitis, with particular attention on non-invasive endoscopic techniques, such as wireless capsule endoscopy. We will also analyze the most commonly used endoscopic scoring systems, including small bowel scoring systems and endoscopic recurrence grading of neo-terminal ileum CD. Moreover, we will focus on the endoscopic management of complications, such as strictures, that commonly require surgery. Lastly, we will discuss cancer surveillance in children with IBD, with particular consideration of the role of high-definition endoscopic equipment and chromoendoscopy in dysplasia detection rates.
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Affiliation(s)
- Sara Isoldi
- Pediatric Gastroenterology and Hepatology Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy
- Maternal and Child Health Department, Santa Maria Goretti Hospital, Sapienza-University of Rome, Latina, Italy
| | - Saverio Mallardo
- Maternal and Child Health Department, Santa Maria Goretti Hospital, Sapienza-University of Rome, Latina, Italy
| | - Paolo Quitadamo
- Pediatric Gastroenterology and Hepatology Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Beatrice Leter
- Department of Women's and Children's Health, Sapienza University of Rome, Rome, Italy
| | - Salvatore Cucchiara
- Department of Women's and Children's Health, Sapienza University of Rome, Rome, Italy
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Bramuzzo M, Cananzi M, Alvisi P, Cardile S, Romano C, Aloi M, Arrigo S, Felici E, Lonoce L, Pieri ES, Scarallo L, Strisciuglio C, Di Siena A, Lega S. Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome in pediatric Inflammatory Bowel Disease: clinical characteristics and outcomes. Eur J Pediatr 2024; 183:5411-5418. [PMID: 39404873 DOI: 10.1007/s00431-024-05772-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 09/01/2024] [Accepted: 09/07/2024] [Indexed: 11/01/2024]
Abstract
Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) in children with inflammatory bowel disease (IBD) has been reported only anecdotally. This study aimed at describing the clinical features and outcomes of children diagnosed with both IBD and HLH/MAS. Data on IBD and HLH/MAS characteristics, biochemical, microbiological and genetic assessments, treatments, and outcomes were collected from the Italian Pediatric IBD Registry and presented using descriptive statistics. Out of 4643 patients with IBD, 18 (0.4%) were diagnosed with HLH/MAS, including 12 with ulcerative colitis and 6 with Crohn disease. Among the 18 patients, 7 (39%) had early-onset IBD, but the median age at HLH/MAS diagnosis was 14.0 years (IQR 11.9-16.0). Half of the patients had active IBD at HLH/MAS diagnosis, 11 (61%) patients were on thiopurines, and 6 (33%) were on anti-TNF biologics. An infectious trigger was identified in 15 (83%) patients. One (5%) patients was diagnosed with XIAP deficiency. All patients discontinued thiopurines and 5 (83.3%) discontinued anti-TNF biologics; 16 (80%) patients received steroids for HLH/MAS. Three (17%) patients had a relapse of HLH/MAS. No patient developed lymphoma or died during a median follow-up of 2.7 years (IQR 0.8-4.4). Conclusions: HLH/MAS mainly affects children with early-onset IBD but primarily develops during adolescence, following an infection while on immunosuppressant treatment. Although the prognosis is generally favorable, it is crucial to investigate an underlying immune deficiency.
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Affiliation(s)
- Matteo Bramuzzo
- Institute for Maternal and Child Health (IRCCS) "Burlo Garofolo", Via Dell' Istria 65, 34137, Trieste, Italy.
| | - Mara Cananzi
- Unit of Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child With Liver Transplantation, Dpt. of Women's and Children's Health, University Hospital of Padova, Padua, Italy
| | - Patrizia Alvisi
- Pediatric Gastroenterology Unit, Maggiore "CA Pizzardi" Hospital, Bologna, Italy
| | - Sabrina Cardile
- Gastroenterology, Digestive Endoscopy and Nutrition Unit, Bambino Gesù Children Hospital IRCCS, Rome, Italy
| | - Claudio Romano
- Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
| | - Marina Aloi
- Pediatric Gastroenterology and Hepatology Unit, Sapienza University of Rome, Umberto I Hospital, Rome, Italy
| | - Serena Arrigo
- Pediatric Gastroenterology and Endoscopy, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Enrico Felici
- Pediatric and Pediatric Emergency Unit, Children Hospital, AOU SS Antonio E Biagio E C. Arrigo, Alessandria, Italy
| | - Luisa Lonoce
- Clinical Pediatrics, Department of Molecular Medicine and Development, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
| | | | - Luca Scarallo
- Gastroenterology and Nutrition Unit, Meyer Children's Hospital IRCCS, Florence, Italy
- Department of NEUROFARBA, University of Florence, Florence, Italy
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Andrea Di Siena
- Division of Pediatrics, Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Sara Lega
- Institute for Maternal and Child Health (IRCCS) "Burlo Garofolo", Via Dell' Istria 65, 34137, Trieste, Italy
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Ehrström A, Jansson S, Jørgensen MH, Wewer V, Malham M. The risk of cancer in pediatric-onset immune-mediated inflammatory diseases - A nationwide study. J Autoimmun 2024; 149:103321. [PMID: 39332234 DOI: 10.1016/j.jaut.2024.103321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/23/2024] [Accepted: 09/21/2024] [Indexed: 09/29/2024]
Abstract
BACKGROUND AND OBJECTIVES Adult-onset immune-mediated inflammatory disease (IMID) increases the risk of several cancers. However, data on pediatric-onset IMID (pIMID) remains scarce. We estimated the long-term cancer risk in pIMID and the association between medical treatment and specific cancers. METHODS We used the nationwide Danish health registers to identify pIMID patients diagnosed from Jan 1, 1980 to Dec 31, 2018. Patients were matched with ten reference individuals based on age, sex, and residence. The primary exposure was pIMID, including autoimmune hepatitis, primary sclerosing cholangitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis, systemic lupus erythematosus, vasculitis, and connective tissue disease. Secondary exposures were immunomodulators and tumor necrosis factor-α antagonists (anti-TNFα). The primary outcome was cancer. Estimates are presented as hazard ratios adjusted for family income at diagnosis (AHR). RESULTS We included 12,664 pIMID patients and 109,274 reference individuals. Median follow-up time was 10.6 (interquartile range: 5.4-17.7) years for patients and 10.2 (interquartile range: 5.2-17.3) years for reference individuals. Patients with pIMID had a twofold higher cancer risk (AHR 2.2 [95 % confidence interval (CI): 1.8-2.6]) compared with reference individuals. Thiopurine treatment was associated with a higher risk of lymphoma (AHR 6.1 [95%CI: 2.2-16.8]) and skin cancer (AHR 6.1 [95%CI: 2.4-15.4]). Anti-TNFα treatment was associated with a higher risk of lymphoma (AHR 4.9 [95%CI: 1.1-22.6]). CONCLUSIONS We found an increased cancer risk in patients with pIMID followed into adulthood. Additionally, thiopurines and anti-TNFα were associated with increased lymphoma and skin cancer risks. This highlights the importance of individualized immunotherapy and cancer surveillance.
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Affiliation(s)
- Andrea Ehrström
- Department of Pediatric and Adolescent Medicine, Copenhagen University Hospital, Amager and Hvidovre Hospital, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents, and Adults, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
| | - Sabine Jansson
- Department of Pediatric and Adolescent Medicine, Copenhagen University Hospital, Amager and Hvidovre Hospital, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents, and Adults, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
| | - Marianne Hørby Jørgensen
- Department of Pediatric and Adolescent Medicine, Copenhagen University Hospital -Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
| | - Vibeke Wewer
- Department of Pediatric and Adolescent Medicine, Copenhagen University Hospital, Amager and Hvidovre Hospital, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents, and Adults, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
| | - Mikkel Malham
- Department of Pediatric and Adolescent Medicine, Copenhagen University Hospital, Amager and Hvidovre Hospital, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents, and Adults, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Department of Pediatric and Adolescent Medicine, Copenhagen University Hospital -Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Departments of Epidemiology and Global Health, Boston University School of Public Health, Boston, USA; Copenhagen Health Complexity Center, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
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Vuijk SA, Camman AE, de Ridder L. Considerations in Paediatric and Adolescent Inflammatory Bowel Disease. J Crohns Colitis 2024; 18:ii31-ii45. [PMID: 39475081 PMCID: PMC11523044 DOI: 10.1093/ecco-jcc/jjae087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/03/2024] [Accepted: 06/11/2024] [Indexed: 11/02/2024]
Abstract
The incidence of inflammatory bowel disease [IBD] is rising most rapidly among children and adolescents. Paediatric-onset IBD is associated with a more extensive and severe disease course compared to adult-onset IBD. At a young age, screening for underlying genetic and immunological disorders is important and may impact treatment management. Early and effective treatment is crucial to reach disease remission and prevent complications of ongoing active disease. In children with Crohn's disease, exclusive enteral nutrition is an effective induction therapy. Other promising dietary therapies, such as the Crohn's disease exclusion diet, are emerging. Within paediatric IBD, anti-tumour necrosis factor therapy is the only approved biological thus far and additional treatment options are crucially needed. Other biological therapies, such as vedolizumab and ustekinumab, are currently prescribed off-label in this population. A specific challenge in paediatric IBD is the unacceptable and major delay in approval of drugs for children with IBD. A guided transfer period of paediatric patients to adult care is associated with improved disease outcomes and is required. Major knowledge gaps and challenges within paediatric IBD include the aetiology, diagnostics, and monitoring of disease, tailoring of treatment, and both understanding and coping with the physical and psychological consequences of living with IBD. Challenges and research gaps in paediatrics should be addressed without any delay in comparison with the adult field, in order to ensure a high quality of care for all patients with IBD, irrespective of the age of onset.
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Affiliation(s)
- Stephanie A Vuijk
- Department of Paediatric Gastroenterology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Anouk E Camman
- Department of Paediatric Gastroenterology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Lissy de Ridder
- Department of Paediatric Gastroenterology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands
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Colman RJ, Vuijk SA, Mathôt RAA, Van Limbergen J, Jongsma MME, Schreurs MWJ, Minar P, de Ridder L, D'Haens GRAM. Infliximab Monotherapy vs Combination Therapy for Pediatric Crohn's Disease Exhibit Similar Pharmacokinetics. Inflamm Bowel Dis 2024; 30:1678-1685. [PMID: 38167922 DOI: 10.1093/ibd/izad307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND The use of concomitant azathioprine may improve efficacy and pharmacokinetic (PK) properties of infliximab (IFX) but is also associated with an increased risk of adverse events. Proactive therapeutic drug monitoring (pTDM) of IFX monotherapy is an alternative strategy to improve PK. The aim of this study was to evaluate whether IFX with an immunomodulator (combo) has PK benefits over IFX-pTDM (mono) in pediatric Crohn's disease (CD). METHODS This PK analysis included pediatric CD patients who started either IFX combo (TISKids study) or IFX mono with pTDM (REFINE cohort). Combo and mono IFX trough levels (TLs) and antibodies-to-infliximab were assessed at infusion 3, 4, and 5. A population PK model was built to compare IFX PK outcomes (clearance [CL], TLs and cumulative exposure) between combo and mono groups at infusion 4 and 5. Clinical response and steroid-free clinical remission (SFCR) was assessed at infusion 4 and 5. RESULTS This study included 128 pediatric CD patients (66 mono and 62 combo). At infusion 5, there was no significant difference between mono and combo median TLs 4.1 µg/mL (2.1, 7.8) vs 5.9 µg/mL (3.2, 9.4; P = .14) or median CL 0.26 L/d (0.21, 0.32) vs 0.26 L/d (0.21, 0.33; P = .81). Mono patients had a lower SFCR rate at infusion 5 (53% [31 of 59] vs 80% [32 of 40]; P = .01). Clinical response rates were significantly higher among combo than mono patients at both infusion 4 and 5. CONCLUSIONS This study suggests that there are no PK differences (TLs and CL) between combo and mono therapy in pediatric CD patients who started IFX.
