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Rosania R, Nord M, Scurt FG, Lux A, Keitel V, von Arnim U, Venerito M. Risk Factors for Intestinal and Extraintestinal Cancers in Inflammatory Bowel Disease: A Retrospective Single-Center Cohort Study. Cancers (Basel) 2025; 17:1396. [PMID: 40361323 PMCID: PMC12071157 DOI: 10.3390/cancers17091396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 04/17/2025] [Accepted: 04/19/2025] [Indexed: 05/15/2025] Open
Abstract
Background/Objectives: Patients with inflammatory bowel disease (IBD) face an increased risk of developing intestinal and extraintestinal cancers. This retrospective single-center study aimed to quantify cancer risk and identify potential risk factors associated with cancer in IBD patients. Methods: The epidemiological data, disease characteristics, treatment regimens, and occurrences of cancer following IBD diagnosis were collected between January 2021 and February 2022. Hazard ratios (HRs) and standardized incidence ratios (SIRs) were estimated. Results: 560 IBD patients were included; 37 patients developed cancer, with 5 patients developing two distinct cancers, resulting in 42 cancers overall. This translated into a twofold increased risk of developing any cancer compared to the general population (SIR 1.94, 95% CI 1.4-2.6). Colorectal (CRC, 29%), skin (19%), and breast cancer (17%) were the most common malignancies. Female patients showed an increased risk for all cancers (SIR 3.1, 95% CI 2.06-4.3), melanoma (SIR 5.6, 95% CI 1.14-16.2), and CRC (SIR 7.5, 95% CI 3-15.4). Conversely, male patients exhibited a significantly increased risk of lymphoma (SIR 26.2, 95% CI 3.2-95.7). Young age at IBD diagnosis and the use of immunomodulators, whether as monotherapy or in combination with biologics, were associated with an increased risk of cancer. Conclusions: The risk of CRC and lymphoma in IBD patients may be higher than previously reported, potentially due to the increasing use of combination therapy. Cancer risk in IBD should be regularly assessed and personalized throughout the disease course.
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Affiliation(s)
- Rosa Rosania
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, 39120 Magdeburg, Germany; (M.N.); (V.K.); (U.v.A.); (M.V.)
| | - Maximilian Nord
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, 39120 Magdeburg, Germany; (M.N.); (V.K.); (U.v.A.); (M.V.)
| | - Florian G. Scurt
- University Clinic for Nephrology and Hypertension, Diabetology and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany;
| | - Anke Lux
- Institute of Biometry and Medical Informatics, Otto-von-Guericke University, 39120 Magdeburg, Germany;
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, 39120 Magdeburg, Germany; (M.N.); (V.K.); (U.v.A.); (M.V.)
| | - Ulrike von Arnim
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, 39120 Magdeburg, Germany; (M.N.); (V.K.); (U.v.A.); (M.V.)
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, 39120 Magdeburg, Germany; (M.N.); (V.K.); (U.v.A.); (M.V.)
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Wang S, Wu Y, Fei B, Zhang M. Fluorescent Nanocomposite Materials with Synergistic Effects for Enhanced Fenelidone Delivery in Diabetic Nephropathy Treatment. J Fluoresc 2025:10.1007/s10895-025-04195-0. [PMID: 39985616 DOI: 10.1007/s10895-025-04195-0] [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: 01/05/2025] [Accepted: 02/09/2025] [Indexed: 02/24/2025]
Abstract
In this study, we designed and synthesized a novel thio-purine analog, compound 1, which exhibits significant fluorescence properties due to its extended conjugated system, heteroatom incorporation (O, S, N), and rigid three-dimensional molecular framework, enabling its use as a fluorescence probe for real-time drug tracking and release monitoring. To enhance the solubility, biocompatibility, and therapeutic efficacy of compound 1, we synthesized a copper(II)-based coordination polymer (CP1) via hydrothermal methods, featuring a three-dimensional framework formed by 1,4-ttb and auxiliary ligand 4,4'-bpdc, as confirmed by comprehensive characterization techniques. Leveraging the synergistic therapeutic effects of compound 1 and fenelidone, we developed a composite drug delivery system, mPEG-PSU@CP1@1@fenelidone, which combines an amphiphilic mPEG-PSU shell with a CP1 core co-encapsulating both drugs. Notably, the fluorescence properties of compound 1 allow for real-time monitoring of drug release, as its fluorescence is quenched when encapsulated in CP1 and restored upon release. This system optimizes controlled drug release while enhancing the synergistic effects of compound 1 and fenelidone in reducing inflammation and renal fibrosis, as demonstrated in diabetic nephropathy (DN) model mice. Overall, the composite system integrates real-time fluorescence monitoring with improved therapeutic efficacy, offering a promising strategy for diabetic nephropathy treatment.
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Affiliation(s)
- Suyu Wang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yanyan Wu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Bingru Fei
- Department of Nephrology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China
| | - Mei Zhang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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Calcaterra V, Penagini F, Rossi V, Abbattista L, Bianchi A, Turzi M, Cococcioni L, Zuccotti G. Thyroid disorders and inflammatory bowel disease: an association present in adults but also in children and adolescents. Front Endocrinol (Lausanne) 2025; 16:1425241. [PMID: 39968296 PMCID: PMC11832402 DOI: 10.3389/fendo.2025.1425241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Abstract
Inflammatory bowel diseases (IBD) represent chronic inflammatory multisystemic disorders that primarily involve the gastrointestinal tract. Patients with ulcerative colitis (UC) and Crohn's disease (CD) exhibit a higher prevalence of thyroid disorders compared to the general population. The aim of this review is to summarize the literature on concomitant IBD and thyroid disorders, specifically autoimmune thyroid diseases such as Graves' disease (GD) and Hashimoto's thyroiditis (HT), as well as thyroid cancer, with a focus on children and adolescents. We provide an overview of the age-related differences between children and adults in the prevalence of this association. Literature shows that relatively few studies have been conducted on this subject in pediatric populations. The etiopathogenetic similarities between IBD and autoimmune thyroiditis are undeniable. Nevertheless, current data does not indicate a unanimous association between GD and HT and chronic IBD (both CD and UC). Although evidence suggests a potential association between IBD and thyroid cancer, particularly papillary thyroid cancer, the precise nature of this relationship varies across studies and is influenced by multiple factors. The limited information regarding the relationship between IBD and thyroid disorders in children highlights a significant knowledge gap. Since the thyroid plays a critical role in the pediatric population's development, it is essential to promptly recognize and treat thyroid diseases. A thyroid function monitoring and future research exploring the genetic and immunologic connections are essential to enhance our understanding of the interrelation between IBD and thyroid disorders.
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Affiliation(s)
- Valeria Calcaterra
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, Pavia, Italy
- Pediatric Department, Buzzi Children’s Hospital, Milano, Italy
| | | | - Virginia Rossi
- Pediatric Department, Buzzi Children’s Hospital, Milano, Italy
| | | | - Alice Bianchi
- Pediatric Department, Buzzi Children’s Hospital, Milano, Italy
| | | | | | - Gianvincenzo Zuccotti
- Pediatric Department, Buzzi Children’s Hospital, Milano, Italy
- Department of Biomedical and Clinical Science, University of Milan, Milano, Italy
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González MB, Olmedo Martín RV, Morales Bermúdez AI, Jiménez Pérez M. Characterization of Inflammatory Bowel Disease in the Elderly According to Age of Onset. J Clin Med 2024; 13:7581. [PMID: 39768503 PMCID: PMC11728034 DOI: 10.3390/jcm13247581] [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: 11/17/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 01/16/2025] Open
Abstract
Background/Objectives: Elderly populations are under-represented in inflammatory bowel disease (IBD) clinical trials, with limited data on phenotype, treatment patterns, outcomes, and comorbidities. The main objective of this study was to evaluate, in an elderly cohort with IBD, demographic and disease characteristics, comorbidity, polypharmacy, and treatment patterns according to the development of IBD at or before old age. Secondarily, the same analysis was performed based on the type of IBD: ulcerative colitis (UC) or Crohn's disease (CD). Materials and Methods: Observational, single-center, retrospective study including patients diagnosed with IBD and aged 65 years or older seen at the IBD office of the Regional University Hospital of Malaga between September and November 2022. Data were recorded on demographic, disease-related, and IBD treatment-related variables, comorbidities, and polypharmacy. A descriptive and analytical study was undertaken according to the age of IBD onset and type of IBD. Results: Of the patients included, 50.8% were male, 55.1% had CD, and 44.9% UC. IBD onset was before age 65 years in 69.5% and ≥65 years in 30.5%. Elderly with IBD who debuted <65 presented longer disease duration (19.67 ± 9.82 years) and required more IBD-related surgeries (37.8%); elderly with IBD who debuted ≥65 were older (77.69 ± 6.26 years), with no differences in the other variables. According to the type of IBD, elderly UC patients were older (74.55 ± 6.9 years), used more aminosalicylates (77.4%), and had higher rates of polypharmacy (90.6%). Elderly patients with CD had higher IBD activity (moderate/severe in 72.3%), used more biologic drugs (58.5%), and required more IBD-related surgeries (44.6%). Conclusions: Elderly patients who develop IBD before or after the age of 65 years are overall very similar in baseline and disease-related characteristics. Elderly with CD have higher IBD activity and require more biologic drugs and IBD-related surgeries. Elderly with UC are older and have higher rates of polypharmacy and aminosalicylate use.
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Affiliation(s)
| | | | | | - Miguel Jiménez Pérez
- UGC de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA) Plataforma BIONAD, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain; (M.B.G.); (R.V.O.M.); (A.I.M.B.)
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5
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Garcia JL, Rosa I, da Silva JP, Moleiro J, Claro I. Incidence and risk factors for neoplasia in inflammatory bowel disease. Asia Pac J Clin Oncol 2024; 20:559-564. [PMID: 36915954 DOI: 10.1111/ajco.13908] [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: 04/28/2022] [Revised: 10/22/2022] [Accepted: 11/24/2022] [Indexed: 03/15/2023]
Abstract
INTRODUCTION Inflammatory Bowel Disease (IBD) patients may have an increased risk of neoplasia. The aim was to evaluate the incidence of malignant neoplasia in IBD patients, associated risk factors and therapy adjustments. METHODS Unicentric retrospective cohort study. All patients followed for IBD in a tertiary portuguese hospital and oncological centre during 2015-2020 were included. RESULTS 318 patients were included female 55.0%, age at diagnosis = 37.24(±15,28), Crohn's disease 52.5%, Primary Sclerosing Cholangitis n = 7, family history of cancer n = 12, previous diagnosis of neoplasia n = 23(7.2%). 42 cancers were diagnosed in 35 patients (11.0%) - median of 12.0(IQR = 7.5-21.0) years after IBD diagnosis. Most affected organs were the skin (n = 15 in 11 patients; melanoma = 1), colon/rectum (n = 8 in 6 patients), prostate (n = 4), breast (n = 3) and anal canal (n = 2). In those with non-melanoma skin cancer, 6 were under active treatment with azathioprine and 2 had stopped it for more than two years. In the univariate analysis, the occurrence of neoplasia was positively associated with tobacco exposure (p = 0.022), age at IBD diagnosis (p = 0.021), and negatively with infliximab exposure (p = 0.046). In 9 cases, cancer treatment was different because of the IBD, while IBD treatment was changed in 9 patients. In those affected by cancer, in the univariate analysis, its cure/remission was negatively associated with tobacco exposure (p = 0.004) and positively with salicylates use (p = 0.007). CONCLUSION In IBD patients, cancer mostly affected the skin and the lower digestive system. As in the general population, tobacco exposure was a risk factor for the development of neoplasia.