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Affiliation(s)
- Ruben J Colman
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Stephanie A Vuijk
- Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Ron A A Mathôt
- Department of Hospital Pharmacy & Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Johan Van Limbergen
- Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers, University of Amsterdam, Emma Children's Hospital, Amsterdam, the Netherlands
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, Amsterdam, the Netherlands
| | - Maria M E Jongsma
- Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands
| | | | - Phillip Minar
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lissy de Ridder
- Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Geert R A M D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands
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Curci D, Lucafò M, Decorti G, Stocco G. Monoclonal antibodies against pediatric ulcerative colitis: a review of clinical progress. Expert Opin Biol Ther 2024; 24:1133-1144. [PMID: 39285823 DOI: 10.1080/14712598.2024.2404076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 09/10/2024] [Indexed: 09/21/2024]
Abstract
INTRODUCTION In children, ulcerative colitis (UC) is often more severe and extensive than in adults and hospitalization for acute exacerbations occurs in around a quarter of subjects. There is a need for effective drugs, which could avoid or reduce the use of corticosteroids which, especially in children, are burdened by a number of severe side effects. The introduction in therapy of monoclonal antibodies has completely changed the therapeutic scenario and the prognosis of the disease. AREAS COVERED In this review, the use of the monoclonal antibodies directed against tumor necrosis factor (TNF)α or other inflammatory targets for the treatment of pediatric UC will be discussed. A search of the literature was done using the keywords 'pediatric,' 'ulcerative colitis,' 'inflammatory bowel disease,' 'monoclonal antibodies;' 'infliximab,' 'adalimumab,' 'golimumab,' vedolizumab," 'ustekinumab' and 'risankizumab.' EXPERT OPINION The use of monoclonal antibodies has greatly increased in recent years in pediatric UC, both in patients who did not respond to conventional therapies, and, more often, as initial therapy. Thanks to therapeutic drug monitoring and to the availability of biologics with different targets, therapy has become more targeted and personalized, with a significant improvement in response, in quality of life, and with a good safety profile.
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Affiliation(s)
- Debora Curci
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Marianna Lucafò
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Giuliana Decorti
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Gabriele Stocco
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
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11
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Le Thi TG, Werkstetter K, Kotilea K, Bontems P, Cabral J, Cilleruelo ML, Kori M, Barrio J, Homan M, Kalach N, Lima R, Tavares M, Urruzuno P, Misak Z, Urbonas V, Koletzko S. Factors Associated With Decision to Treat or Not to Treat Helicobacter pylori Infection in Children: Data From the EuroPedHp Registry. Helicobacter 2024; 29:e13134. [PMID: 39252494 DOI: 10.1111/hel.13134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 07/29/2024] [Accepted: 08/16/2024] [Indexed: 09/11/2024]
Abstract
BACKGROUND European and North-American guidelines on management of H. pylori infection in children provide the option not to treat even if the infection is endoscopically confirmed. We used data from the EuroPedHp Registry to identify factors associated with therapy decisions. METHODS We included treatment-naïve patients reported between 2017 and 2020 from 30 centers in 17 European countries. Multivariable logistic regression identified factors including comorbidities within and outside the gastrointestinal (GI) tract influencing the decision for or against therapy. RESULTS Of 1165 patients (52% females, median age 12.8), 28% (321/1165) reported any alarm symptom, 26% (307/1165) comorbidities, and 16% (192/1165) did not receive eradication treatment. Therapy was initiated less often in children having any GI comorbidity (57%, n = 181), particularly in those with eosinophilic esophagitis (60%, n = 35), inflammatory bowel disease (54%, n = 28), and celiac disease (43%, n = 58), compared to those with non-GI (86%, n = 126) or no comorbidity (89%, n = 858), despite similar frequencies of alarm and non-alarm symptoms, ulcers, erosions, and nodular gastritis. Patients with GI and without comorbidities remained more likely untreated in high versus low H. pylori prevalence countries (p < 0.0001). In children without comorbidities, factors favoring therapy included older age, being overweight, having symptoms, erosions, antral nodularity, and available antibiotic susceptibility results. CONCLUSION In this cohort, H. pylori-infected children with GI comorbidities compared to no comorbidity showed 75% reduced chance of receiving eradication therapy. We found no evidence supporting different management strategies in infected patients with GI comorbidities compared to all pediatric patients with endoscopically proven H. pylori infection.
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Affiliation(s)
- Thu Giang Le Thi
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital Munich, München, Germany
| | - Katharina Werkstetter
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital Munich, München, Germany
| | - Kallirroi Kotilea
- Université Libre de Bruxelles, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium
| | - Patrick Bontems
- Université Libre de Bruxelles, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium
| | - José Cabral
- Child and Adolescent Centre, CUF Tejo Hospital, Lisbon, Portugal
| | - Maria Luz Cilleruelo
- Pediatrics Department, Gastroenterology Unit, University Hospital Puerta de Hierro Majadahonda, Madrid, Spain
| | - Michal Kori
- Pediatric Gastroenterology, Kaplan Medical Centre, Rehovot, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Josefa Barrio
- Pediatrics Department, Gastroenterology Unit, University Hospital de Fuenlabrada, Fuenlabrada, Madrid, Spain
| | - Matjaž Homan
- Department of Gastroenterology, Hepatology, and Nutrition, University Children's Hospital, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nicolas Kalach
- Saint Antoine Pediatric Clinic, Saint Vincent de Paul Hospital, Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Catholic University, Lille, France
| | - Rosa Lima
- Division of Pediatrics, Pediatric Gastroenterology Department, Centro Materno Infantil do Norte, ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal
| | - Marta Tavares
- Division of Pediatrics, Pediatric Gastroenterology Department, Centro Materno Infantil do Norte, ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal
| | - Pedro Urruzuno
- Pediatric Gastroenterology Unit, Hospital 12 de Octubre, Madrid, Spain
| | - Zrinjka Misak
- Referral Centre for Pediatric Gastroenterology and Nutrition, Children's Hospital Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Vaidotas Urbonas
- Clinic of Children's Diseases of Vilnius University Faculty of Medicine, Vilnius, Lithuania
| | - Sibylle Koletzko
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital Munich, München, Germany
- Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
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12
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Klomberg RCW, Croft NM, de Ridder L. Rare and severe adverse events in children with inflammatory bowel disease - Authors' reply. THE LANCET. CHILD & ADOLESCENT HEALTH 2024; 8:e9-e10. [PMID: 39142746 DOI: 10.1016/s2352-4642(24)00197-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 07/19/2024] [Indexed: 08/16/2024]
Affiliation(s)
- Renz C W Klomberg
- Department of Pediatric Gastroenterology, Erasmus Medical Centre, Sophia Children's Hospital, Rotterdam 3000 CA, Netherlands
| | - Nicholas M Croft
- Paediatric Gastroenterology, Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Lissy de Ridder
- Department of Pediatric Gastroenterology, Erasmus Medical Centre, Sophia Children's Hospital, Rotterdam 3000 CA, Netherlands.
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13
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Sun J, Arnell H, Ludvigsson JF, Olén O. Rare and severe adverse events in children with inflammatory bowel disease. THE LANCET. CHILD & ADOLESCENT HEALTH 2024; 8:e8. [PMID: 39142745 DOI: 10.1016/s2352-4642(24)00176-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 06/29/2024] [Accepted: 07/03/2024] [Indexed: 08/16/2024]
Affiliation(s)
- Jiangwei Sun
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 65, Sweden.
| | - Henrik Arnell
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm 171 65, Sweden; Pediatric Gastroenterology, Hepatology and Nutrition Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 65, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - Ola Olén
- Division of Clinical Epidemiology, Department of Medicine, Karolinska Institutet, Stockholm 171 65, Sweden; Sachs' Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden
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14
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Klomberg RCW, Hellendoorn AE, Kemos P, Rizopoulos D, Ruemmele FM, Croft NM, de Ridder L. Rare and severe adverse events in children with inflammatory bowel disease: analysis of data from the PIBD-SETQuality Safety Registry. THE LANCET. CHILD & ADOLESCENT HEALTH 2024; 8:422-432. [PMID: 38697175 DOI: 10.1016/s2352-4642(24)00078-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/21/2024] [Accepted: 03/22/2024] [Indexed: 05/04/2024]
Abstract
BACKGROUND Rare and severe adverse events can occur in children with inflammatory bowel disease (IBD), and the relationship with disease or drug treatment is often uncertain. We aimed to establish a method of reporting adverse events of interest in children with IBD, allowing for estimates of incidence rates with comparison between different regions, and, if possible, to compare with published data on rates of adverse events in children overall. METHODS For this analysis, we used data from the Paediatric Inflammatory Bowel Disease Network for Safety, Efficacy and Treatment and Quality improvement of care (PIBD-SETQuality) Safety Registry, which collects data on multiple rare and severe adverse events in children younger than 19 years with IBD. Overall, the registry collected data on ten prespecified rare and severe adverse events in children with IBD, as established by a panel of paediatric IBD experts, via reports from paediatric gastroenterologists at participating hospitals between Nov 1, 2016, and March 31, 2023. Reporting physicians, who could only be paediatric gastroenterologists or IBD nurses reporting on behalf of paediatric gastroenterologists, were recruited through invitations sent to both national and international IBD networks and at conferences. Once per month, participating paediatric gastroenterologists received an email with an anonymous and unique link to an online survey asking them to report whether any of ten rare and severe adverse events had occurred in a patient in their paediatric-IBD population in the previous month. Prevalent or retrospective rare and severe adverse events were excluded, as were events occurring in children with an unconfirmed diagnosis of IBD or for whom inflammatory colitis was part of a monogenic immunodeficiency disorder. Duplicates and events that did not meet the definitions and criteria were excluded. Physicians could also report other, non-categorised adverse events if they considered them rare and severe. In case of no response, up to two reminders were sent for each per-month survey. Annual denominator data surveys were sent to obtain the total number of person-years for the estimation of incidence rates, which were calculated via Poisson regression models. FINDINGS Responses were gathered from 220 paediatric gastroenterologists from 167 centres. 121 centres were in Europe, 23 centres were in North America, 17 centres were in Asia, and six centres were in Oceania. Combined, the total population with paediatric IBD consisted of an estimated 30 193 children with 114 528 person-years of follow-up. 451 adverse events were initially reported. After excluding and reorganising adverse events, 402 were eligible; 261 (65%) were categorised and 141 (35%) were non-categorised. The most frequently reported adverse events were venous-thromboembolic events (n=66), renal failure (n=43), opportunistic infections (n=42), and cancer (n=33). Haemophagocytic lymphohistiocytosis (n=4) and liver failure (n=3) were the least frequently reported adverse events. Incidence rates per 10 000 person-years were 5·50 (95% CI 4·25-6·97) for venous-thromboembolic events, 3·75 (2·74-4·99) for renal failure, 3·67 (2·67-4·89) for opportunistic infection, and 2·88 (2·01-3·98) for cancer. Of 66 venous-thromboembolic events, 31 (47%) involved cerebral venous sinus thrombosis at an incidence rate of 2·71 (95% CI 1·86-3·77). INTERPRETATION The PIBD-SETQuality Safety Registry enabled us to identify incidence rates of rare and severe adverse events in children with IBD. Our findings can guide physicians and enhance awareness of the incidence of adverse events in children with IBD that are considered to be rare. FUNDING EU Horizon 2020 Research and Innovation Programme.
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Affiliation(s)
- Renz C W Klomberg
- Department of Pediatric Gastroenterology, Erasmus Medical Centre, Sophia Children's Hospital, Rotterdam, Netherlands
| | - Astrid E Hellendoorn
- Department of Pediatric Gastroenterology, Erasmus Medical Centre, Sophia Children's Hospital, Rotterdam, Netherlands
| | - Polychronis Kemos
- Paediatric Gastroenterology, Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Dimitris Rizopoulos
- Department of Epidemiology, Erasmus Medical Centre, Sophia Children's Hospital, Rotterdam, Netherlands
| | - Frank M Ruemmele
- Department of Pediatric Gastroenterology, Université Paris Descartes, Sorbonne Paris Cité, Assistance Publique Hôpitaux de Paris, Hôpital Necker Enfants Malades, Paris, France
| | - Nicholas M Croft
- Paediatric Gastroenterology, Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Lissy de Ridder
- Department of Pediatric Gastroenterology, Erasmus Medical Centre, Sophia Children's Hospital, Rotterdam, Netherlands.
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15
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Mansilla-Polo M, Morgado-Carrasco D. Biologics Versus JAK Inhibitors. Part I: Cancer Risk. A Narrative Review. Dermatol Ther (Heidelb) 2024; 14:1389-1442. [PMID: 38763966 PMCID: PMC11169156 DOI: 10.1007/s13555-024-01166-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 04/10/2024] [Indexed: 05/21/2024] Open
Abstract
INTRODUCTION Biological drugs (BD) and Janus kinase inhibitors (JAKi) have revolutionized the treatment of diverse dermatoses. However, there are concerns regarding their safety, especially the risk of cancer and opportunistic infections. Here, we discuss the risk of cancer associated with the BD and JAKi used in dermatology. METHODS A narrative review was carried out. All relevant articles evaluating the risk of cancer associated with BD or JAKi and published between January 2010 and February 2024 were selected. RESULTS Multiple large studies have evaluated the association between BD, JAKi and cancer risk. However, there is a lack of prospective, comparative studies. Overall, patients undergoing BD and JAKi present a cutaneous cancer incidence similar to that in the general population. The drugs more strongly associated with non-skin cancer risk were anti-tumor necrosis factor (anti-TNFs) agents and JAKi (especially tofacitinib and oral ruxolitinib). This risk appears to increase with age, the presence of other factors (such as chronic immunosuppression from previous drugs or other comorbidities), and specific diseases such as rheumatoid arthritis (RA) and myelodysplastic syndrome. Conversely, BD such as interleukin (IL)-17 and IL-23 inhibitors may even reduce the risk of some visceral and hematological malignancies. In patients with dermatological conditions such as psoriasis and atopic dermatitis, the risk of malignancies may be lower than in other subgroups, and probably comparable to the general population. CONCLUSIONS The incidence of cancer in patients undergoing BD or JAKi is generally low. This incidence can be higher in elderly patients with RA or myelodysplastic syndrome, and in those undergoing prolonged therapy with tofacitinib or ruxolitinib (oral), or anti-TNF agents.
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Affiliation(s)
- Miguel Mansilla-Polo
- Department of Dermatology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
- Instituto de Investigación Sanitaria (IIS) La Fe, Valencia, Spain
- Department of Dermatology, Faculty of Medicine, Universitat de València, Villarroel 170, 08036, Valencia, Spain
| | - Daniel Morgado-Carrasco
- Department of Dermatology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.
- Department of Dermatology, Hospital de Figueres, Fundació Alt Empurdà, Figueres, Spain.
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16
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O'Connell DM, Moses J. Invited commentary to immunotherapy withdrawal by step-down to mesalamine in pediatrics patients with ulcerative colitis. JPGN REPORTS 2024; 5:95-96. [PMID: 38756131 PMCID: PMC11093890 DOI: 10.1002/jpr3.12047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/17/2023] [Accepted: 12/29/2023] [Indexed: 05/18/2024]
Affiliation(s)
- Daniel M. O'Connell
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and NutritionUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
| | - Jonathan Moses
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and NutritionStanford University School of MedicinePalo AltoCaliforniaUSA
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17
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Pasternak B. Medical management of pediatric inflammatory bowel disease. Semin Pediatr Surg 2024; 33:151398. [PMID: 38582057 DOI: 10.1016/j.sempedsurg.2024.151398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2024]
Abstract
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.
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Affiliation(s)
- Brad Pasternak
- Division of Pediatric Gastroenterology, Department of Pediatrics, Phoenix Children's Hospital, Phoenix, Arizona, USA.
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18
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Mao YQ, Sun SP, Lv B, Fan YH. Progress in understanding of relationship between use of biological agents and risk of malignant tumors in patients with inflammatory bowel disease. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:221-227. [DOI: 10.11569/wcjd.v32.i3.221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2024]
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19
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Losa A, Gomes R, Mourão FR, Cardoso SS, Vieira PM, Correia MR, Silva HM, Silva G, Tavares M, Silva ES, Lima R. Drug-Related Adverse Reactions in Pediatric Inflammatory Bowel Disease. J Clin Pharmacol 2024; 64:103-110. [PMID: 37611322 DOI: 10.1002/jcph.2339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 08/18/2023] [Indexed: 08/25/2023]
Abstract
The therapeutic approach to inflammatory bowel disease (IBD) is complex, often involving multiple pharmacologic classes. We aimed to evaluate the prevalence of drug-related adverse reactions (ARs) associated with therapies used in pediatric IBD. We conducted a retrospective study of pediatric patients with IBD followed in a tertiary hospital from 2010 to 2022. Ninety-nine patients were included (62.6% were male), with a median age at diagnosis of 13 years (interquartile range [IQR] 11-15 years). The majority had Crohn's disease (69.7%), followed by ulcerative colitis (21.2%) and unclassified IBD (9.1%). The most prescribed therapies were: immunomodulators (n = 75, 75.8%), exclusive enteral nutrition (n = 61, 61.6%), and biologics (n = 58, 58.6%). During a median follow-up time of 31 months (IQR 11-51 months), the incidence of ARs was 16.2% (16 ARs occurred in 14 patients). The main drug involved was azathioprine (12/16) and the most frequent AR was hepatitis (5/16). Drug discontinuation was necessary in all but 1 case. Of the ARs recorded, 75% were mild to moderate and 81.3% did not require specific treatment; all patients had clinical and/or analytical normalization. There was a positive association between the cumulative number of prescribed drugs and the occurrence of ARs (P = .044). The incidence of ARs was similar to the rates reported in the few existing previous studies. The majority of ARs were mild, but implied the discontinuation of therapy or dose reduction, with a possible impact on disease control.
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Affiliation(s)
- Ana Losa
- Pediatrics Department, Centro Materno Infantil do Norte Albino Aroso, Centro Hospitalar Universitário de Santo António (CMIN-CHUdSA), Porto, Portugal
| | - Rita Gomes
- Pediatrics Department, Centro Materno Infantil do Norte Albino Aroso, Centro Hospitalar Universitário de Santo António (CMIN-CHUdSA), Porto, Portugal
| | | | | | - Paula Manuel Vieira
- Pediatrics Department, Centro Materno Infantil do Norte Albino Aroso, Centro Hospitalar Universitário de Santo António (CMIN-CHUdSA), Porto, Portugal
| | | | | | - Gisela Silva
- Gastroenterology Unit, Pediatrics Department, CMIN-CHUdSA, Porto, Portugal
| | - Marta Tavares
- Gastroenterology Unit, Pediatrics Department, CMIN-CHUdSA, Porto, Portugal
| | | | - Rosa Lima
- Gastroenterology Unit, Pediatrics Department, CMIN-CHUdSA, Porto, Portugal
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20
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Atia O, Friss C, Ledderman N, Greenfeld S, Kariv R, Daher S, Yanai H, Loewenberg Weisband Y, Matz E, Dotan I, Turner D. Thiopurines Have Longer Treatment Durability than Methotrexate in Adults and Children with Crohn's Disease: A Nationwide Analysis from the epi-IIRN Cohort. J Crohns Colitis 2023; 17:1614-1623. [PMID: 37099729 DOI: 10.1093/ecco-jcc/jjad076] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Indexed: 04/28/2023]
Abstract
BACKGROUND Thiopurines and methotrexate have long been used to maintain remission in Crohn's disease [CD]. In this nationwide study, we aimed to compare the effectiveness and safety of these drugs in CD. METHODS We used data from the epi-IIRN cohort, including all patients with CD diagnosed in Israel. Outcomes were compared by propensity-score matching and included therapeutic failure, hospitalisations, surgeries, steroid dependency, and adverse events. RESULTS Of the 19264 patients diagnosed with CD since 2005, 3885 [20%] ever received thiopurines as monotherapy and 553 [2.9%] received methotrexate. Whereas the use of thiopurines declined from 22% in 2012-2015 to 12% in 2017-2020, the use of methotrexate remained stable. The probability of sustaining therapy at 1, 3, and 5 years was 64%, 51%, and 44% for thiopurines and 56%, 30%, and 23% for methotrexate, respectively [p <0.001]. Propensity-score matching, including 303 patients [202 with thiopurines, 101 with methotrexate], demonstrated a higher rate of 5-year durability for thiopurines [40%] than methotrexate [18%; p <0.001]. Time to steroid dependency [p = 0.9], hospitalisation [p = 0.8], and surgery [p = 0.1] were comparable between groups. These outcomes reflect also shorter median time to biologics with methotrexate (2.2 [IQR 1.6-3.1 years) versus thiopurines (6.6 [2.4-8.5]; p = 0.02). The overall adverse events rate was higher with thiopurines [20%] than methotrexate [12%; p <0.001], including three lymphoma cases in males, although the difference was not significant [4.8 vs 0 cases/10 000 treatment-years, respectively; p = 0.6]. CONCLUSION Thiopurines demonstrated higher treatment durability than methotrexate but more frequent adverse events. However, disease outcomes were similar, partly due to more frequent escalation to biologics with methotrexate.