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Affiliation(s)
- Joana Lemos Garcia
- Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal
| | - Isadora Rosa
- Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal
| | | | - Joana Moleiro
- Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal
| | - Isabel Claro
- Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal
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Moon W, Park JJ. [Risks of Cancer Associated with Therapeutic Drugs for Inflammatory Bowel Disease]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2024; 83:233-242. [PMID: 38918036 DOI: 10.4166/kjg.2024.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/21/2024] [Accepted: 06/21/2024] [Indexed: 06/27/2024]
Abstract
Crohn's disease and ulcerative colitis are lifelong chronic inflammatory conditions, with many patients requiring ongoing immunomodulatory drug therapy for maintenance treatment. Recent therapeutic goals in inflammatory bowel disease (IBD) are not only aimed at symptomatic remission but also at achieving mucosal healing to improve the natural course of the disease. In this context, therapeutic approaches are being applied in clinical settings that involve early and appropriate use of drugs, such as immunomodulators or biologics, that have the potential to induce healing of the inflamed intestine before irreversible intestinal damage occurs. All drugs that continuously control intestinal inflammation in IBD can heal the mucosa and potentially reduce the incidence of colitis-associated bowel cancer; however, the continuous use of immunosuppressants can potentially increase the risk of malignancies. The safety issues of the drugs used in clinical practice are partly confirmed during their development processes or shortly after initial marketing, but in other cases, they are estimated through post-marketing case reports or epidemiological studies, sometimes decades after drug approval. This review explores the risks associated with malignancies related to the treatment of IBD, focusing on drugs currently approved in Republic of Korea.
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Affiliation(s)
- Won Moon
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| | - Jae Jun Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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7
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Boudabbous M, Barkia B, Feki W, Gdoura H, Chtourou L, Moalla M, Mnif L, Amouri A, Mnif Z, Tahri N. Squamous cell carcinoma and Crohn's disease: a sometimes-challenging diagnosis. Future Sci OA 2024; 10:FSO907. [PMID: 38827804 PMCID: PMC11140648 DOI: 10.2144/fsoa-2023-0109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 09/20/2023] [Indexed: 06/05/2024] Open
Abstract
Aim: Non-melanoma skin cancers are more common in people with inflammatory bowel disease. However, these tumors can rarely mimic a cutaneous manifestation of the disease, which delays diagnosis and clouds prognosis. Observation: A 35-year-old man with stenosing and fistulizing ileocolic Crohn's disease developed squamous cell carcinoma mimicking a groin fold abscess. After surgical drainage of the abscess, despite antibiotics and therapy combining azathioprine with infliximab, the abscess has recurred. Biopsies revealed a cutaneous squamous cell carcinoma. Palliative radiotherapy-chemotherapy was initiated, but the patient died after 3 months. Conclusion: This observation illustrates the increased risk of non-melanoma skin cancers in inflammatory bowel disease patients, particularly those exposed to thiopurines, and the value of diagnosing them at an early stage.
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Affiliation(s)
- Mona Boudabbous
- Gastroenterology Department, Hédi Chaker Hospital, Sfax, 3000, Tunisia
- Medecin Sfax University, Sfax university, 3000, Tunisia
| | - Baha Barkia
- Gastroenterology Department, Hédi Chaker Hospital, Sfax, 3000, Tunisia
- Medecin Sfax University, Sfax university, 3000, Tunisia
| | - Wiem Feki
- Radiology Department, Hédi Chaker Hospital, Sfax, 3000, Tunisia
- Medecin Sfax University, Sfax university, 3000, Tunisia
| | - Héla Gdoura
- Gastroenterology Department, Hédi Chaker Hospital, Sfax, 3000, Tunisia
- Medecin Sfax University, Sfax university, 3000, Tunisia
| | - Lassad Chtourou
- Gastroenterology Department, Hédi Chaker Hospital, Sfax, 3000, Tunisia
- Medecin Sfax University, Sfax university, 3000, Tunisia
| | - Manel Moalla
- Gastroenterology Department, Hédi Chaker Hospital, Sfax, 3000, Tunisia
- Medecin Sfax University, Sfax university, 3000, Tunisia
| | - Leila Mnif
- Gastroenterology Department, Hédi Chaker Hospital, Sfax, 3000, Tunisia
- Medecin Sfax University, Sfax university, 3000, Tunisia
| | - Ali Amouri
- Gastroenterology Department, Hédi Chaker Hospital, Sfax, 3000, Tunisia
- Medecin Sfax University, Sfax university, 3000, Tunisia
| | - Zeinab Mnif
- Radiology Department, Hédi Chaker Hospital, Sfax, 3000, Tunisia
- Medecin Sfax University, Sfax university, 3000, Tunisia
| | - Nabil Tahri
- Gastroenterology Department, Hédi Chaker Hospital, Sfax, 3000, Tunisia
- Medecin Sfax University, Sfax university, 3000, Tunisia
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8
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Gordon H, Burisch J, Ellul P, Karmiris K, Katsanos K, Allocca M, Bamias G, Barreiro-de Acosta M, Braithwaite T, Greuter T, Harwood C, Juillerat P, Lobaton T, Müller-Ladner U, Noor N, Pellino G, Savarino E, Schramm C, Soriano A, Michael Stein J, Uzzan M, van Rheenen PF, Vavricka SR, Vecchi M, Zuily S, Kucharzik T. ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis 2024; 18:1-37. [PMID: 37351850 DOI: 10.1093/ecco-jcc/jjad108] [Citation(s) in RCA: 74] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Indexed: 06/24/2023]
Affiliation(s)
- Hannah Gordon
- Department of Gastroenterology, Barts Health NHS Trust, London, Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, UK
| | - Johan Burisch
- Gastrounit, medical division, Hvidovre Hospital, University of Copenhagen, Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | | | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, Ioannina, Greece
| | - Mariangela Allocca
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Manuel Barreiro-de Acosta
- University Hospital Santiago De Compostela CHUS, Department of Gastroenterology - IBD Unit, Santiago De Compostela, Spain
| | - Tasanee Braithwaite
- School of Immunology and Microbiology, King's College London, The Medical Eye Unit, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Thomas Greuter
- Division of Gastroenterology and Hepatology, GZO - Zurich Regional Health Center, Wetzikon, Division of Gastroenterology and Hepatology, University Hospital Lausanne - CHUV, Lausanne, Switzerland; Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Catherine Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London; Department of Dermatology, Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Pascal Juillerat
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland; Crohn and Colitis Center, Gastro-entérologie Beaulieu SA, Lausanne, Switzerland
| | - Triana Lobaton
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent; Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus Liebig University Giessen, Bad Nauheim, Germany
| | - Nurulamin Noor
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Gianluca Pellino
- Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona UAB, Barcelona, Spain; Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua, Italy
| | - Christoph Schramm
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alessandra Soriano
- Gastroenterology Division and IBD Center, Internal Medicine Department, Azienda Unità Sanitaria Locale - IRCCS, 42122 Reggio Emilia, Italy
| | - Jürgen Michael Stein
- Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt/Main, Department of Gastroenterology and Clinical Nutrition, DGD Clinics Sachsenhausen, Frankfurt/Main, Germany
| | - Mathieu Uzzan
- Department of Gastroenterology, Hôpital Henri Mondor, APHP, Créteil, France
| | - Patrick F van Rheenen
- Department of Paediatric Gastroenterology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - Maurizio Vecchi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Stephane Zuily
- Vascular Medicine Division and French Referral Center for Rare Auto-Immune Diseases, Université de Lorraine, INSERM, DCAC and CHRU-Nancy, Nancy, France
| | - Torsten Kucharzik
- Department of Gastroenterology, Lüneburg Hospital, University of Münster, Lüneburg, Germany
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9
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Zhang H, Shi Y, Lin C, He C, Wang S, Li Q, Sun Y, Li M. Overcoming cancer risk in inflammatory bowel disease: new insights into preventive strategies and pathogenesis mechanisms including interactions of immune cells, cancer signaling pathways, and gut microbiota. Front Immunol 2024; 14:1338918. [PMID: 38288125 PMCID: PMC10822953 DOI: 10.3389/fimmu.2023.1338918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 12/26/2023] [Indexed: 01/31/2024] Open
Abstract
Inflammatory bowel disease (IBD), characterized primarily by gastrointestinal inflammation, predominantly manifests as Crohn's disease (CD) and ulcerative colitis (UC). It is acknowledged that Inflammation plays a significant role in cancer development and patients with IBD have an increased risk of various cancers. The progression from inflammation to carcinogenesis in IBD is a result of the interplay between immune cells, gut microbiota, and carcinogenic signaling pathways in epithelial cells. Long-term chronic inflammation can lead to the accumulation of mutations in epithelial cells and the abnormal activation of carcinogenic signaling pathways. Furthermore, Immune cells play a pivotal role in both the acute and chronic phases of IBD, contributing to the transformation from inflammation to tumorigenesis. And patients with IBD frequently exhibit dysbiosis of the intestinal microbiome. Disruption of the gut microbiota and subsequent immune dysregulation are central to the pathogenesis of both IBD and colitis associated colorectal cancer (CAC). The proactive management of inflammation combined with regular endoscopic and tumor screenings represents the most direct and effective strategy to prevent the IBD-associated cancer.
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Affiliation(s)
- Haonan Zhang
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yulu Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chanchan Lin
- Department of Gastroenterology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Chengcheng He
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shanping Wang
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qingyuan Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan Sun
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mingsong Li
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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10
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Lutz M, Caldera F, Schroeder K, Gazis D, Crawford JM, Long MD, Barnes EL. Prevalence of Immunomodulator Use as Combination Therapy With Vedolizumab or Ustekinumab in Inflammatory Bowel Disease. Clin Transl Gastroenterol 2023; 14:e00620. [PMID: 37450671 PMCID: PMC10684180 DOI: 10.14309/ctg.0000000000000620] [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: 03/09/2023] [Accepted: 07/06/2023] [Indexed: 07/18/2023] Open
Abstract
INTRODUCTION The benefit of adding an immunomodulator to vedolizumab and ustekinumab remains unclear and may compromise the safety of these biologics. We evaluated the prevalence and predictors of immunomodulator use with vedolizumab or ustekinumab in patients with inflammatory bowel disease in a large longitudinal cohort. METHODS Clinical information was ascertained from electronic medical records of patients enrolled in TARGET-IBD, a prospective longitudinal observational cohort of patients with inflammatory bowel disease (IBD) at 34 sites. The prevalence of immunomodulator use with vedolizumab, ustekinumab, and antitumor necrosis factor therapies and predictors of immunomodulator use with vedolizumab and ustekinumab were estimated. Rates of combination therapy were additionally stratified by time from drug approval. RESULTS Four thousand thirty-nine adults with IBD were identified, of whom 18.8% were treated with vedolizumab and 13.0% were treated with ustekinumab. Combination therapy with vedolizumab and ustekinumab exceeded 30% (30.7% and 36.2%, respectively) and was more likely in those with perianal disease or previous biologic exposure. Age and presence of extraintestinal manifestations did not consistently predict the use of an immunomodulator. Combination therapy decreased in the years after drug approval. DISCUSSION Combination therapy with vedolizumab or ustekinumab was common and was associated with perianal disease and greater exposure to other biologics, although the practice is decreasing with time. Further data are needed to determine the efficacy and safety of combination therapy in patients initiating vedolizumab or ustekinumab for IBD.