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Affiliation(s)
- Ohad Atia
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Israel
| | - Chagit Friss
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Israel
| | | | - Shira Greenfeld
- Maccabi Health Services, Tel-Aviv, Israel and the Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Revital Kariv
- Maccabi Health Services, Tel-Aviv, Israel and the Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Saleh Daher
- Israel Defense Forces Medical Corps, Department of Medical Services, Jerusalem, Israel and Hadadsah-Hebrew University Medical Center, Institute of Gastrointestinal and Liver Diseases, Jerusalem, Israel
| | - Henit Yanai
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, and the Sackler Faculty of Medicine, Tel Aviv University, Israel
| | | | - Eran Matz
- Leumit Health Services, Tel-Aviv, Israel
| | - Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, and the Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Dan Turner
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Israel
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21
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Gallagher J, Rosh JR, Sahn B. The Future of Advanced Therapies for Pediatric Crohn's Disease. Paediatr Drugs 2023; 25:621-633. [PMID: 37612580 DOI: 10.1007/s40272-023-00590-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/07/2023] [Indexed: 08/25/2023]
Abstract
Pediatric Crohn's disease commonly presents with moderate-to-severe intestinal inflammation with a greater risk of complications if remission is not achieved. Anti-tumor necrosis factor therapies have offered the possibility of deep and durable remission; however, many children do not respond or no longer respond over time. Further, some children do not require broader systemic immunosuppression to achieve remission and are better served by an alternative treatment strategy. Proper utilization of advanced biologic and small-molecule therapies, which have become available for adult patients since anti-tumor necrosis factor medications, is paramount for tighter disease control for a large proportion of children. Newer advanced therapies such as anti-integrin and anti-interleukin biologics, and several small-molecule agents capitalize on various mechanisms through narrower immunologic targets and reduced immunogenicity. Given limited regulatory approvals of these agents for use in children with Crohn's disease, clinicians continue to rely on data extrapolated from clinical trials in adult patients, sparse pediatric studies, and a growing real-world experience for treatment selection and optimization. In this article, we discuss currently available treatment options, pipeline drugs, and relevant data as they pertain to some of the most pressing clinical challenges faced in treating pediatric Crohn's disease.
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Affiliation(s)
- Julie Gallagher
- Division of Pediatric Gastroenterology, Liver Diseases, and Nutrition, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA
| | - Joel R Rosh
- Division of Pediatric Gastroenterology, Liver Diseases, and Nutrition, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA
| | - Benjamin Sahn
- Division of Pediatric Gastroenterology, Liver Diseases, and Nutrition, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA.
- Feinstein Institutes for Medical Research, Manhasset, NY, USA.
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22
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Ancona S, Signa S, Longo C, Cangemi G, Carfora R, Drago E, La Rosa A, Crocco M, Chiaro A, Gandullia P, Arrigo S. Dose escalation of adalimumab as a strategy to overcome anti-drug antibodies: A case report of infantile-onset inflammatory bowel disease. World J Gastroenterol 2023; 29:5428-5434. [PMID: 37900586 PMCID: PMC10600799 DOI: 10.3748/wjg.v29.i38.5428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/21/2023] [Accepted: 07/27/2023] [Indexed: 10/12/2023] Open
Abstract
BACKGROUND Treatment of infantile-onset inflammatory bowel disease (IO-IBD) is often challenging due to its aggressive disease course and failure of standard therapies with a need for biologics. Secondary loss of response is frequently caused by the production of anti-drug antibodies, a well-known problem in IBD patients on biologic treatment. We present a case of IO-IBD treated with therapeutic drug monitoring (TDM)-guided high-dose anti-tumor necrosis factor therapy, in which dose escalation monitoring was used as a strategy to overcome anti-drug antibodies. CASE SUMMARY A 5-mo-old boy presented with a history of persistent hematochezia from the 10th d of life, as well as relapsing perianal abscess and growth failure. Hypoalbuminemia, anemia, and elevated inflammatory markers were also present. Endoscopic assessment revealed skip lesions with deep colic ulcerations, inflammatory anal sub-stenosis, and deep fissures with persistent abscess. A diagnosis of IO-IBD Crohn-like was made. The patient was initially treated with oral steroids and fistulotomy. After the perianal abscess healed, adalimumab (ADA) was administered with concomitant gradual tapering of steroids. Clinical and biochemical steroid-free remission was achieved with good trough levels. After 3 mo, antibodies to ADA (ATA) were found with undetectable trough levels; therefore, we optimized the therapy schedule, first administering 10 mg weekly and subsequently up to 20 mg weekly (2.8 mg/kg/dose). After 2 mo of high-dose treatment, ATA disappeared, with concomitant high trough levels and stable clinical and biochemical remission of the disease. CONCLUSION TDM-guided high-dose ADA treatment as a monotherapy overcame ATA production. This strategy could be a good alternative to combination therapy, especially in very young patients.
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Affiliation(s)
- Silvana Ancona
- Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università degli Studi di Genova, Genova 16126, Italy
| | - Sara Signa
- Pediatric Gastroenterology and Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy
| | - Chiara Longo
- Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università degli Studi di Genova, Genova 16126, Italy
- Pediatric Gastroenterology and Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy
| | - Giuliana Cangemi
- Chromatography and Mass Spectrometry Section, Central Laboratory of Analysis, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy
| | - Roberta Carfora
- Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università degli Studi di Genova, Genova 16126, Italy
| | - Enrico Drago
- Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università degli Studi di Genova, Genova 16126, Italy
| | - Alessandro La Rosa
- Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università degli Studi di Genova, Genova 16126, Italy
- Pediatric Gastroenterology and Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy
| | - Marco Crocco
- Pediatric Gastroenterology and Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy
| | - Andrea Chiaro
- Pediatric Gastroenterology and Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy
| | - Paolo Gandullia
- Pediatric Gastroenterology and Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy
| | - Serena Arrigo
- Pediatric Gastroenterology and Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy
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23
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Zhang X, Rosh JR. Safety Summary of Pediatric Inflammatory Bowel Disease Therapies. Gastroenterol Clin North Am 2023; 52:535-548. [PMID: 37543398 DOI: 10.1016/j.gtc.2023.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/07/2023]
Abstract
Therapeutic options for the treatment of pediatric inflammatory bowel disease include aminosalicylates, enteral nutrition, corticosteroids, immunomodulators, biologics, and emerging small molecule agents. Infectious risk due to systemic immunosuppression should be mitigated by appropriate screening before therapy initiation. Rare but serious malignancies have been associated with thiopurine use alone and in combination with anti-tumor necrosis factor agents, often in the setting of a primary Epstein-Barr virus infection. Potential agent-specific adverse events such as cytopenias, hepatotoxicity, and nephrotoxicity warrant regular clinical and laboratory monitoring.
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Affiliation(s)
- Xiaoyi Zhang
- Pediatric Gastroenterology, Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Indiana University, 705 Riley Hospital Drive, ROC 4210, Indianapolis, IN 46202, USA. https://twitter.com/xtzhang
| | - Joel R Rosh
- Pediatric Gastroenterology, Division of Pediatric Gastroenterology, Liver Disease, and Nutrition, Cohen Children's Medical Center of New York, 1991 Marcus Avenue, Suite M100, Lake Success, NY 11042, USA.
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24
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Hyams JS, Russell RK. The State of Clinical Trials in Pediatric Inflammatory Bowel Disease. Gastroenterol Clin North Am 2023; 52:589-597. [PMID: 37543402 DOI: 10.1016/j.gtc.2023.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/07/2023]
Abstract
The gap between available biologic and small molecule therapy for inflammatory bowel disease for children and adults remains large. At present only 2 anti-TNF agents are licensed for pediatric use compared with multiple other agents with different mechanisms of action being used in adults. The reasons are many but largely revolve around the inadequate acceptance of adult efficacy data to children, and the reluctance of industry to commit to early pediatric drug development for fear of inadequate return on investment. We suggest common sense steps that need to be taken to improve this situation.
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Affiliation(s)
- Jeffrey S Hyams
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, 282 Washington Street, Hartford, CT 06106, USA; University of Connecticut School of Medicine, Farmington, CT, USA.
| | - Richard K Russell
- Department of Paediatric Gastroenterology, Royal Hospital for Children and Young People, Clinical Staff Offices, 2nd Floor, 50 Little France Crescent, Edinburgh EH16 4TJ
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25
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Murthy SK, Kuenzig ME, Windsor JW, Matthews P, Tandon P, Benchimol EI, Bernstein CN, Bitton A, Coward S, Jones JL, Kaplan GG, Lee K, Targownik LE, Peña-Sánchez JN, Rohatinsky N, Ghandeharian S, Meka S, Chis RS, Gupta S, Cheah E, Davis T, Weinstein J, Im JHB, Goddard Q, Gorospe J, Loschiavo J, McQuaid K, D’Addario J, Silver K, Oppenheim R, Singh H. The 2023 Impact of Inflammatory Bowel Disease in Canada: Cancer and IBD. J Can Assoc Gastroenterol 2023; 6:S83-S96. [PMID: 37674502 PMCID: PMC10478814 DOI: 10.1093/jcag/gwad006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/08/2023] Open
Abstract
Cancer is a major cause of morbidity and mortality among people with inflammatory bowel disease (IBD). Intestinal cancers may arise as a complication of IBD itself, while extra-intestinal cancers may arise due to some of the immunosuppressive therapies used to treat IBD. Colorectal cancer (CRC) and small bowel cancer risks remain elevated among persons with IBD as compared to age-and sex-matched members of the general population, and the lifetime risk of these cancers is strongly correlated to cumulative intestinal inflammatory burden. However, the cumulative risk of cancer, even among those with IBD is still low. Some studies suggest that IBD-CRC incidence has declined over the years, possibly owing to improved treatment standards and improved detection and management of early neoplastic lesions. Across studies of extra-intestinal cancers, there are generally higher incidences of melanoma, hepatobiliary cancer, and lung cancer and no higher incidences of breast cancer or prostate cancer, with equivocal risk of cervical cancer, among persons with IBD. While the relative risks of some extra-intestinal cancers are increased with treatment, the absolute risks of these cancers remain low and the decision to forego treatment in light of these risks should be carefully weighed against the increased risks of intestinal cancers and other disease-related complications with undertreated inflammatory disease. Quality improvement efforts should focus on optimized surveillance of cancers for which surveillance strategies exist (colorectal cancer, hepatobiliary cancer, cervical cancers, and skin cancers) and the development of cost-effective surveillance strategies for less common cancers associated with IBD.