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Affiliation(s)
- Megan Lutz
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Wisconsin—Madison, School of Medicine & Public Health, Madison, Wisconsin, USA
| | - Freddy Caldera
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Wisconsin—Madison, School of Medicine & Public Health, Madison, Wisconsin, USA
| | - Katie Schroeder
- Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Derek Gazis
- TARGET RWE, Inc., Durham, North Carolina, USA
| | | | - Millie D. Long
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Edward L. Barnes
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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11
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Jansen FM, den Broeder N, Lubeek SFK, Savelkoul EHJ, Marcus CM, Hoentjen F, van Dop WA. Cumulative thiopurine dosing and keratinocyte skin cancer in inflammatory bowel disease: a case-control study. Eur J Gastroenterol Hepatol 2023; 35:1123-1130. [PMID: 37665613 DOI: 10.1097/meg.0000000000002617] [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: 09/05/2023]
Abstract
BACKGROUND AND AIM Patients with inflammatory bowel disease (IBD) treated with thiopurines are at increased risk of keratinocyte skin cancer (KSC). Most international guidelines recommend yearly dermatological screening of thiopurine-treated patients. Whether the association between the development of KSC and the use of thiopurines is dose-dependent remains unclear. The aim of this study was to investigate the association between the cumulative thiopurine dose and KSC development in patients with IBD which can be helpful to assist in further skin cancer risk stratification and personalization of screening recommendations in patients with IBD. METHODS We performed a single-center case-control study, including patients with IBD with and without a history of KSC (cases and controls, respectively). The primary outcome was the association of cumulative azathioprine, mercaptopurine and thioguanine dose with KSC development. Univariable and multivariable logistic regression analyses were performed, the latter corrected for age and smoking, known risk factors of KSC. RESULTS We included 50 cases and 150 controls, predominantly white population. Age and current azathioprine use were univariably significantly associated with KSC development. In multivariable logistic regression analyses, age at inclusion remained significantly associated. Cumulative doses of thiopurines (separate or combined) or duration of thiopurine use did not impact KSC risk, also after correcting for age and smoking. CONCLUSION Cumulative thiopurine dose and duration did not show an association with KSC development. Future KSC risk stratification, based on all available KSC risk factors, may aid in selecting individuals who can benefit most from dermatologic screening programs.
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Affiliation(s)
- Fenna M Jansen
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
| | - Nathan den Broeder
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
| | - Satish F K Lubeek
- Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Edo H J Savelkoul
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
| | - Carlijne M Marcus
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
| | - Frank Hoentjen
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada
| | - Willemijn A van Dop
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
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12
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Massano A, Bertin L, Zingone F, Buda A, Visaggi P, Bertani L, de Bortoli N, Fassan M, Scarpa M, Ruffolo C, Angriman I, Bezzio C, Casini V, Ribaldone DG, Savarino EV, Barberio B. Extraintestinal Cancers in Inflammatory Bowel Disease: A Literature Review. Cancers (Basel) 2023; 15:3824. [PMID: 37568640 PMCID: PMC10417189 DOI: 10.3390/cancers15153824] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a group of chronic multifactorial inflammatory disorders including two major entities: Crohn's disease (CD) and ulcerative colitis (UC). Preliminary evidence suggests that patients with IBD may be at increased risk of developing intestinal and extraintestinal cancers (EICs). Actually, little is known about the association between IBD and EICs, and there is ever-growing concern regarding the safety of immunomodulators and biological therapy, which may represent a risk factor for carcinogenesis. AIMS The aim of this review is to summarize the evidence regarding the association between IBD and EICs, the safety of immunomodulators and biological therapy and the management of immunomodulators and biologic agents in IBD patients with prior or current EICs. RESULTS IBD patients have a higher risk of developing different forms of extraintestinal solid organ tumors and hematological malignancies. Immunomodulators and biological therapy may increase the risk of developing some types of EICs and may be consciously used in patients with IBD and current or prior history of malignancy. CONCLUSIONS Decisions regarding the use of immunomodulators or biological therapies should be made on an individual basis, considering a multidisciplinary approach involving oncologists.
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Affiliation(s)
- Alessandro Massano
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (A.M.); (L.B.); (F.Z.); (B.B.)
| | - Luisa Bertin
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (A.M.); (L.B.); (F.Z.); (B.B.)
| | - Fabiana Zingone
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (A.M.); (L.B.); (F.Z.); (B.B.)
| | - Andrea Buda
- Gastroenterology Unit, Department of Gastrointestinal Oncological Surgery, S. Maria del Prato Hospital, 32032 Feltre, Italy;
| | - Pierfrancesco Visaggi
- Gastroenterology Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (P.V.); (L.B.); (N.d.B.)
| | - Lorenzo Bertani
- Gastroenterology Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (P.V.); (L.B.); (N.d.B.)
| | - Nicola de Bortoli
- Gastroenterology Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (P.V.); (L.B.); (N.d.B.)
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine, University of Padova, 35138 Padova, Italy;
| | - Marco Scarpa
- General Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35138 Padova, Italy; (M.S.); (C.R.); (I.A.)
| | - Cesare Ruffolo
- General Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35138 Padova, Italy; (M.S.); (C.R.); (I.A.)
| | - Imerio Angriman
- General Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35138 Padova, Italy; (M.S.); (C.R.); (I.A.)
| | - Cristina Bezzio
- IBD Center, Gastroenterology Unit, Rho Hospital, ASST Rhodense, 20017 Rho, Italy;
| | | | - Davide Giuseppe Ribaldone
- Department of Medical Sciences, Division of Gastroenterology, University of Turin, 10126 Turin, Italy;
| | - Edoardo Vincenzo Savarino
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (A.M.); (L.B.); (F.Z.); (B.B.)
| | - Brigida Barberio
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (A.M.); (L.B.); (F.Z.); (B.B.)
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13
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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: 5] [Impact Index Per Article: 2.5] [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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14
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Conceição D, Saraiva MR, Rosa I, Claro I. Inflammatory Bowel Disease Treatment in Cancer Patients-A Comprehensive Review. Cancers (Basel) 2023; 15:3130. [PMID: 37370740 DOI: 10.3390/cancers15123130] [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: 04/30/2023] [Revised: 05/30/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disease for which medical treatment with immunomodulating drugs is increasingly used earlier to prevent disability. Additionally, cancer occurrence in IBD patients is increased for several reasons, either IBD-related or therapy-associated. Doctors are therefore facing the challenge of managing patients with IBD and a past or current malignancy and the need to balance the risk of cancer recurrence associated with immunosuppressive drugs with the potential worsening of IBD activity if they are withdrawn. This review aims to explore the features of different subtypes of cancer occurring in IBD patients to present current evidence on malignancy recurrence risk associated with IBD medical therapy along with the effects of cancer treatment in IBD and finally to discuss current recommendations on the management of these patients. Due to sparse data, a case-by-case multidisciplinary discussion is advised, including inputs from the gastroenterologist, oncologist, and patient.
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Affiliation(s)
- Daniel Conceição
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal
| | - Margarida R Saraiva
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal
| | - Isadora Rosa
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal
| | - Isabel Claro
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal
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15
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Wu S, Xie S, Yuan C, Yang Z, Liu S, Zhang Q, Sun F, Wu J, Zhan S, Zhu S, Zhang S. Inflammatory Bowel Disease and Long-term Risk of Cancer: A Prospective Cohort Study Among Half a Million Adults in UK Biobank. Inflamm Bowel Dis 2023; 29:384-395. [PMID: 35639937 DOI: 10.1093/ibd/izac096] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND This study aims to examine the prospective association of inflammatory bowel disease (IBD) with long-term risk of overall, site-specific cancer and cancer-specific mortality in middle-aged and older people. METHODS The study included participants free of any cancer at baseline from the UK Biobank, with IBD patients as an exposure group and non-IBD patients as a reference group. Primary outcome was the incidence of overall cancer and cancer-specific mortality. Secondary outcomes included site-specific cancers and types of digestive cancers. Cox proportional hazard model was used to investigate the associated risk of incident malignancies and related mortality. RESULTS Among 455 927 participants, 5142 were diagnosed with IBD (3258 ulcerative colitis [UC]; 1449 Crohn's disease [CD]; others unspecified). During a median of 12.2-year follow-up, 890 cases of incident cancer were identified in IBD patients (15.74 per 1000 person years) compared with 63 675 cases in reference individuals (12.46 per 1000 person years). Of these cases, 220 and 12 838 cancer-specific deaths occurred in IBD and non-IBD groups. Compared with non-IBD participants, the adjusted hazard ratio (AHR) for overall cancer and cancer-specific mortality was 1.17 (95% CI, 1.09-1.25) and 1.26 (95% CI, 1.18-1.35) among IBD patients, with an AHR of 1.15 (95% CI, 1.02-1.31) and 1.38 (95% CI, 1.08-1.75) in UC and 1.15 (95% CI, 1.06-1.25) and 1.25 (95% CI, 1.06-1.49) in CD, respectively. Specifically, increased risk of digestive (1.33; 95% CI, 1.12-1.57), nonmelanoma (1.25; 95% CI, 1.11-1.41), and male genital (1.29; 95% CI, 1.09-1.52) cancers was observed in IBD patients. CONCLUSIONS Compared with non-IBD, IBD may be associated with an increased risk of overall cancer and cancer-specific mortality, particularly digestive cancers, nonmelanoma and male genital cancers.
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Affiliation(s)
- Shanshan Wu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Sian Xie
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Changzheng Yuan
- School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Zhirong Yang
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
- Primary Care Unit, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, CB18RN, UK
| | - Si Liu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Qian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Feng Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, 100191, China
| | - Jing Wu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Siyan Zhan
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, 100191, China
| | - Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China
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16
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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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17
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Faye AS, Axelrad JE. Editorial: safety in numbers-cycling of biologics does not increase risk of adverse outcomes. Aliment Pharmacol Ther 2022; 55:1459-1460. [PMID: 35538352 PMCID: PMC9102742 DOI: 10.1111/apt.16936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Adam S. Faye
- Inflammatory Bowel Disease Center at NYU Langone Health, Division of Gastroenterology, Department of Medicine, NYU Grossman School of Medicine, New York, New York, U.S.,Correspondence to: Adam S. Faye, M.D., M.S., New York University School of Medicine, Division of Gastroenterology & Hepatology, NYU IBD Center, 303 East 33 Street, NYC, NY 10016, Tel: (855) 698-4232, Fax: (212) 263-3096,
| | - Jordan E. Axelrad
- Inflammatory Bowel Disease Center at NYU Langone Health, Division of Gastroenterology, Department of Medicine, NYU Grossman School of Medicine, New York, New York, U.S
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18
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Venner JM, Bernstein CN. Immunomodulators: still having a role? Gastroenterol Rep (Oxf) 2022; 10:goac061. [PMID: 36381225 PMCID: PMC9642324 DOI: 10.1093/gastro/goac061] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/08/2022] [Accepted: 10/09/2022] [Indexed: 11/09/2022] Open
Abstract
Immunomodulators, particularly the thiopurines and to a lesser extent methotrexate, were standard of care for inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, for >40 years. While there has been a renaissance in available therapies with the advent of biologics and small molecules, an impetus remains for the ongoing use of thiopurines and methotrexate. This is particularly true for the maintenance of remission and when used in combination therapy with infliximab to suppress anti-biologic antibodies. This article summarizes the data behind immunomodulator use in Crohn’s disease, focusing on the beneficial role these drugs still have while acknowledging their clinical limitations.
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Affiliation(s)
- Jeffery M Venner
- University of Manitoba IBD Clinical and Research Centre , Winnipeg, Manitoba, Canada
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba , Winnipeg, Manitoba, Canada
| | - Charles N Bernstein
- University of Manitoba IBD Clinical and Research Centre , Winnipeg, Manitoba, Canada
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba , Winnipeg, Manitoba, Canada
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Turbayne AK, Sparrow MP. Low-Dose Azathioprine in Combination with Allopurinol: The Past, Present and Future of This Useful Duo. Dig Dis Sci 2022; 67:5382-5391. [PMID: 36242689 PMCID: PMC9652213 DOI: 10.1007/s10620-022-07719-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 10/03/2022] [Indexed: 01/05/2023]
Abstract
The inflammatory bowel diseases (IBD) are complex immune-mediated inflammatory diseases that are associated with significant morbidity around the world. As our understanding of IBD, and other immune-mediated inflammatory diseases, advances the number of therapeutic targets has increased which has rapidly driven the development and introduction of new therapies. While these new therapies have shown promise they come with the significant drawback of high costs. For many IBD patients around the world the cost of newer therapies is prohibitive which means treating clinicians often need to turn to optimising simpler, older, and inexpensive medications. The concept of optimising well established cheaper medications is not unique to the management of IBD as health systems all over the world look to reduce costs while simultaneously improving patient outcomes. Despite thiopurines being used in the management IBD for over 60 years, many clinicians are still hesitant to use them due to perceptions around limited efficacy and poor tolerance. One method identified to potentially increase utilisation of thiopurines involves the coadministration of allopurinol. In this review we will explore the history, pharmacology, recent studies and give recommendations for the utilisation of the usual duo of azathioprine combined with allopurinol.
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Affiliation(s)
- Alexander Keith Turbayne
- grid.1623.60000 0004 0432 511XDepartment of Gastroenterology, Alfred Hospital, 55 Commercial Road, Melbourne, VIC 3004 Australia
| | - Miles Patrick Sparrow
- grid.1623.60000 0004 0432 511XDepartment of Gastroenterology, Alfred Hospital, 55 Commercial Road, Melbourne, VIC 3004 Australia ,grid.1002.30000 0004 1936 7857Monash University, Clayton, Melbourne, VIC 3800 Australia
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20
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Singh A, Mahajan R, Kedia S, Dutta AK, Anand A, Bernstein CN, Desai D, Pai CG, Makharia G, Tevethia HV, Mak JWY, Kaur K, Peddi K, Ranjan MK, Arkkila P, Kochhar R, Banerjee R, Sinha SK, Ng SC, Hanauer S, Verma S, Dutta U, Midha V, Mehta V, Ahuja V, Sood A. Use of thiopurines in inflammatory bowel disease: an update. Intest Res 2022; 20:11-30. [PMID: 33845546 PMCID: PMC8831775 DOI: 10.5217/ir.2020.00155] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 02/19/2021] [Accepted: 03/01/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.
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Affiliation(s)
- Arshdeep Singh
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Ramit Mahajan
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Amit Kumar Dutta
- Department of Gastroenterology, Christian Medical College, Vellore, India
| | - Abhinav Anand
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Charles N. Bernstein
- University of Manitoba IBD Clinical and Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Devendra Desai
- P. D. Hinduja Hospital and Medical Research Centre, Mumbai, India
| | - C. Ganesh Pai
- Department of Gastroenterology, Kasturba Medical College, Manipal, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | - Joyce WY Mak
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Kirandeep Kaur
- Department of Pharmacology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Kiran Peddi
- Citizens Centre for Digestive Disorders, Hyderabad, India
| | - Mukesh Kumar Ranjan
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Perttu Arkkila
- Department of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland
| | - Rakesh Kochhar
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rupa Banerjee
- Asian Institute of Gastroenterology Hyderabad, Hyderabad, India
| | - Saroj Kant Sinha
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Siew Chien Ng
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Stephen Hanauer
- Department of Medicine, Northwestern University, Chicago, IL, USA
| | - Suhang Verma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Usha Dutta
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vandana Midha
- Department of Internal Medicine, Dayanand Medical College, Ludhiana, India
| | - Varun Mehta
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, India
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21
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Mala A, Foteinogiannopoulou K, Koutroubakis IE. Solid extraintestinal malignancies in patients with inflammatory bowel disease. World J Gastrointest Oncol 2021; 13:1956-1980. [PMID: 35070035 PMCID: PMC8713323 DOI: 10.4251/wjgo.v13.i12.1956] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 07/06/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Malignancies constitute the second cause of death in patients with inflammatory bowel diseases (IBD), after cardiovascular diseases. Although it has been postulated that IBD patients are at greater risk of colorectal cancer compared to the general population, lately there has been evidence supporting that this risk is diminishing over time as a result of better surveillance, while the incidence of extraintestinal cancers (EICs) is increasing. This could be attributed either to systemic inflammation caused by IBD or to long-lasting immunosuppression due to IBD treatments. It seems that the overall risk of EICs is higher for Crohn’s disease patients and it is mainly driven by skin cancers, and liver-biliary cancers in patients with IBD and primary sclerosing cholangitis. The aims of this review were first to evaluate the prevalence, characteristics, and risk factors of EICs in patients with IBD and second to raise awareness regarding a proper surveillance program resulting in early diagnosis, better prognosis and survival, especially in the era of new IBD treatments that are on the way.
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Affiliation(s)
- Anastasia Mala
- Department of Medical Oncology, University Hospital of Heraklion, Heraklion 71110, Crete, Greece
| | | | - Ioannis E Koutroubakis
- Department of Gastroenterology, University Hospital of Heraklion, Heraklion 71110, Crete, Greece
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22
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Lee J, Lemons N, Lorenze A, Chowdhary TS, Zinn Z, Gayam S. Management of cutaneous side effects of inflammatory bowel disease therapy: A dermatologic viewpoint. J Gastroenterol Hepatol 2021; 36:3278-3285. [PMID: 34139789 DOI: 10.1111/jgh.15570] [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: 12/01/2020] [Revised: 06/01/2021] [Accepted: 06/06/2021] [Indexed: 12/09/2022]
Abstract
Medications used in the treatment of inflammatory bowel disease cause a wide range of dermatologic side effects, and minimal guidance exists on how to manage them. The intention of this review article is to summarize common dermatologic adverse reactions related to inflammatory bowel disease therapy and to provide evidence-based guidance on management. We conducted a scoping review using PubMed and Google Scholar to identify studies reporting clinical information on dermatologic side effects of medications used in the treatment of inflammatory bowel disease. The most commonly reported dermatological adverse effects from inflammatory bowel disease therapy were cutaneous malignancy and cutaneous infections. Thiopurines, methotrexate, tumor necrosis factor (TNF) inhibitors, interleukin (IL)-12/23 inhibitors, and integrin inhibitors can be continued if nonmelanoma skin cancer arises during therapy and the malignancy should be surgically excised. TNF inhibitors and IL-12/23 inhibitors can be continued in the setting of stage I surgically resectable melanoma but should be discontinued in advanced melanoma. For complicated cutaneous bacterial infections, methotrexate and TNF inhibitors should be halted, and IV antibiotics should be administered. Complicated herpes zoster infection warrants discontinuation of TNF inhibitors, whereas IL-12/23 and JAK inhibitors can be continued. Inflammatory bowel disease therapies are associated with several dermatological adverse effects, and management options vary by agent. Certain agents may require discontinuation in the setting of nonmelanoma skin cancer, melanoma, and cutaneous infections. Many other dermatological adverse effects from inflammatory bowel disease therapy require specialized management or referral to dermatology.
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Affiliation(s)
- Justin Lee
- Department of Dermatology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Noelle Lemons
- Department of Dermatology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Alyssa Lorenze
- Department of Internal Medicine and Pediatrics, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Tarika Sejal Chowdhary
- Department of Internal Medicine, West Virginia University, Morgantown, West Virginia, USA
| | - Zachary Zinn
- Department of Dermatology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Swapna Gayam
- Section of Gastroenterology and Hepatology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
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23
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Syal G, Serrano M, Jain A, Cohen BL, Rieder F, Stone C, Abraham B, Hudesman D, Malter L, McCabe R, Holubar S, Afzali A, Cheifetz AS, Gaidos JKJ, Moss AC. Health Maintenance Consensus for Adults With Inflammatory Bowel Disease. Inflamm Bowel Dis 2021; 27:1552-1563. [PMID: 34279600 PMCID: PMC8861367 DOI: 10.1093/ibd/izab155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND With the management of inflammatory bowel disease (IBD) becoming increasingly complex, incorporating preventive care health maintenance measures can be challenging. The aim of developing these updated recommendations is to provide more specific details to facilitate their use into a busy clinical practice setting. METHOD Fifteen statements were formulated with recommendations regarding the target, timing, and frequency of the health maintenance interventions in patients with IBD. We used a modified Delphi method and a literature review to establish a consensus among the panel of experts. The appropriateness of each health maintenance statement was rated on a scale of 1 to 5 (1-2 as inappropriate, and 4-5 as appropriate) by each panelist. Interventions were considered appropriate, and statements were accepted if ≥80% of the panelists agreed with a score ≥4. RESULTS The panel approved 15 health maintenance recommendations for adults with IBD based on the current literature and expert opinion. These recommendations include explicit details regarding specific screening tools, timing of screening, and vaccinations for adults with IBD. CONCLUSIONS Patients with IBD are at an increased risk for infections, malignancies, and other comorbidities. Given the complexity of caring for patients with IBD, this focused list of recommendations can be easily incorporated in to clinical care to help eliminate the gap in preventative care for patients with IBD.