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Affiliation(s)
- Sanjay K Murthy
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- The Ottawa Hospital IBD Centre, Ottawa, Ontario, Canada
| | - M Ellen Kuenzig
- SickKids Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Child Health Evaluative Sciences, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Joseph W Windsor
- Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | | | - Parul Tandon
- Department of Gastroenterology and Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Eric I Benchimol
- SickKids Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Child Health Evaluative Sciences, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- ICES, Toronto, Ontario, Canada
- Department of Paediatrics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Institute of Health Policy, Management, and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Charles N Bernstein
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Alain Bitton
- Division of Gastroenterology and Hepatology, McGill University Health Centre IBD Centre, McGill University, Montréal, Quebec, Canada
| | - Stephanie Coward
- Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Jennifer L Jones
- Departments of Medicine, Clinical Health, and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Gilaad G Kaplan
- Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Kate Lee
- Crohn’s and Colitis Canada, Toronto, Ontario, Canada
| | - Laura E Targownik
- Division of Gastroenterology and Hepatology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Juan-Nicolás Peña-Sánchez
- Department of Community Health and Epidemiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Noelle Rohatinsky
- College of Nursing, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | | | - Saketh Meka
- Department of Neuroscience, McGill University, Montreal, Quebec, Canada
| | - Roxana S Chis
- Department of Gastroenterology and Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Sarang Gupta
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Eric Cheah
- Department of Gastroenterology and Clinical Nutrition, The Royal Children’s Hospital Melbourne, Parkville, Australia
| | - Tal Davis
- SickKids Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Child Health Evaluative Sciences, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Jake Weinstein
- SickKids Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Child Health Evaluative Sciences, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - James H B Im
- SickKids Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
- Child Health Evaluative Sciences, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Quinn Goddard
- Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Julia Gorospe
- Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | | | | | | | - Ken Silver
- Crohn’s and Colitis Canada, Toronto, Ontario, Canada
| | | | - Harminder Singh
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- CancerCare Manitoba Research Institute, Winnipeg, Manitoba, Canada
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26
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Jongsma MME, Costes LMM, Tindemans I, Cozijnsen MA, Raatgreep R(HC, van Pieterson M, Li Y, Escher JC, de Ridder L, Samsom JN. Serum Immune Profiling in Paediatric Crohn's Disease Demonstrates Stronger Immune Modulation With First-Line Infliximab Than Conventional Therapy and Pre-Treatment Profiles Predict Clinical Response to Both Treatments. J Crohns Colitis 2023; 17:1262-1277. [PMID: 36934327 PMCID: PMC10441564 DOI: 10.1093/ecco-jcc/jjad049] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Indexed: 03/20/2023]
Abstract
BACKGROUND Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual paediatric Crohn's disease [CD] patients is needed. We assessed how serum immune profiles before and after first-line infliximab [FL-IFX] or conventional [CONV] induction therapy associate with disease remission at week 52. METHODS Pre- [n = 86], and 10-14-week post-treatment [n = 84] sera were collected from patients with moderate-to-severe paediatric CD in the TISKids trial, randomized to FL-IFX [n = 48; five 5-mg/kg infusions over 22 weeks] or CONV [n = 43; exclusive enteral nutrition or oral prednisolone]; both groups received azathioprine maintenance. The relative concentrations of 92 inflammatory proteins were determined with Olink Proteomics; fold changes [FC] with |log2FC| > 0.5 after false discovery rate adjustment were considered significant. RESULTS FL-IFX modulated a larger number of inflammatory proteins and induced stronger suppression than CONV; 18/30 proteins modulated by FL-IFX were not regulated by CONV. Hierarchical clustering based on IFX-modulated proteins at baseline revealed two clusters of patients: CD-hi patients had significantly higher concentrations of 23/30 IFX-modulated proteins [including oncostatin-M, TNFSF14, HGF and TGF-α], and higher clinical disease activity, C-reactive protein and blood neutrophils at baseline than CD-lo patients. Only 24% of CD-hi FL-IFX-treated patients maintained remission without escalation at week 52 vs 58% of CD-lo FL-IFX-treated patients. Similarly, 6% of CD-hi CONV-treated patients achieved remission vs 20% of CONV-treated CD-lo patients. Clustering based on immune profiles post-induction therapy did not relate to remission at week 52. CONCLUSION FL-IFX leads to stronger reductions and modulates more immune proteins than CONV. Stratification on pre-treatment profiles of IFX-modulated proteins directly relates to maintenance of remission without treatment escalation. TRIAL REGISTRATION NUMBER NCT02517684.
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Affiliation(s)
- Maria M E Jongsma
- Department of Pediatric Gastroenterology, Erasmus University Medical Center/Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Lea M M Costes
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center/Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Irma Tindemans
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center/Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Martinus A Cozijnsen
- Department of Pediatric Gastroenterology, Erasmus University Medical Center/Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Rolien (H) C Raatgreep
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center/Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Merel van Pieterson
- Department of Pediatric Gastroenterology, Erasmus University Medical Center/Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Yunlei Li
- Department of Pathology & Clinical Bioinformatics, Erasmus University Medical Center/Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Johanna C Escher
- Department of Pediatric Gastroenterology, Erasmus University Medical Center/Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Lissy de Ridder
- Department of Pediatric Gastroenterology, Erasmus University Medical Center/Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Janneke N Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center/Sophia Children’s Hospital, Rotterdam, the Netherlands
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27
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Gibson M, Subedi S, Barker DH, Masur S, Mallette MM, Lingannan A, Recinos Soto AA, Esharif D, Maxwell SH, Riaz MS, Herzlinger MI, Shalon LB, Cerezo CS, Kasper VL, Ross AM, Leleiko NS, Shapiro JM. Safety and Durability of Accelerated Infliximab Dosing Strategies in Pediatric IBD: A Single Center, Retrospective Study. J Pediatr Gastroenterol Nutr 2023; 77:207-213. [PMID: 37084343 DOI: 10.1097/mpg.0000000000003794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/23/2023]
Abstract
OBJECTIVES Infliximab (IFX) is commonly used to treat children with inflammatory bowel disease (IBD). We previously reported that patients with extensive disease started on IFX at a dose of 10 mg/kg had greater treatment durability at year one. The aim of this follow-up study is to assess the long-term safety and durability of this dosing strategy in pediatric IBD. METHODS We performed a retrospective single-center study of pediatric IBD patients started on IFX over a 10-year period. RESULTS Two hundred ninety-one patients were included (mean age = 12.61, 38% female) with a follow-up range of 0.1-9.7 years from IFX induction. One hundred fifty-five (53%) were started at a dose of 10 mg/kg. Only 35 patients (12%) discontinued IFX. The median duration of treatment was 2.9 years. Patients with ulcerative colitis ( P ≤ 0.01) and patients with extensive disease ( P = 0.01) had lower durability, despite a higher starting dose of IFX ( P = 0.03). Adverse events (AEs) were observed to occur at a rate of 234 per 1000 patient-years. Patients with a higher serum IFX trough level (≥20 µg/mL) had a higher rate of AEs ( P = 0.01). Use of combination therapy had no impact on risk of AEs ( P = 0.78). CONCLUSIONS We observed an excellent IFX treatment durability, with only 12% of patients discontinuing therapy over the observed timeframe. The overall rate of AEs was low, the majority being infusion reactions and dermatologic conditions. Higher IFX dose and serum trough level> 20 µg/mL were associated with higher risk of AEs, the majority being mild and not resulting in cessation of therapy.
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Affiliation(s)
- Meghan Gibson
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - Shova Subedi
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - David H Barker
- the Department of Child and Adolescent Psychiatry, Rhode Island Hospital, Providence, RI
| | - Samuel Masur
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
- the Department of Pediatrics, Hasbro Children's Hospital, Providence, RI
| | | | - Archana Lingannan
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - Aldo Alejandro Recinos Soto
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - Dyadin Esharif
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - Sarah H Maxwell
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
- the Department of Pediatrics, Hasbro Children's Hospital, Providence, RI
| | - Muhammad Safwan Riaz
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - Michael I Herzlinger
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - Linda B Shalon
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - Carolina S Cerezo
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - Vania L Kasper
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - Albert M Ross
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
| | - Neal S Leleiko
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Columbia University Irving Medical Center, New York, NY
| | - Jason M Shapiro
- From Warren Alpert Medical School of Brown University, Providence, RI
- the Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hasbro Children's Hospital, Providence, RI
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28
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Baldwin K, Grossi V, Hyams JS. Managing pediatric Crohn's disease: recent insights. Expert Rev Gastroenterol Hepatol 2023; 17:949-958. [PMID: 37794692 DOI: 10.1080/17474124.2023.2267431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 10/03/2023] [Indexed: 10/06/2023]
Abstract
INTRODUCTION Children and adolescents with Crohn's disease present unique challenges due to extensive disease at diagnosis and the effect of bowel inflammation on growth. Historical approaches with corticosteroids and immunomodulators are far less effective than early treatment with anti-TNF biologics. AREAS COVERED This review covers recent literature delineating the crucial role of early anti-TNF therapy in the treatment of moderate- to- severe Crohn's disease in children and adolescents. The potential risks and benefits of concomitant immunomodulators are discussed, along with therapeutic anti-TNF drug monitoring, and reassessment by endoscopy and cross-sectional imaging to evaluate success beyond symptom control. EXPERT OPINION Standard of care therapy for moderate-to-severe pediatric Crohn's disease now entails precision dosing of anti-TNF therapy with periodic reassessment of bowel inflammation. The role of dietary modification continues to evolve. Current and future efforts need to be directed to elucidating ways to predict response to anti-TNF therapy and quickly changing to agents with other mechanisms of action when needed. Inordinate regulatory delays in approval of new therapies approved for adults continue to handicap pediatric clinicians and frequently limits their treatment choices, or forces them to give medications "off label." Only a concerted effort by clinicians, pharma, and regulators will improve this situation.
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Affiliation(s)
- Katherine Baldwin
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA
- Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Victoria Grossi
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA
- Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Jeffrey S Hyams
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA
- Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA
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29
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Malham M, Jansson S, Malmborg P, Olén O, Paerregaard A, Virta LJ, Jakobsen C, Kolho KL, Wewer V. Risk Factors of Cancer in Pediatric-Onset Inflammatory Bowel Disease in Denmark and Finland. J Pediatr Gastroenterol Nutr 2023; 77:55-61. [PMID: 36961906 DOI: 10.1097/mpg.0000000000003781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/26/2023]
Abstract
OBJECTIVES Pediatric-onset inflammatory bowel disease (pIBD) increases the risk of developing several different cancer forms. In this case-control study, we aimed to assess the impact of medical treatment and disease activity on the risk of developing disease-associated cancer (DAC) and treatment-associated cancer (TAC). METHODS In a previous study, we identified 27 cases of DAC (colorectal cancer, small bowel cancer, and cholangiocarcinoma) and 28 TAC (lymphoma and skin cancer) in 6689 patients with pIBD in Denmark and Finland during the period 1992-2015. In this study, the patient charts were reviewed manually. Cancer-free patients from another population-based pIBD cohort were included as controls. We recorded data on phenotype, medical treatment, surgery, and relapses. Logistic regression was used to estimate adjusted odds ratios (aOR) with 95% confidence intervals (95% CI) to estimate the relative risk. RESULTS We included 16 cases with DAC, 21 with TAC, and 331 controls. For DAC, lower frequencies of IBD-relapses were associated with an increased risk of cancer (OR 0.2 [95% CI: 0.04-0.8]). For TAC, we found an increased risk in patients receiving thiopurines at any point during the follow-up period (aOR: 11.7 [95% CI: 2.1-116.2]) and an association with proportion of follow-up time being exposed to thiopurines (aOR 5.6 [95% CI: 1.1-31.5]). CONCLUSIONS In this nation-wide study, covering all pIBD patients from Denmark and Finland, we found that pIBD patients treated with thiopurines had an increased risk of TAC.