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Affiliation(s)
- Gaurav Syal
- Cedars-Sinai Medical Center, Los Angeles, California, USA
| | | | - Animesh Jain
- University of North Carolina, Chapel Hill, North Carolina, USA
| | | | | | - Christian Stone
- Comprehensive Digestive Institute of Nevada, Las Vegas, Nevada, USA
| | | | - David Hudesman
- New York University Langone Medical Center, New York, New York, USA
| | - Lisa Malter
- NYU Grossman School of Medicine, Bellevue Hospital Center, New York, New York, USA
| | | | | | - Anita Afzali
- Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Adam S Cheifetz
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | | | - Alan C Moss
- Boston University School of Medicine, Boston, Massachusetts, USA
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24
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Nguyen ALH, Sparrow MP. Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules. Dig Dis Sci 2021; 66:3250-3262. [PMID: 33073334 DOI: 10.1007/s10620-020-06662-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 10/06/2020] [Indexed: 12/09/2022]
Abstract
In recent years, with the increasing availability of biologic therapies and due to safety concerns, the role of thiopurines in the management of inflammatory bowel disease has been questioned. While acknowledging that the benefit/risk ratio of biologic therapies is very high, they are expensive and are not required by a majority of patients. Therefore, thiopurines do retain an important role as steroid-sparing and maintenance agents when used as monotherapy, and in combination therapy with biologics due to their clinical and pharmacokinetic optimization of anti-tumor necrosis factor agents in particular. Safety concerns with thiopurines are real but also relatively rare, and with careful pre-treatment screening and ongoing monitoring thiopurine benefits outweigh risks in the majority of appropriately selected patients. Measurement of newer pharmacogenomic markers such as nudix hydrolase 15 (NUDT15), when combined with knowledge of existing known mutations (e.g., thiopurine S-methyltransferase-TPMT), will hopefully minimize the risk of potentially life-threatening leukopenia by allowing for pre-treatment dosing stratification. Further optimization of thiopurine dosing via measurement of thiopurine metabolites should be performed routinely and is superior to weight-based dosing. The association of thiopurines with malignancies including lymphoproliferative disorders needs to be recognized in all patients and individualized in each patient. The decrease in lymphoma risk after thiopurine cessation provides an incentive for thiopurine de-escalation in appropriate patients after a period of prolonged deep remission. This review will summarize the current role of thiopurines in inflammatory bowel disease management and provide recommendations for commencing and monitoring therapy, and when to consider de-escalation.
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Affiliation(s)
- Anke L H Nguyen
- Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia.,Monash University, Melbourne, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia. .,Monash University, Melbourne, Australia.
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25
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Greuter T, Vavricka S, König AO, Beaugerie L, Scharl M. Malignancies in Inflammatory Bowel Disease. Digestion 2021; 101 Suppl 1:136-145. [PMID: 32799195 DOI: 10.1159/000509544] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 05/11/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, primarily of, but not restricted to, the gut. Association between IBD and cancer has been clearly established and is uniformly accepted. SUMMARY IBD patients are at particular risk for intestinal and extraintestinal cancers. There are 2 underlying mechanisms: (1) IBD-related inflammation triggers initiation and progression of tumor formation. This particularly results in the development of colorectal cancer, small bowel adenocarcinoma, intestinal lymphoma, anal cancer, and cholangiocarcinoma. (2) Immunosuppressive drugs exhibit carcinogenic properties such as shown for azathioprine and anti-TNF promoting lymphoproliferative malignancies and melanoma and nonmelanoma skin cancer. However, within the last years, IBD-related cancer incidence and prevalence have been decreasing, which might be attributed to better treatment options and surveillance strategies. Moreover, novel biological drugs have been introduced in clinical practice and have dramatically changed long-term IBD management. Therefore, we sought to summarize up-to-date knowledge about (1) overall cancer risk; (2) risk and protective factors for cancer development; and (3) inflammation- and immunosuppression-related malignancies in the current anti-TNF era of IBD. Key Messages: Recent studies and meta-analyses questioned the excess rates of cancer in IBD patients. However, IBD still is associated with cancer development due to ongoing intestinal inflammation and the use of potential carcinogenic drugs. Patients should be educated about the increased risk of cancer with IBD and IBD drugs. However, they should also be informed that most malignancy subtypes are possibly preventable by controlling intestinal inflammation and by using adequate screening strategies.
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Affiliation(s)
- Thomas Greuter
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland, .,Department of Internal Medicine, GZO - Zurich Regional Health Center, Wetzikon, Switzerland,
| | - Stephan Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.,Center for Gastroenterology and Hepatology, Zurich, Switzerland
| | - Alexander O König
- Department of Gastroenterology and Hepatology, University of Göttingen, Göttingen, Germany
| | - Laurent Beaugerie
- Department of Gastroenterology, Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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26
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Bakulin IG, Skalinskaya MI, Maev IV, Skazyvaeva EV, Zhuravleva MS, Gaikovaya LB, Bakulina NV, Ermakov AI, Alekseenko ES, Ivanova KN, Solovev MV. Pharmacotherapy of inflammatory bowel diseases: efficacy performance and safety management. TERAPEVT ARKH 2021; 93:841-852. [DOI: 10.26442/00403660.2021.08.200982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 08/30/2021] [Indexed: 12/30/2022]
Abstract
Treatment of inflammatory bowel diseases IBD (Crohns disease, ulcerative colitis) is aimed at achieving clinical, endoscopic and histological remission, minimizing surgical complications, and ensuring a normal quality of life. However, the use of medical treatment is potentially associated with various adverse events, among which infectious complications, malignant neoplasms, as well as myelotoxicity, hepatotoxicity, skin lesions and others. The risk of side effects depends on the type of drug therapy (5-aminosalicylates, thiopurines, biologicals, etc.), the duration of treatment, the presence of extra-intestinal manifestations, etc. The article provides an overview of data on both the effectiveness and frequency of various side effects of the main classes of drugs in IBD, presents methods of investigation which can predict the effectiveness and development of side effects, the implementation of which can be considered as a variant of personalized therapy in IBD.
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27
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Singh S, Proctor D, Scott FI, Falck-Ytter Y, Feuerstein JD. AGA Technical Review on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease. Gastroenterology 2021; 160:2512-2556.e9. [PMID: 34051985 PMCID: PMC8986997 DOI: 10.1053/j.gastro.2021.04.023] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The incidence and prevalence of Crohn's disease (CD) is rising globally. Patients with moderate to severe CD are at high risk for needing surgery and hospitalization and for developing disease-related complications, corticosteroid dependence, and serious infections. Optimal management of outpatients with moderate to severe luminal and/or fistulizing (including perianal) CD often requires the use of immunomodulator (thiopurines, methotrexate) and/or biologic therapies, including tumor necrosis factor-α antagonists, vedolizumab, or ustekinumab, either as monotherapy or in combination (with immunomodulators) to mitigate these risks. Decisions about optimal drug therapy in moderate to severe CD are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Since the last iteration of these guidelines published in 2013, significant advances have been made in the field, including the regulatory approval of 2 new biologic agents, vedolizumab and ustekinumab. Therefore, the American Gastroenterological Association prioritized updating clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The review addressed the following focused questions (in adult outpatients with moderate to severe luminal CD): overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to tumor necrosis factor-α antagonists, comparative efficacy and safety of biologic monotherapy vs combination therapy with immunomodulators, comparative efficacy of a top-down (upfront use of biologics and/or immunomodulator therapy) vs step-up treatment strategy (acceleration to biologic and/or immunomodulator therapy only after failure of mesalamine), and the role of corticosteroids and mesalamine for induction and/or maintenance of remission. Finally, in adult outpatients with moderate to severe fistulizing CD, this review addressed the efficacy of pharmacologic interventions for achieving fistula and the role of adjunctive antibiotics without clear evidence of active infection.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology and Division of Biomedical Informatics, Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Deborah Proctor
- Division of Gastroenterology, Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Frank I. Scott
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Yngve Falck-Ytter
- Division of Gastroenterology and Liver Disease, Case Western Reserve University, Cleveland, Ohio CA
| | - Joseph D. Feuerstein
- Division of Gastroenterology and Center for Inflammatory Bowel Diseases, Beth Israel Deaconess Medical Center, Boston, MA
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28
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Roth K, Coussement L, Knatko EV, Higgins M, Steyaert S, Proby CM, de Meyer T, Dinkova-Kostova AT. Clinically relevant aberrant Filip1l DNA methylation detected in a murine model of cutaneous squamous cell carcinoma. EBioMedicine 2021; 67:103383. [PMID: 34000624 PMCID: PMC8138604 DOI: 10.1016/j.ebiom.2021.103383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies. Understanding the impact of DNA methylation in cSCC may provide avenues for new therapeutic strategies. METHODS We used reduced-representation bisulfite sequencing for DNA methylation analysis of murine cSCC. Differential methylation was assessed at the CpG level using limma. Next, we compared with human cSCC Infinium HumanMethylation BeadArray data. Genes were considered to be of major relevance when they featured at least one significantly differentially methylated CpGs (RRBS) / probes (Infinium) with at least a 30% difference between tumour vs. control in both a murine gene and its human orthologue. The human EPIC Infinium data were used to distinguish two cSCC subtypes, stem-cell-like and keratinocyte-like tumours. FINDINGS We found increased average methylation in mouse cSCC (by 12.8%, p = 0.0011) as well as in stem-cell like (by 3.1%, p=0.002), but not keratinocyte-like (0.2%, p = 0.98), human cSCC. Comparison of differentially methylated genes revealed striking similarities between human and mouse cSCC. Locus specific methylation changes in mouse cSCC often occurred in regions of potential regulatory function, including enhancers and promoters. A key differentially methylated region was located in a potential enhancer of the tumour suppressor gene Filip1l and its expression was reduced in mouse tumours. Moreover, the FILIP1L locus showed hypermethylation in human cSCC and lower expression in human cSCC cell lines. INTERPRETATION Deregulation of DNA methylation is an important feature of murine and human cSCC that likely contributes to silencing of tumour suppressor genes, as shown for Filip1l. FUNDING British Skin Foundation, Cancer Research UK.
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Affiliation(s)
- Kevin Roth
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom
| | - Louis Coussement
- Biobix, Department of Data Analysis and Mathematical Modelling, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium; CRIG, Cancer Research Institute Ghent, Sint-Pietersnieuwstraat 25, 9000, Ghent, Belgium
| | - Elena V Knatko
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom
| | - Maureen Higgins
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom
| | - Sandra Steyaert
- Biobix, Department of Data Analysis and Mathematical Modelling, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium
| | - Charlotte M Proby
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom
| | - Tim de Meyer
- Biobix, Department of Data Analysis and Mathematical Modelling, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium; CRIG, Cancer Research Institute Ghent, Sint-Pietersnieuwstraat 25, 9000, Ghent, Belgium
| | - Albena T Dinkova-Kostova
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom; Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore MD 21205, USA.
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29
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Moyer AM. NUDT15: A bench to bedside success story. Clin Biochem 2021; 92:1-8. [PMID: 33675810 DOI: 10.1016/j.clinbiochem.2021.02.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/10/2021] [Accepted: 02/14/2021] [Indexed: 12/13/2022]
Abstract
Recently, the enzyme nudix hydrolase 15 (NUDT15) has been identified as an additional component of the thiopurine metabolism pathway. NUDT15 (also known as MTH2) catalyzes the dephosphorylation of 6-thioguanosine triphosphate (6-TGTP) and 6-thio-deoxyguanosine triphosphate (6-TdGTP), which is the active metabolite of thiopurine medications. Thiopurine compounds, which were first synthesized in the 1950s, are widely used in the treatment of childhood leukemia, inflammatory bowel disease, and autoimmune disorders. For many years, TPMT has been recognized as an enzyme that is involved in thiopurine metabolism, and interindividual variation in TPMT activity has been known to contribute to differences in risk of thiopurine toxicity. Genetic variation that leads to decreased NUDT15 activity has been recognized as an additional contributor, beyond TPMT, to thiopurine toxicity. In some populations, including Asian and Latino populations, NUDT15 genetic variants are more common than TPMT variants, making this a significant biomarker of toxicity. Clinical genetic testing is now available for a subset of NUDT15 variants, representing a remarkably fast translation from bench to bedside. This review will focus on NUDT15 - from discovery to clinical implementation.
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Affiliation(s)
- Ann M Moyer
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States.
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30
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Calafat M, Mañosa M, Cañete F, Domènech E. Clinical Considerations Regarding the Use of Thiopurines in Older Patients with Inflammatory Bowel Disease. Drugs Aging 2021; 38:193-203. [PMID: 33438138 DOI: 10.1007/s40266-020-00832-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2020] [Indexed: 12/19/2022]
Abstract
The number of older patients with inflammatory bowel disease (IBD) is increasing due to both improvements in the life expectancy of patients with long-lasting IBD and later onset of the disease. In spite of a less aggressive IBD phenotype, disease management in older patients is hampered by comorbidities and polypharmacy (which increase the risk of drug-related adverse events and errors in medication intake) and also by an increased risk of the infections and malignancies associated with the immunosuppressive drugs that are frequently used to treat IBD. Thiopurines are the most frequently used immunosuppressive drugs in IBD, though they are often discontinued due to adverse events. However, when tolerated, thiopurines are efficient in the maintenance of remission in ulcerative colitis and Crohn's disease. In fact, thiopurines still have a role to play in the treatment algorithm of older patients with IBD because anti-tumor necrosis factor agents do not provide clear advantages for this population in terms of their safety profile, while data on the new biological drugs are still scarce. In this article, we review the optimal use of thiopurines in older patients with IBD.
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Affiliation(s)
- Margalida Calafat
- Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Catalonia, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepaticas y Digestivas, Madrid, Spain
| | - Míriam Mañosa
- Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Catalonia, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepaticas y Digestivas, Madrid, Spain
| | - Fiorella Cañete
- Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Catalonia, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepaticas y Digestivas, Madrid, Spain
| | - Eugeni Domènech
- Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Catalonia, Spain.
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepaticas y Digestivas, Madrid, Spain.
- Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
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31
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Solitano V, D'Amico F, Correale C, Peyrin-Biroulet L, Danese S. Thiopurines and non-melanoma skin cancer: partners in crime in inflammatory bowel diseases. Br Med Bull 2020; 136:107-117. [PMID: 33200781 DOI: 10.1093/bmb/ldaa033] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 09/02/2020] [Accepted: 09/09/2020] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Several studies have shown that inflammatory bowel diseases (IBD) patients treated with thiopurines have an increased risk of developing skin cancer. SOURCES OF DATA This review is based on recent published literature regarding the use of thiopurines in IBD and skin malignancies. AREAS OF AGREEMENT Exposure to thiopurines is significantly associated with nonmelanoma skin cancer, but not with melanoma. Primary and secondary prevention including sun-protective measures and regular dermatologic screening are recommended in IBD patients, particularly in those exposed to thiopurines. AREAS OF CONTROVERSY Both when and how immunosuppressive therapy should be resumed in patients with a prior history of skin cancer still remain debatable topics. GROWING POINTS The benefit-risk balance between thiopurine therapy and risk of skin cancer should be evaluated in the drug decision process. AREAS TIMELY FOR DEVELOPING RESEARCH The approval of new effective strategies requires the re-evaluation of the positioning of thiopurines within the therapeutic algorithm based on an increasingly individualized approach.
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Affiliation(s)
- Virginia Solitano
- Department of Biomedical Sciences, Humanitas University, 4 Rita Levi Montalcini Street, Pieve Emanuele, 20090 Milan, Italy
| | - Ferdinando D'Amico
- Department of Biomedical Sciences, Humanitas University, 4 Rita Levi Montalcini Street, Pieve Emanuele, 20090 Milan, Italy.,Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, 5 allèe du Morvan, 54500 Vandoeuvre-lès-Nancy, France
| | - Carmen Correale
- Department of Gastroenterology, IBD Center, Humanitas Clinical and Research Center, IRCCS, 56 Manzoni Street, Rozzano, 20089 Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, 5 allèe du Morvan, 54500 Vandoeuvre-lès-Nancy, France
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, 4 Rita Levi Montalcini Street, Pieve Emanuele, 20090 Milan, Italy.,Department of Gastroenterology, IBD Center, Humanitas Clinical and Research Center, IRCCS, 56 Manzoni Street, Rozzano, 20089 Milan, Italy
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Vasudevan A, Parthasarathy N, Con D, Nicolaides S, Apostolov R, Chauhan A, Bishara M, Luber RP, Joshi N, Wan A, Rickard JA, Long T, Connoley D, Sparrow MP, Gibson PR, van Langenberg DR. Thiopurines vs methotrexate: Comparing tolerability and discontinuation rates in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2020; 52:1174-1184. [PMID: 32794599 DOI: 10.1111/apt.16039] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/17/2020] [Accepted: 07/23/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND There are safety concerns regarding immunomodulators (thiopurines and methotrexate) for treatment of inflammatory bowel disease (IBD). AIM To compare the long-term tolerability, and persistence of thiopurine and methotrexate therapy in IBD. METHODS A retrospective cohort study was performed at two hospitals between 1 January 2004 and 31 December 2016 for patients commenced on thiopurines or methotrexate for IBD. Treatment discontinuation rates, intolerances and disease activity were obtained from medical records. RESULTS There were 782 patients commenced on immunomodulator therapy; 244 (31%) on methotrexate with folate (67% subcutaneous therapy) and 538 (69%) on thiopurine (73% azathioprine). Median follow-up was 42 vs 47 months (P = 0.09). In patients on thiopurines, median 6-TGN was 298 pmol/8 x 108 RBCs, while the median dose of methotrexate was 25 mg weekly. Methotrexate recipients had a higher rate of prior immunomodulator intolerance, were typically older and had a longer disease duration (54% vs 3%, median 43 vs 36 years, 6 vs 5 years, respectively, each P < 0.05). Overall, 208 (27%) discontinued therapy due to adverse events, (40% on methotrexate vs 19% on thiopurines, P < 0.001), including nausea (18% vs 4%), fatigue (7% vs 2%) and hepatotoxicity (8% vs 2%, each P < 0.001). Hospitalisations from adverse events (0.8% vs 0.9%) and serious infections (9% vs 12%), and deaths (1% vs 0%) were comparable between groups (all P > 0.05). Discontinuation due to adverse events occurred later in patients on methotrexate than on thiopurines (median 7 vs 5 months, P = 0.08). CONCLUSION Discontinuation of methotrexate occurred at rates twice that of dose-optimised thiopurine therapy.
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Affiliation(s)
- Abhinav Vasudevan
- Department of Gastroenterology and Hepatology, Monash University, Eastern Health Clinical School, Victoria, Australia
| | - Nina Parthasarathy
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Danny Con
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Steven Nicolaides
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Ross Apostolov
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Ayushi Chauhan
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Maria Bishara
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Raphael P Luber
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - Neetima Joshi
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - Anna Wan
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - James A Rickard
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Tony Long
- Monash University, Eastern Health Clinical School, Victoria, Australia
| | - Declan Connoley
- Monash University, Eastern Health Clinical School, Victoria, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - Daniel R van Langenberg
- Department of Gastroenterology and Hepatology, Monash University, Eastern Health Clinical School, Victoria, Australia
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Miele E, Benninga MA, Broekaert I, Dolinsek J, Mas E, Orel R, Pienar C, Ribes-Koninckx C, Thomassen RA, Thomson M, Tzivinikos C, Thapar N. Safety of Thiopurine Use in Paediatric Gastrointestinal Disease. J Pediatr Gastroenterol Nutr 2020; 71:156-162. [PMID: 32520827 DOI: 10.1097/mpg.0000000000002802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Thiopurines, alone or in combination with other agents, have a pivotal role in the treatment of specific gastrointestinal and hepatological disorders. In inflammatory bowel disease and autoimmune hepatitis thiopurines have proven their value as steroid sparing agents for the maintenance of remission and may be considered for preventing postoperative Crohn disease recurrence where there is moderate risk of this occurring. Their use with infliximab therapy reduces antibody formation and increases biologic drug levels. The routine clinical use of thiopurines has, however, been questioned due to a number of potential adverse effects. The aim of this article is to provide information regarding the use, and in particular, safety of these agents in clinical practice in the light of such potentially severe, albeit rare, effects.
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Affiliation(s)
- Erasmo Miele
- Department of Translational Medical Science, Section of Paediatrics, University of Naples "Federico II", Italy
| | - Marc A Benninga
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Emma Children's Hospital/Amsterdam UMC, Amsterdam, The Netherlands
| | - Ilse Broekaert
- Faculty of Medicine and University Hospital Cologne, Department of Pediatrics, University of Cologne, Cologne, Germany
| | - Jernej Dolinsek
- Department of Pediatrics, Gastroenterology Unit, University Medical Centre Maribor.,Department of Paediatrics, Medical Faculty of University of Maribor, Maribor, Slovenia
| | - Emmanuel Mas
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS.,Unité de Gastroentérologie, Hépatologie, Nutrition, Diabétologie et Maladies Héréditaires du Métabolisme, Hôpital des Enfants, CHU de Toulouse, Toulouse, France
| | - Rok Orel
- Department of Gastroenterology, Hepatology and Nutrition, Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Corina Pienar
- Paediatrics Department, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Carmen Ribes-Koninckx
- Pediatric Gastroenterolgy, Hepatology and Nutrition, La Fe University Hospital, Valencia, Spain
| | - Rut A Thomassen
- Pediatric Nutrition and Dietetics Unit, Department of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - Mike Thomson
- Department of Paediatric Gastroenterology, Sheffield Children's NHS Foundation Trust, Sheffield
| | - Christos Tzivinikos
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates
| | - Nikhil Thapar
- Neurogastroenterology and Motility Unit, UCL Great Ormond Street Institute for Child Health and Great Ormond Street Hospital, London, United Kingdom.,Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia
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34
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Wu Y, Ghaly S, Kerr S, Jackson B, Hanigan K, Martins D, Krishnaprasad K, Mountifield RE, Whiteman DC, Bampton PA, Gearry RB, Radford-Smith GL, Lawrance IC. Level of UV Exposure, Skin Type, and Age Are More Important than Thiopurine Use for Keratinocyte Carcinoma Development in IBD Patients. Dig Dis Sci 2020; 65:1172-1179. [PMID: 31493039 DOI: 10.1007/s10620-019-05818-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 08/23/2019] [Indexed: 12/09/2022]
Abstract
BACKGROUND Retrospective studies observe an increased risk of keratinocyte carcinomas (KCs) in patients with inflammatory bowel disease (IBD) on thiopurine (TP) medication. The role of traditional risk factors such as skin type and sun protection behavior has not been studied in this population. This study aimed to examine traditional KC risk factors and thiopurine use on skin cancer development in an IBD cohort. METHODS Consecutive IBD patients were recruited from four specialist centers in Australia and New Zealand, each with varying UV exposure indices. Data pertaining to race, skin color, freckling and sun protection behavior, dose of TP therapy, and skin cancer development were elicited through a self-reported questionnaire. RESULTS A total of 691 IBD patients were included with 62 reporting KC development. Thiopurine usage was similar among patients who developed skin cancer compared with those who did not (92% vs. 89%, p = 0.3). There was no statistically significant association between KC development and TP dose or 6-thioguanine nucleotide levels. In multivariate modeling, four factors were independently and significantly associated with KC: age over 61 years old versus less than 30 years old (OR 6.76; 95% CI 2.38-19.18), residing in Brisbane versus Christchurch (OR 3.3; 95% CI 1.6-6.8), never staying in the shade versus staying in the shade ≥ 50% of the time (OR 3.8; 95% CI 1.4-10.5), and having a skin type that never tanned versus other skin types (OR 6.9; 95% CI 2.9-16.0). CONCLUSION Skin type, age, and sun protection behavior are more important risk factors for KC development than thiopurine medication use in this IBD population.