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Affiliation(s)
- Mikkel Malham
- From the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Copenhagen Centre for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Sabine Jansson
- From the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Copenhagen Centre for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - Petter Malmborg
- Sachs' Children and Youth Hospital, Stockholm, Sweden
- the Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ola Olén
- Sachs' Children and Youth Hospital, Stockholm, Sweden
- the Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Anders Paerregaard
- From the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Copenhagen Centre for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - Lauri J Virta
- the Research Department, Social Insurance Institution of Finland, Turku, Finland
| | - Christian Jakobsen
- From the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Copenhagen Centre for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - Kaija-Leena Kolho
- Children's Hospital, Helsinki University Hospital, Helsinki, Finland
| | - Vibeke Wewer
- From the Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- the Copenhagen Centre for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
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Kim ES, Kang B. Infliximab vs adalimumab: Points to consider when selecting anti-tumor necrosis factor agents in pediatric patients with Crohn’s disease. World J Gastroenterol 2023; 29:2784-2797. [PMID: 37274072 PMCID: PMC10237103 DOI: 10.3748/wjg.v29.i18.2784] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/20/2023] [Accepted: 04/17/2023] [Indexed: 05/11/2023] Open
Abstract
Biologic agents with various mechanisms against Crohn’s disease (CD) have been released and are widely used in clinical practice. However, two anti-tumor necrosis factor (TNF) agents, infliximab (IFX) and adalimumab (ADL), are the only biologic agents approved by the Food and Drug Administration for pediatric CD currently. Therefore, in pediatric CD, the choice of biologic agents should be made more carefully to achieve the therapeutic goal. There are currently no head-to-head trials of biologic agents in pediatric or adult CD. There is a lack of accumulated data for pediatric CD, which requires the extrapolation of adult data for the positioning of biologics in pediatric CD. From a pharmacokinetic point of view, IFX is more advantageous than ADL when the inflammatory burden is high, and ADL is expected to be advantageous over IFX in sustaining remission in the maintenance phase. Additionally, we reviewed the safety profile, immunogenicity, preference, and compliance between IFX and ADL and provide practical insights into the choice of anti-TNF therapy in pediatric CD. Careful evaluation of clinical indications and disease behavior is essential when prescribing anti-TNF agents. In addition, factors such as the efficacy of induction and maintenance of remission, safety profile, immunogenicity, patient preference, and compliance play an important role in evaluating and selecting treatment options.
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Affiliation(s)
- Eun Sil Kim
- Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, South Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
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31
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Claßen M, Hoerning A. Current Role of Monoclonal Antibody Therapy in Pediatric IBD: A Special Focus on Therapeutic Drug Monitoring and Treat-to-Target Strategies. CHILDREN 2023; 10:children10040634. [PMID: 37189883 DOI: 10.3390/children10040634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
In the last two decades, biologicals have become essential in treating children and adolescents with inflammatory bowel disease. TNF-α inhibitors (infliximab, adalimumab and golimumab) are preferentially used. Recent studies suggest that early application of TNF-α inhibitors is beneficial to inducing disease remission and preventing complications such as development of penetrating ulcers and fistulas. However, treatment failure occurs in about one third of pediatric patients. Particularly, children and adolescents differ in drug clearance, emphasizing the importance of pharmacokinetic drug monitoring in the pediatric setting. Here, current data on the choice and effectiveness of biologicals and therapeutic drug monitoring strategies are reviewed.
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Wei HT, Xue XW, Ling Q, Wang PY, Zhou WX. Positive correlation between latent Epstein-Barr virus infection and severity of illness in inflammatory bowel disease patients. World J Gastrointest Surg 2023; 15:420-429. [PMID: 37032795 PMCID: PMC10080598 DOI: 10.4240/wjgs.v15.i3.420] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/16/2023] [Accepted: 03/05/2023] [Indexed: 03/27/2023] Open
Abstract
BACKGROUND Emerging studies indicate the critical involvement of microorganisms, such as Epstein-Barr virus (EBV), in the pathogenesis of inflammatory bowel disease (IBD). Immunosuppressive therapies for IBD can reactivate latent EBV, complicating the clinical course of IBD. Moreover, the clinical significance of EBV expression in B lymphocytes derived from IBD patients’ intestinal tissues has not been explored in detail.
AIM To explore the clinical significance of latent EBV infection in IBD patients.
METHODS Latent EBV infection was determined by double staining for EBV encoded RNA and CD20 in colon specimens of 43 IBD patients who underwent bowel resection. Based on the staining results, the patients were divided into two groups, according to their latent EBV infection states - negative (n = 33) and positive (n = 10). Illness severity of IBD were assigned according to Crohn’s disease activity index (ulcerative colitis) and Mayo staging system (Crohn’s disease). The clinic-pathological data were analyzed between the two different latent EBV groups and also between the mild-to-moderate and severe disease groups.
RESULTS Systolic pressure (P = 0.005), variety of disease (P = 0.005), the severity of illness (P = 0.002), and pre-op corticosteroids (P = 0.025) were significantly different between the EBV-negative and EBV-positive groups. Systolic pressure (P = 0.001), variety of disease (P = 0.000), pre-op corticosteroids (P = 0.011) and EBV infection (P = 0.003) were significantly different between the mild-to-moderate and severe disease groups.
CONCLUSION IBD patients with latent EBV infection may manifest more severe illnesses. It is suggested that the role of EBV in IBD development should be further investigated, latent EBV infection in patients with serious IBD should be closely monitored, and therapeutic course should be optimized.
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Affiliation(s)
- Hong-Tao Wei
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Xiao-Wei Xue
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China
| | - Qing Ling
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China
| | - Peng-Yan Wang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China
| | - Wei-Xun Zhou
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China
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Adalimumab Therapy in Pediatric Crohn Disease: A 2-Year Follow-Up Comparing "Top-Down" and "Step-Up" Strategies. J Pediatr Gastroenterol Nutr 2023; 76:166-173. [PMID: 36305799 DOI: 10.1097/mpg.0000000000003643] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES European Crohn's Colitis Organization (ECCO) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines recommend the early use of anti-tumor necrosis factor (TNF) biologicals in pediatric Crohn disease (CD) patients with positive predictors for poor outcome. The objective of the present study was to compare early "Top-Down" use of adalimumab (ADA) immunomodulator/biologics-naive patients to conventional "Step-Up" management. METHODS One hundred and twenty consecutive patients with a confirmed diagnosis of CD and treated with ADA between 2008 and 2019 were included and allocated to the ADA-Top Down (n = 59) or ADA-Step Up group (n = 61). The primary endpoint was prolonged steroid-/enteral nutrition-free clinical remission at 24 months, defined by a weighted Pediatric Crohn's Disease Activity Index (wPCDAI) < 12.5. Clinical and biological data were collected at 12 and 24 months. RESULTS At start of ADA, disease activity was comparable between the ADA-Top Down group and the ADA-Step Up group (wPCDAI = 31 ± 16 vs 31.3 ± 15.2, respectively, P = 0.84). At 24 months, the remission rate was significantly higher in the ADA-Top Down group (73% vs 51%, P < 0.01). After propensity score, the Top-Down strategy is still more effective than the Step-Up strategy in maintaining remission at 24 months [hazard ratio (HR) = 0.36, 95% CI (0.15-0.87), P = 0.02]. Patients in the ADA-Top Down group were mainly on monotherapy compared to patients in the ADA-Step Up group (53/55 vs 28/55 respectively, P < 0.001). Serum levels of ADA were higher in the ADA-Top Down group than in the ADA-Step Up group (12.8 ± 4.3 vs 10.4 ± 3.9 µg/mL, respectively, P < 0.01). There were no serious adverse events. CONCLUSIONS Early use of ADA appears to be more effective in maintaining relapse-free remission at 2 years, while using it as monotherapy. These findings further favor the recommendation of early anti-TNF use in high-risk CD patients.
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Low Risk of Lymphoma in Children With IBD Is Reassuring to Clinicians and Families. Am J Gastroenterol 2023; 118:261-262. [PMID: 36735558 DOI: 10.14309/ajg.0000000000002117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 11/21/2022] [Indexed: 02/04/2023]
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Egberg MD, Zhang X, Smitherman AB, Kappelman MD. Low Risk of Lymphoma in Pediatric Patients Treated for Inflammatory Bowel Disease. Am J Gastroenterol 2023; 118:354-359. [PMID: 36219181 PMCID: PMC9898086 DOI: 10.14309/ajg.0000000000002053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 10/06/2022] [Indexed: 11/07/2022]
Abstract
INTRODUCTION Despite the effectiveness of immune-suppressing therapies in treating pediatric inflammatory bowel diseases (IBDs), concerns of lymphoma may limit their use. We used a large administrative claims database to evaluate the risk of lymphoma in pediatric IBD and conducted a case series analysis of medication exposure in children diagnosed with lymphoma. METHODS We analyzed administrative claims from the 2007 to 2018 IQVIA database and identified pediatric (≤18 years) patients with Crohn's disease or ulcerative colitis using International Classification of Diseases, 9th or 10th Revision codes and pharmacy claims. Lymphoma cases were identified by diagnosis codes and confirmed by independent claim-by-claim review by a pediatric oncologist and gastroenterologist. We calculated incidence rates for lymphoma among patients with and without pharmacy claims for treatment followed by treatment description among those who developed lymphoma during follow-up. RESULTS A total of 10,777 pediatric patients with IBD received ≥1 IBD therapy (median age 15 years [12-17], 45% female and 61% diagnosed with Crohn's disease) during 28,292 patient-years of follow-up. Among treated patients, 5 lymphoma cases were identified (incidence rate 17.7/100,000 patient-years; 95% confidence interval 6.5-39.2). Of these, 4 were treated with a thiopurine before lymphoma diagnosis, and none received anti-tumor necrosis factor-α (anti-TNF) monotherapy. DISCUSSION The overall lymphoma incidence was low among our cohort of treated pediatric patients with IBD. We observed no cases of lymphoma among patients prescribed anti-TNF monotherapy. These findings reinforce the relative safety of anti-TNF monotherapy for the treatment of pediatric IBD.
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Affiliation(s)
- Matthew D. Egberg
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Xian Zhang
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Andrew B. Smitherman
- Department of Pediatrics, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Michael D. Kappelman
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Colman RJ, Dykes DMH, Arce-Clachar AC, Saeed SA, Minar P. Infliximab Therapy for Pediatric Crohn Disease and Ulcerative Colitis. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:407-422. [DOI: 10.1007/978-3-031-14744-9_31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Dailey J, Hyams JS. Natural History of Ulcerative Colitis in Children. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:103-111. [DOI: 10.1007/978-3-031-14744-9_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Rosh JR. Methotrexate. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:401-406. [DOI: 10.1007/978-3-031-14744-9_30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Urlep D, Miele E. Mercaptopurine Therapy. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:391-399. [DOI: 10.1007/978-3-031-14744-9_29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Abstract
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.
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Nasab AS, Finkler M, DeLozier S, Sferra TJ, Splawski J, Moses J. Comparison of Short-Term Outcomes for Standard Versus Nonstandard Induction Dosing of Infliximab for Pediatric Inflammatory Bowel Disease. J Pediatr Pharmacol Ther 2022; 27:732-738. [DOI: 10.5863/1551-6776-27.7.732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 01/10/2022] [Indexed: 11/18/2022]
Abstract
OBJECTIVE
Recent studies have emphasized the early use of infliximab (IFX) in pediatric patients with inflammatory bowel disease. Standard dosing of 5 mg/kg/dose may not be sufficient to achieve optimal clinical outcomes. The aim of our study was to compare short-term outcomes with standard dosing of IFX to higher, nonstandard dosing of IFX for induction therapy.