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Affiliation(s)
- Yang Wu
- Department of Gastroenterology, St Vincent's Hospital, 390 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia.
| | - Simon Ghaly
- Department of Gastroenterology, St Vincent's Hospital, 390 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia
| | | | - Bryce Jackson
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | - Katherine Hanigan
- IBD Research Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Deborah Martins
- IBD Research Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Division of Plastic and Reconstructive Surgery, University of California San Francisco, 505 Parnassus Ave, Suite M-593, San Francisco, CA, 94143-0932, USA
| | - Krupa Krishnaprasad
- IBD Research Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Reme E Mountifield
- Department of Gastroenterology, Flinders Medical Centre, Adelaide, SA, Australia
| | - David C Whiteman
- Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Peter A Bampton
- Department of Gastroenterology, Flinders Medical Centre, Adelaide, SA, Australia
| | - Richard B Gearry
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | - Graham L Radford-Smith
- IBD Research Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.,University of Queensland School of Medicine, Brisbane, QLD, Australia
| | - Ian C Lawrance
- Centre of Inflammatory Bowel Diseases, St John of God Hospital, Subiaco, WA, Australia.,School of Medicine and Pharmacology, Harry Perkins Institute of Medical Research, University of Western Australia, Murdoch, WA, Australia
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Singh S, Allegretti JR, Siddique SM, Terdiman JP. AGA Technical Review on the Management of Moderate to Severe Ulcerative Colitis. Gastroenterology 2020; 158:1465-1496.e17. [PMID: 31945351 PMCID: PMC7117094 DOI: 10.1053/j.gastro.2020.01.007] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A subset of patients with ulcerative colitis (UC) present with, or progress to, moderate to severe disease activity. These patients are at high risk for colectomy, hospitalization, corticosteroid dependence, and serious infections. The risk of life-threatening complications and emergency colectomy is particularly high among those patients hospitalized with acute severe ulcerative colitis. Optimal management of outpatients or inpatients with moderate to severe UC often requires the use of immunomodulator and/or biologic therapies, including thiopurines, methotrexate, cyclosporine, tacrolimus, TNF-α antagonists, vedolizumab, tofacitnib, or ustekinumab, either as monotherapy or in combination (with immunomodulators), to mitigate these risks. Decisions about optimal drug therapy in moderate to severe UC are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Therefore, the American Gastroenterological Association prioritized development of clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework. Focused questions in adult outpatients with moderate to severe UC included: (1) overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to TNF-α antagonists, (2) comparative efficacy and safety of biologic monotherapy vs combination therapy with immunomodulators, (3) comparative efficacy of top-down (upfront use of biologics and/or immunomodulator therapy) vs step-up therapy (acceleration to biologic and/or immunomodulator therapy only after failure of 5-aminosalicylates, and (4) role of continuing vs stopping 5-aminosalicylates in patients being treated with immunomodulator and/or biologic therapy for moderate to severe UC. Focused questions in adults hospitalized with acute severe ulcerative colitis included: (5) overall and comparative efficacy of pharmacologic interventions for inpatients refractory to corticosteroids, in reducing risk of colectomy, (6) optimal dosing regimens for intravenous corticosteroids and infliximab in these patients, and (7) role of adjunctive antibiotics in the absence of confirmed infections.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology, University of California, San Diego, La Jolla, California
| | - Jessica R Allegretti
- Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Shazia Mehmood Siddique
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Jonathan P Terdiman
- Division of Gastroenterology, University of California, San Francisco, California
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36
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Increased Risk of Liver Cirrhosis during Azathioprine Therapy for Crohn's Disease. Case Rep Gastrointest Med 2020; 2020:6726384. [PMID: 32082651 PMCID: PMC7008285 DOI: 10.1155/2020/6726384] [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: 09/30/2019] [Revised: 11/27/2019] [Accepted: 12/18/2019] [Indexed: 11/25/2022] Open
Abstract
Azathioprine is a cornerstone of the therapy of Crohn's disease. Unfortunately, infections and malignancies are relatively common adverse effects related to this drug; however, cirrhosis is exceptionally reported as a side effect. We report the case of a 49-year-old male patient with ileocolonic steno-penetrating Crohn's disease who developed hepatic cirrhosis while treated with azathioprine. After taking azathioprine for 3 years with regular follow-up, he developed pancytopenia, and liver cirrhosis was diagnosed with ultrasound, abdomen computed tomography scan, transient elastography, and liver biopsy. As all other causes of liver damage were excluded, azathioprine was believed to be the cause of liver injury and therefore was interrupted.
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Bayoumy AB, Simsek M, Seinen ML, Mulder CJJ, Ansari A, Peters GJ, De Boer NK. The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review. Expert Opin Drug Metab Toxicol 2020; 16:111-123. [PMID: 32090622 DOI: 10.1080/17425255.2020.1719996] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 01/16/2020] [Indexed: 12/11/2022]
Abstract
Introduction: In the 1950s, thioguanine (TG), a thiopurine-derivative together with azathioprine (AZA) and mercaptopurine (MP), were developed for the treatment of childhood leukemia. Over the years, the use of TG was also explored for other, mainly immune-mediated and inflammatory, diseases such as in the field of dermatology and rheumatology (e.g. psoriasis, systemic lupus erythematosus (SLE)) and gastroenterology and hepatology (e.g. inflammatory bowel diseases (IBD), autoimmune hepatitis).Areas covered: This review provides a comprehensive overview of all the clinical uses of TG and describes its mechanism of action, pharmacokinetic/pharmacodynamic features, and toxicity.Expert opinion: Thioguanine has shown beneficial clinical effects in hematological (particularly leukemia) and several immune-inflammatory diseases including psoriasis, SLE, polycythemia vera, Churg-Strauss syndrome, IBD, collagenous sprue, refractory celiac disease, and autoimmune hepatitis. Thioguanine is not effective in treating solid-cancers. At relatively low dosages, i.e. 0.2- 0.3mg/kg/day or 20 mg/day, TG has a favorable risk-benefit ratio and is a safe and effective drug in the long-term treatment of amongst other IBD patients. Thioguanine toxicity, especially myelotoxicity, and hepatotoxicity, including nodular regenerative hyperplasia (NRH) of the liver, is limited when dosed adequately. The occurrence of NRH appears dose-dependent and has been especially described during high dose TG above 40 mg/day.
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Affiliation(s)
- Ahmed B Bayoumy
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Melek Simsek
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, AG&M Research Institute, Amsterdam, Netherlands
| | - Margien L Seinen
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Chris J J Mulder
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Azhar Ansari
- Department of Gastroenterology, Surrey and Sussex NHS, Easy Surrey Hospital, Surrey, UK
| | - Godefridus J Peters
- Amsterdam UMC, VU University Medical Center, Laboratory Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Nanne K De Boer
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, AG&M Research Institute, Amsterdam, Netherlands
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Sands BE, Armuzzi A, Marshall JK, Lindsay JO, Sandborn WJ, Danese S, Panés J, Bressler B, Colombel J, Lawendy N, Maller E, Zhang H, Chan G, Salese L, Tsilkos K, Marren A, Su C. Efficacy and safety of tofacitinib dose de-escalation and dose escalation for patients with ulcerative colitis: results from OCTAVE Open. Aliment Pharmacol Ther 2020; 51:271-280. [PMID: 31660640 PMCID: PMC9328429 DOI: 10.1111/apt.15555] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/15/2019] [Accepted: 10/02/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND For patients with UC, flexible maintenance dosing therapy may confer advantages for safety, efficacy, costs and patient preference. Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. AIM To assess the efficacy and safety of tofacitinib dose de-escalation and escalation in patients with UC. METHODS We evaluated data (November 2017 data cut-off) from OCTAVE Open, an ongoing, open-label, long-term extension study. The dose de-escalation group comprised 66 tofacitinib induction responders in remission following 52 weeks' tofacitinib 10 mg b.d. maintenance therapy, subsequently de-escalated to 5 mg b.d. in OCTAVE Open. The dose escalation group comprised 57 tofacitinib induction responders who experienced treatment failure while receiving 5 mg b.d. maintenance therapy, subsequently escalated to 10 mg b.d. in OCTAVE Open. RESULTS After tofacitinib de-escalation, 92.4% (61/66) and 84.1% (53/63) of patients maintained clinical response and 80.3% (53/66) and 74.6% (47/63) maintained remission, at months 2 and 12, respectively. After dose escalation, 57.9% (33/57) and 64.9% (37/57) of patients recaptured clinical response and 35.1% (20/57) and 49.1% (28/57) were in remission, at months 2 and 12, respectively. The incidence rate of herpes zoster with dose escalation (7.6 patients with events/100 patient-years) was numerically higher than in the overall tofacitinib UC programme. CONCLUSIONS Following tofacitinib de-escalation in patients already in remission on 10 mg b.d., most maintained remission, although 25.4% lost remission, at month 12. For induction responders who dose-escalated following treatment failure on 5 mg b.d. maintenance therapy, 49.1% achieved remission by month 12. (ClinicalTrials.gov number: NCT01470612).
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Affiliation(s)
| | - Alessandro Armuzzi
- Fondazione Policlinico Universitario A. Gemelli IRCCSUniversità Cattolica del Sacro CuoreRomeItaly
| | - John K. Marshall
- Farncombe Family Digestive Health Research InstituteMcMaster UniversityHamiltonONCanada
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Segal JP, Htet HMT, Limdi J, Hayee B. How to manage IBD in the 'elderly'. Frontline Gastroenterol 2019; 11:468-477. [PMID: 33101625 PMCID: PMC7569512 DOI: 10.1136/flgastro-2019-101218] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/24/2019] [Accepted: 11/03/2019] [Indexed: 02/04/2023] Open
Abstract
As the incidence of inflammatory bowel disease (IBD) rises and the global population ages, the number of older people living with these conditions will inevitably increase. The challenges posed by comorbid conditions, polypharmacy, the unintended consequences of long-term treatment and the real but often underestimated mismatch between chronological and biological ages underpin management. Significantly, there may be differences in disease characteristics, presentation and management of an older patient with IBD, together with other unique challenges. Importantly, clinical trials often exclude older patients, so treatment decisions are frequently pragmatic, extrapolated from a number of sources of evidence and perhaps primarily dictated by concerns around adverse effects. This review aimed to discuss the epidemiology, clinical features and considerations with management in older patients with IBD.