METHODS
Retrospective study of 162 pediatric patients receiving either standard (5–6 mg/kg, n = 90) or nonstandard (>6 mg/kg, n = 72) dosing of IFX during induction was performed. Patient demographics, clinical outcomes, and laboratory data were collected. Need for dose escalation during the first 6 months, combination therapy with immunomodulators, and steroid-free progression were investigated.
RESULTS
Clinical remission rates between the 2 groups were significantly different, with patients receiving nonstandard dosing demonstrating higher rates (58% vs 78%; p = 0.012). Use of combination therapy with immunomodulators was significantly different between standard and nonstandard groups (80% vs 48%; p < 0.001). Numeric trend in need for IFX dose escalation in the first 6 months was seen between standard and nonstandard groups (54% vs 39%, respectively; p = 0.087). Post-induction IFX trough concentrations, rates of antibody development, drug discontinuation, and infusion reaction were similar.
CONCLUSIONS
Nonstandard induction dosing of IFX was associated with higher rates of clinical remission, despite similar rates of serum IFX trough concentrations. There was a numeric trend towards the standard group requiring dose escalation within the first 6 months of therapy. Patients given nonstandard dosing may achieve superior clinical outcomes compared with those on standard dosing.
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Affiliation(s)
- Arian S. Nasab
- Department of Pediatrics (ASN), UH–Rainbow Babies and Children's Hospital Cleveland, OH
| | - Michael Finkler
- Division of Pediatric Gastroenterology (MF, TJS, JS, JM), UH–Rainbow Babies and Children's Hospital Cleveland, OH
| | - Sarah DeLozier
- Center for Clinical Research (SD), University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Thomas J. Sferra
- Division of Pediatric Gastroenterology (MF, TJS, JS, JM), UH–Rainbow Babies and Children's Hospital Cleveland, OH
| | - Judy Splawski
- Division of Pediatric Gastroenterology (MF, TJS, JS, JM), UH–Rainbow Babies and Children's Hospital Cleveland, OH
| | - Jonathan Moses
- Division of Pediatric Gastroenterology (MF, TJS, JS, JM), UH–Rainbow Babies and Children's Hospital Cleveland, OH
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Bayoumy AB, Jagt JZ, van Wering HM, de Ridder L, Hummel T, Wolters VM, Stapelbroek J, Benninga MA, Mulder CJ, de Boer NK, de Meij TG. Safety of Thioguanine in Pediatric Inflammatory Bowel Disease: A Multi-Center Case Series. J Pediatr Gastroenterol Nutr 2022; 75:e111-e115. [PMID: 36136124 PMCID: PMC9645549 DOI: 10.1097/mpg.0000000000003621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/11/2022] [Indexed: 01/12/2023]
Abstract
OBJECTIVES Thioguanine (TG) has been shown as a safe alternative in adults with inflammatory bowel disease (IBD) who did not tolerate conventional thiopurines [azathioprine (AZA)/mercaptopurine]. However, data in pediatric IBD are scarce. Therefore, we aimed to assess the safety of TG as maintenance therapy. METHODS A retrospective, multicenter cohort study of children with IBD on TG was performed in the Netherlands. TG-related adverse events (AE) were assessed and listed according to the common terminology criteria for AE. RESULTS Thirty-six children with IBD (median age 14.5 years) on TG (median dose 15 mg/day) were included in 6 centers. Five AE occurred during follow-up [pancreatitis (grade 3), hepatotoxicity (grade 3) (n = 2), Clostridium difficile infection (grade 2), and abdominal pain (grade 2)]. All patients (n = 8) with a previously AZA-induced pancreatitis did not redevelop pancreatitis on TG. CONCLUSIONS In pediatric IBD, TG seems a safe alternative in case of AZA-induced pancreatitis. Further research assessing long-term TG-related safety and efficacy is needed.
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Affiliation(s)
- Ahmed B. Bayoumy
- From the Faculty of Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Jasmijn Z. Jagt
- the Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- the Amsterdam UMC, Vrije Universiteit Amsterdam, Paediatric Gastroenterology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Herbert M. van Wering
- the Department of Pediatric Gastroenterology, Amphia Hospital, Breda, the Netherlands
| | - Lissy de Ridder
- the Department of Pediatric Gastroenterology, Erasmus MC Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Thalia Hummel
- the Department of Pediatric Gastroenterology, Medisch Spectrum Twente, Enschede, the Netherlands
| | - Victorien M. Wolters
- the Department of Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Janneke Stapelbroek
- the Department of Pediatric Gastroenterology, Catharina Hospital, Eindhoven, the Netherlands
| | - Marc A. Benninga
- the Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Chris J.J. Mulder
- the Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Nanne K.H. de Boer
- the Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Tim G.J. de Meij
- the Department of Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- the Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
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Outcomes and Predictors of Sustained Remission After Drug Withdrawal in Pediatric Crohn Disease. J Pediatr Gastroenterol Nutr 2022; 75:608-615. [PMID: 35976282 DOI: 10.1097/mpg.0000000000003589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES The primary aim of this study was to determine the proportion of pediatric Crohn disease (CD) subjects in sustained drug-free remission 52 weeks after stopping pharmacological therapy. We also aimed to explore the effects of the Crohn Disease Exclusion Diet (CDED) and microbiome composition on remission. METHODS We performed a prospective study following 18 CD patients ages 13-21 years in deep clinical remission withdrawing from immunomodulator (n = 7) or anti-TNFα (n = 11) monotherapy at two tertiary care centers. Stool for calprotectin and microbiome analyses was collected over 52 weeks. Participants followed either the CDED or free diet after drug withdrawal. The primary endpoint was sustained relapse-free drug-free remission (calprotectin <250 µg/g) at 52 weeks. RESULTS Seventeen participants were followed through 52 weeks with 11 (64.7%) in sustained remission. There was no improvement in remission among participants following the CDED (5/9; 55.6%), P = 0.63. By 104 weeks, only 8 (47.1 %) participants remained off immunosuppressive therapies. Analysis of shotgun metagenomic sequence data revealed that taxonomic and gene function abundance in the gut microbiome was relatively stable for participants in remission and relapse. However, a predictive model incorporating gut microbial gene pathway abundance for amino sugar/nucleotide sugar metabolism and galactose metabolism from baseline samples predicted relapse at 52 weeks with 80% accuracy. CONCLUSIONS After withdrawal of immunomodulator or anti-TNFα monotherapy among a small cohort of pediatric CD subjects in deep remission, nearly 65% sustained remission at 52 weeks. Baseline microbiome alterations predicted relapse. Large prospective studies are needed to better understand outcomes after treatment de-escalation.
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Pigneur B, Ruemmele FM. A critical review of adalimumab for the treatment of moderate-to-severe active ulcerative colitis in children. Expert Rev Gastroenterol Hepatol 2022; 16:1023-1028. [PMID: 36395503 DOI: 10.1080/17474124.2022.2149489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Anti-tumor necrosis factor (TNF) antibodies play a major role in treating inflammatory bowel disease (IBD), both in adult and pediatric patients. While there is a large number of studies on efficacy and safety of infliximab in treating children and adolescents with ulcerative colitis (UC), data on adalimumab (ADA) are scarce. AREAS COVERED Here, we review published case reports, cohort and real-time data, as well as the first randomized trial, ENVISION I, using ADA for treating pediatric UC. Available evidence confirms good efficacy in inducing and maintaining remission in children and adolescents with UC, with even higher response rates compared to adult UC. ENVISION I showed that in UC patients responding to ADA induction therapy, almost half of the patients remained in remission after 52 weeks of therapy on high-dosing ADA (weekly administration). As already well experienced with other biologics, dosing schemes are different between pediatric and adult patients, with children often requiring higher dosing. EXPERT OPINION Further data are required to better understand how to optimize ADA therapy. The present and still-growing evidence places subcutaneous (sc.) anti-TNF-medication as alternative first-line therapy also for pediatric UC. This is also reflected by the preference for sc. medication of adolescent patients allowing less frequent and autonomous drug administration.
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Affiliation(s)
- Bénédicte Pigneur
- Service de Gastro-entérologie et Nutrition pédiatrique, Centre de Référence des Maladies rares digestives (MARDI), Assistance Publique - Hôpitaux de Paris, Hôpital Necker Enfants malades, Paris, France.,INSERM UMR S 1139, Faculté de Pharmacie de Paris, Paris, France.,Faculté de Médecine, Université de Paris Cite, Paris, France
| | - Frank M Ruemmele
- Service de Gastro-entérologie et Nutrition pédiatrique, Centre de Référence des Maladies rares digestives (MARDI), Assistance Publique - Hôpitaux de Paris, Hôpital Necker Enfants malades, Paris, France.,Faculté de Médecine, Université de Paris Cite, Paris, France.,INSERM UMR 1163, Immunité intestinale, Institut Imagine, Paris, France
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Advancing Biologic Therapy for Refractory Autoimmune Hepatitis. Dig Dis Sci 2022; 67:4979-5005. [PMID: 35147819 DOI: 10.1007/s10620-021-07378-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/27/2021] [Indexed: 01/05/2023]
Abstract
Biologic agents may satisfy an unmet clinical need for treatment of refractory autoimmune hepatitis. The goals of this review are to present the types and results of biologic therapy for refractory autoimmune hepatitis, indicate opportunities to improve and expand biologic treatment, and encourage comparative clinical trials. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Rituximab (monoclonal antibodies against CD20 on B cells), infliximab (monoclonal antibodies against tumor necrosis factor-alpha), low-dose recombinant interleukin 2 (regulatory T cell promoter), and belimumab (monoclonal antibodies against B cell activating factor) have induced laboratory improvement in small cohorts with refractory autoimmune hepatitis. Ianalumab (monoclonal antibodies against the receptor for B cell activating factor) is in clinical trial. These agents target critical pathogenic pathways, but they may also have serious side effects. Blockade of the B cell activating factor or its receptors may disrupt pivotal B and T cell responses, and recombinant interleukin 2 complexed with certain interleukin 2 antibodies may selectively expand the regulatory T cell population. A proliferation-inducing ligand that enhances T cell proliferation and survival is an unevaluated, potentially pivotal, therapeutic target. Fully human antibodies, expanded target options, improved targeting precision, more effective delivery systems, and biosimilar agents promise to improve efficacy, safety, and accessibility. In conclusion, biologic agents target key pathogenic pathways in autoimmune hepatitis, and early experiences in refractory disease encourage clarification of the preferred target, rigorous clinical trial, and comparative evaluations.
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Dupont-Lucas C, Leroyer A, Ley D, Spyckerelle C, Bertrand V, Turck D, Savoye G, Maunoury V, Guillon N, Fumery M, Sarter H, Gower-Rousseau C. Increased risk of cancer and mortality in a large French population-based paediatric-onset inflammatory bowel disease retrospective cohort. J Crohns Colitis 2022; 17:524-534. [PMID: 36316987 DOI: 10.1093/ecco-jcc/jjac166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND AND AIMS Paediatric-onset IBD (pIBD) is associated with an increased risk of cancer and mortality in adulthood. The aims of this study were to measure the incidence of cancer and mortality in patients with pIBD and identify factors associated with mortality and cancer. METHODS All patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) before the age of 17 years between 1988 and 2011 in the EPIMAD registry, were retrospectively followed until 2013 for cancer and 2015 for mortality. Standardized incidence (SIR) and mortality ratios (SMR) were estimated compared to the general population. Cox regression was used to compare effect of exposures on cancer and mortality among IBD patients. RESULTS We included 1,344 patients (52% males, 75% CD), totalising 12,957 patient-years for cancer incidence and 18,817 patient-years for mortality. There were 14 cases of cancer (median age 27.8 years) and 15 deaths (median age 28.8 years). The incidence of cancer and of mortality were increased compared to the general population: all-cancer SIR = 2.7 (95%CI: 1.5-4.8), SMR = 1.7 (95%CI: 1.0-2.8). Colorectal cancer had the highest SIR and SMR: SIR=41.2 (95%CI: 17.2-99.0), SMR=70.4 (95%CI 22.7-218.2). Cancer was associated with (HR, 95%CI): active smoking at diagnosis (5.5, 1.8-16.5), p=0.002, any exposure to anti-TNF (6.1, 1.7-22.3), p=0.0065 and exposure to combination therapy (7.4, 1.8-29.7), p=0.0047. Mortality was associated with extraintestinal manifestations (HR 4.9 (95% CI: 1.7-13.8), p=0.003). CONCLUSIONS In this large population-based cohort, patients with pIBD had an increased risk of both cancer (2.7-fold) and mortality (1.7-fold), particularly for colorectal cancer.
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Affiliation(s)
- Claire Dupont-Lucas
- Department of Paediatrics, Caen University Hospital, F-14000 Caen, France.,INSERM UMR 1073 ADEN, Institute for Biomedical Research, F-76000 Rouen, France
| | - Ariane Leroyer
- Lille Hospital and University, Public Health, Epidemiology and Economic Health, EPIMAD registry, Regional house of clinical research, F-59000 Lille, France.,Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Delphine Ley
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France.,CHU Lille, Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, F-59000 Lille, France
| | - Claire Spyckerelle
- Department of Paediatrics, St Vincent de Paul Hospital and Lille Catholic University, F-59000 Lille, France
| | - Valérie Bertrand
- Department of Paediatrics, Jacques Monod Hospital, F-76600 Le Havre, France
| | - Dominique Turck
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France.,CHU Lille, Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, F-59000 Lille, France
| | - Guillaume Savoye
- INSERM UMR 1073 ADEN, Institute for Biomedical Research, F-76000 Rouen, France.,Department of Gastroenterology, Rouen University Hospital, F-76000 Rouen, France
| | - Vincent Maunoury
- Department of Gastroenterology, Claude Huriez Hospital, Lille University Hospital, F- 59000 Lille, France
| | - Nathalie Guillon
- Lille Hospital and University, Public Health, Epidemiology and Economic Health, EPIMAD registry, Regional house of clinical research, F-59000 Lille, France.,Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Mathurin Fumery
- Department of Gastroenterology, Amiens University Hospital, F-80000 Amiens, France.,INSERM UMR I01, PERITOX, Jules Verne University of Picardy, F-80000 Amiens, France
| | - Hélène Sarter
- Lille Hospital and University, Public Health, Epidemiology and Economic Health, EPIMAD registry, Regional house of clinical research, F-59000 Lille, France.,Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Corinne Gower-Rousseau
- Lille Hospital and University, Public Health, Epidemiology and Economic Health, EPIMAD registry, Regional house of clinical research, F-59000 Lille, France.,Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France.,Epidemiology Unit, Robert Debré Hospital, Reims University Hospital, F-51100 Reims, France
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47
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PD-1 Blockader-associated Atypical Hemophagocytic Lymphohistiocytosis: A Cautionary Case Report. Transfus Apher Sci 2022; 62:103603. [PMID: 36470726 DOI: 10.1016/j.transci.2022.103603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/12/2022] [Accepted: 11/16/2022] [Indexed: 11/21/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a fatal immune hyperactivity syndrome with high mortality. It seriously endangers human health. HLH associated with immune checkpoint inhibitors is rare, and no particular diagnostic guidelines or treatment regimens exist. A 36-year-old patient with metastatic right atrial angiosarcoma was treated with programmed cell death-1 (PD-1) blockader toripalimab and pazopanib, a vascular endothelial growth factor receptor blockader. However, the patient presented to our center with HLH, and he accepted combination therapy of therapeutic plasma exchange (TPE) and immunotherapy. The patient improved quickly, after only one TPE procedure. Finally, he was discharged after completing two TPE procedures. We summarize a case of PD-1 blocker associated atypical HLH that was successfully treated with TPE. Further evidence is needed to elucidate whether TPE has therapeutic potential for immunotherapy associated HLH.
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48
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Kornitzer G, Rosenstein M, Turcotte M, Godin D, Groleau V, Renaud C, Touzot F, Jantchou P, Ovetchkine P, Deslandres C. Epstein–Barr
virus seroprevalence and viral load at disease onset in children with inflammatory bowel disease. JGH Open 2022; 6:625-629. [PMID: 36091316 PMCID: PMC9446410 DOI: 10.1002/jgh3.12799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/10/2022] [Indexed: 11/23/2022]
Abstract
Background and Aim Patients with inflammatory bowel disease (IBD) are at increased risk for life‐threatening complications of Epstein–Barr virus (EBV), including lymphoproliferative diseases. These complications are likely related to inherent immune dysfunction and immunomodulating therapies often used. We aimed to determine the seroprevalence of EBV at diagnosis in our population, its impact on disease at onset, and the risk of active EBV infection. Methods We included patients newly diagnosed with IBD for whom an EBV serology was performed over a 2‐year period. Demographic information and data on disease characteristics were collected retrospectively. Stored serum from the time of diagnosis was retrieved when available for the patients with positive EBV serology, and quantitative polymerase chain reaction testing was performed to assess the pre‐treatment viral load of EBV. Results One hundred twenty patients were included in the study. Fifty‐three patients (44.2%) had positive EBV serology at diagnosis. Stratified by age group, the prevalence of seropositive patients was for 0 to <10 years 35%, 10 to <17 years 46%, and ≥17 years 50%. Overall, therapies started within 6 months of diagnosis were similar in both the seropositive and seronegative groups. Within the seropositive group, 66% received systemic corticosteroids, 32.1% infliximab, 5.7% adalimumab, and 5.7% azathioprine. Conclusion EBV seroprevalence is high in pediatric patients with IBD. EBV seropositivity did not seem to influence the severity of disease at onset or initial choice of therapy.
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Affiliation(s)
- Gaël Kornitzer
- Faculty of Medicine University of Montreal Montreal Canada
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics CHU Sainte‐Justine Montreal Canada
| | - Michelle Rosenstein
- Faculty of Medicine University of Montreal Montreal Canada
- Division of Paediatrics, Department of Paediatrics CHU Sainte‐Justine Montreal Canada
| | - Marie‐Catherine Turcotte
- Faculty of Medicine University of Montreal Montreal Canada
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics CHU Sainte‐Justine Montreal Canada
| | - David Godin
- Faculty of Medicine University of Montreal Montreal Canada
- Research Center CHU Sainte‐Justine Montreal Canada
| | - Véronique Groleau
- Faculty of Medicine University of Montreal Montreal Canada
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics CHU Sainte‐Justine Montreal Canada
- Research Center CHU Sainte‐Justine Montreal Canada
| | - Christian Renaud
- Faculty of Medicine University of Montreal Montreal Canada
- Research Center CHU Sainte‐Justine Montreal Canada
- Division of Infectious Diseases, Department of Paediatrics CHU Sainte‐Justine Montreal Canada
| | - Fabien Touzot
- Faculty of Medicine University of Montreal Montreal Canada
- Research Center CHU Sainte‐Justine Montreal Canada
- Division of Immunology, Department of Paediatrics CHU Sainte‐Justine Montreal Canada
| | - Prevost Jantchou
- Faculty of Medicine University of Montreal Montreal Canada
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics CHU Sainte‐Justine Montreal Canada
- Research Center CHU Sainte‐Justine Montreal Canada
| | - Philippe Ovetchkine
- Faculty of Medicine University of Montreal Montreal Canada
- Research Center CHU Sainte‐Justine Montreal Canada
- Division of Infectious Diseases, Department of Paediatrics CHU Sainte‐Justine Montreal Canada
| | - Colette Deslandres
- Faculty of Medicine University of Montreal Montreal Canada
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics CHU Sainte‐Justine Montreal Canada
- Research Center CHU Sainte‐Justine Montreal Canada
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49
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Anderson K, Moss K, Campbell B, Moote D, Kakazu K, Hyams JS. Follicular Dendritic Cell Sarcoma in a Patient With Adolescent-Onset Crohn's Disease Exposed to Multiple Immunomodulator and Biologic Therapies. JPGN REPORTS 2022; 3:e231. [PMID: 37168632 PMCID: PMC10158454 DOI: 10.1097/pg9.0000000000000231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/06/2022] [Indexed: 05/13/2023]
Abstract
Children and adolescents with inflammatory bowel disease are often treated with immunomodulators (thiopurines, methotrexate) and biologics (anti-TNF, anti-integrin) for extended periods despite concerns about long-term safety. Here, we report a case of follicular dendritic cell sarcoma, a very rare malignancy, and the first reported presentation in a patient with inflammatory bowel disease exposed to infliximab, methotrexate, and vedolizumab. We review the key clinical features and diagnostic factors of this malignancy. The pathogenesis of follicular dendritic cell sarcoma is largely unknown, however, knock out of B-cell TNF in mice has been related to follicular dendritic cell dysregulation through its impact on NF-κB pathways and CXCL13 chemokines. It is unknown whether any relationship exists between this patient's diagnosis of Crohn's disease and therapeutic exposures to this rare malignancy. We document this case in the literature to raise awareness among other clinicians who may observe a similar case.
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Affiliation(s)
- Kaitlyn Anderson
- From the Department of Graduate Medical Education, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
| | - Kerry Moss
- Department of Hematology/Oncology, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
| | - Brendan Campbell
- Department of Surgery, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
| | - Douglas Moote
- Department of Radiology, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
| | - Kari Kakazu
- Department of Pathology, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
| | - Jeffrey S. Hyams
- Department of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children’s Medical Center, The University of Connecticut School of Medicine, Hartford, CT
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50
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Myelolipoma After Infliximab Treatment for Crohn's Disease. ACG Case Rep J 2022; 9:e00791. [PMID: 35784510 PMCID: PMC9246070 DOI: 10.14309/crj.0000000000000791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 02/23/2022] [Indexed: 11/17/2022] Open
Abstract
A 20-year-old woman with Crohn's disease receiving infliximab therapy presented to the emergency department with lower extremity swelling secondary to compression of the common iliac vein. On magnetic resonance imaging, an enlarging pelvic mass was identified. The pathology of the mass was consistent with myelolipoma. We believe this is the first case of myelolipoma in a patient on immunosuppression with infliximab.
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