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Affiliation(s)
| | | | - Jimmy Limdi
- Section of IBD, Division of Gastroenterology, The Pennine Acute Hospitals NHS Trust, Manchester, UK,Department of Gastroenterology, Manchester Academic Health Science Centre, Manchester, UK
| | - Bu'Hussain Hayee
- Department of Gastroenterology, King's College Hospital, London, UK
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Mortality Associated With Development of Squamous Cell Cancer in Patients With Inflammatory Bowel Diseases Receiving Treatment With Thiopurines. Clin Gastroenterol Hepatol 2019; 17:2262-2268. [PMID: 30853615 DOI: 10.1016/j.cgh.2019.03.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/26/2019] [Accepted: 03/01/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Treatment with thiopurines is associated with an increased risk of squamous cell carcinoma of the skin (SCC) in patients with inflammatory bowel diseases (IBD). We studied outcomes of patients with IBD who developed SCC while receiving thiopurine therapy. METHODS We conducted a retrospective cohort study of 54,919 patients with IBD followed in the nationwide Veterans Affairs Healthcare System from January 1, 2000, through May 23, 2018. From this cohort, we created a sub-cohort of patients with an incident diagnosis of SCC, confirmed by review of patients' medical records; we identified those who had received treatment with thiopurines (exposed group) vs those treated with mesalamine and no prior exposure to thiopurines or tumor necrosis factor antagonists (unexposed group). The primary outcome was death associated with SCC (SCC mortality). We collected data on baseline demographic features, exposure to ultraviolet light, Charlson comorbidity index, smoking status, and environmental exposures. Follow up began at the time of incident SCC diagnosis and ended at death or last recorded date in the health system. Cause-specific hazard models were used to estimate the adjusted and unadjusted hazard ratio (HRs), with 95% CIs, for SCC mortality. RESULTS We identified 467 patients with incident SCC and included 449 patients (161 exposed and 288 unexposed) in our final analysis. Eleven patients from complications of SCC (8 in the exposed group and 3 in the unexposed group). The estimated 5- and 10-year cumulative mortality values were 2.9% and 2.9% in the exposed group and 0.4% and 0.9% in the unexposed group, respectively. The unadjusted and adjusted cause-specific HRs for SCC mortality associated with exposure were 7.0 (95% CI, 1.8-28.0; P = .006) and 8.0 (95% CI, 2.0-32.8; P = .004), respectively. CONCLUSIONS Although the cause-specific mortality is relatively low, patients with IBD exposed to thiopurines who develop SCC have an increased risk of SCC-associated death compared to patients exposed to only mesalamine.
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Anticipatory care of children and adolescents with inflammatory bowel disease: a primer for primary care providers. Curr Opin Pediatr 2019; 31:654-660. [PMID: 31205126 DOI: 10.1097/mop.0000000000000795] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW About 10-20% of patients with newly diagnosed inflammatory bowel disease (IBD) are under 18 years of age, with incidence increasing in young children. Children with IBD have unique healthcare needs, which require coordination between primary care providers and pediatric gastroenterologists to provide appropriate care. This review highlights some key elements of anticipatory care in pediatric IBD, including vaccination, risk of serious infection and malignancy, psychosocial and educational needs, and cannabis use. RECENT FINDINGS Therapies for IBD that include anti-tumor necrosis factor medications, especially when combined with corticosteroids are associated with higher risks of serious infections. Vaccination remains the best way to prevent infections. Live vaccinations should be avoided during immunosuppression, but the schedule should be otherwise completed, including vaccination for influenza, pneumococcus and meningococcus, and human papillomavirus. Malignancy risk is increased in IBD patients, both because of disease factors and resulting from immunomodulatory medications. Children with IBD are at risk for mental health disorders and negative educational outcomes, so identification of at-risk children and early intervention are important. SUMMARY High-quality care in pediatric IBD requires coordination between pediatric gastroenterologists and primary care providers, with careful attention paid to the specific needs of children with IBD.
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Health Maintenance and Vaccination of Patients With Inflammatory Bowel Disease: Practice and Perception of Responsibility of Gastroenterologists vs Primary Care Providers. Ochsner J 2019; 19:210-219. [PMID: 31528131 DOI: 10.31486/toj.18.0086] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background: Although it is well established that patients with inflammatory bowel disease (IBD) are at increased risk of complicating diseases and vaccination-preventable infections, whether gastroenterologists (GIs) or primary care providers (PCPs) assume responsibility for these patients' health maintenance is not clear. Methods: We anonymously surveyed a convenience sample of 94 PCPs and 61 GIs at Saint Louis University School of Medicine in St. Louis, MO, about their practice and perception of the health maintenance and vaccination of patients with IBD. Results: Response rates were 82% and 93% for GIs and PCPs, respectively. GIs were as likely as PCPs to screen for smoking (88% vs 89%) and were significantly less likely to screen for depression/anxiety (24% vs 54%) or to provide pertussis (14% vs 44%) or diphtheria (20% vs 48%) vaccines. GIs were significantly more likely than PCPs to assess for colonoscopy need (94% vs 80%); to screen for nonmelanoma skin cancer (62% vs 14%), melanoma (56% vs 7%), osteoporosis (72% vs 51%), or tuberculosis (94% vs 44%); to prescribe calcium/vitamin D (74% vs 53%); to perform nutritional assessment (78% vs 33%); or to provide hepatitis A (60% vs 39%) or hepatitis B (86% vs 56%) vaccines. GIs were as likely as PCPs (64% vs 75%) to perceive that PCPs should order vaccinations and significantly more likely to perceive that GIs should track vaccinations (58% vs 16%) and other health maintenance issues (90% vs 49%). We found positive associations between performing the various health maintenance and vaccination tasks and the perception of responsibility. Conclusion: Several health maintenance aspects are inadequately addressed by GIs and PCPs, in part because of conflicting perceptions of responsibility. Clear guidelines and better GI/PCP communication are required to ensure effective health maintenance for patients with IBD.
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Mack DR, Benchimol EI, Critch J, deBruyn J, Tse F, Moayyedi P, Church P, Deslandres C, El-Matary W, Huynh H, Jantchou P, Lawrence S, Otley A, Sherlock M, Walters T, Kappelman MD, Sadowski D, Marshall JK, Griffiths A. Canadian Association of Gastroenterology Clinical Practice Guideline for the Medical Management of Pediatric Luminal Crohn's Disease. J Can Assoc Gastroenterol 2019; 2:e35-e63. [PMID: 31294379 PMCID: PMC6619414 DOI: 10.1093/jcag/gwz018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS We aim to provide guidance for medical treatment of luminal Crohn's disease in children. METHODS We performed a systematic search of publication databases to identify studies of medical management of pediatric Crohn's disease. Quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. We developed statements through an iterative online platform and then finalized and voted on them. RESULTS The consensus includes 25 statements focused on medical treatment options. Consensus was not reached, and no recommendations were made, for 14 additional statements, largely due to lack of evidence. The group suggested corticosteroid therapies (including budesonide for mild to moderate disease). The group suggested exclusive enteral nutrition for induction therapy and biologic tumor necrosis factor antagonists for induction and maintenance therapy at diagnosis or at early stages of severe disease, and for patients failed by steroid and immunosuppressant induction therapies. The group recommended against the use of oral 5-aminosalicylate for induction or maintenance therapy in patients with moderate disease, and recommended against thiopurines for induction therapy, corticosteroids for maintenance therapy, and cannabis in any role. The group was unable to clearly define the role of concomitant immunosuppressants during initiation therapy with a biologic agent, although thiopurine combinations are not recommended for male patients. No consensus was reached on the role of aminosalicylates in treatment of patients with mild disease, antibiotics or vedolizumab for induction or maintenance therapy, or methotrexate for induction therapy. Patients in clinical remission who are receiving immunomodulators should be assessed for mucosal healing within 1 year of treatment initiation. CONCLUSIONS Evidence-based medical treatment of Crohn's disease in children is recommended, with thorough ongoing assessments to define treatment success.
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Affiliation(s)
- David R Mack
- Children's Hospital of Eastern Ontario Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
- Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
| | - Eric I Benchimol
- Children's Hospital of Eastern Ontario Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
- Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Jeff Critch
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- Faculty of Medicine, Memorial University, St John's, Newfoundland and Labrador, Canada
| | - Jennifer deBruyn
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- Section of Pediatric Gastroenterology, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
| | - Frances Tse
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Paul Moayyedi
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Peter Church
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- IBD Centre, Department of Paediatrics, SickKids Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Colette Deslandres
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Centre Hospitalier Universitaire, Sainte-Justine, Montréal, Quebec, Canada
| | - Wael El-Matary
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- Section of Pediatric Gastroenterology, Department of Pediatrics, Health Sciences Centre, Winnipeg, Manitoba, Canada
| | - Hien Huynh
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- Department of Pediatrics (Gastroenterology), Stollery Children's Hospital, Edmonton, Alberta, Canada
| | - Prévost Jantchou
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Centre Hospitalier Universitaire, Sainte-Justine, Montréal, Quebec, Canada
| | - Sally Lawrence
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Anthony Otley
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- Division of Gastroenterology and Nutrition, IWK Health Centre, Halifax, Nova Scotia, Canada
| | - Mary Sherlock
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- Division of Pediatric Gastroenterology, McMaster University, Hamilton, Ontario, Canada
| | - Thomas Walters
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- IBD Centre, Department of Paediatrics, SickKids Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Michael D Kappelman
- Division of Pediatric Gastroenterology, University of North Carolina, Hospital-Children's Specialty Clinic, Chapel Hill, North Carolina
| | - Dan Sadowski
- Division of Gastroenterology, Royal Alexandra Hospital, Edmonton, Alberta, Canada
| | - John K Marshall
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Anne Griffiths
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
- IBD Centre, Department of Paediatrics, SickKids Hospital, University of Toronto, Toronto, Ontario, Canada
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Mack DR, Benchimol EI, Critch J, deBruyn J, Tse F, Moayyedi P, Church P, Deslandres C, El-Matary W, Huynh H, Jantchou P, Lawrence S, Otley A, Sherlock M, Walters T, Kappelman MD, Sadowski D, Marshall JK, Griffiths A. Canadian Association of Gastroenterology Clinical Practice Guideline for the Medical Management of Pediatric Luminal Crohn's Disease. Gastroenterology 2019; 157:320-348. [PMID: 31320109 DOI: 10.1053/j.gastro.2019.03.022] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 02/28/2019] [Accepted: 03/02/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS We aim to provide guidance for medical treatment of luminal Crohn's disease in children. METHODS We performed a systematic search of publication databases to identify studies of medical management of pediatric Crohn's disease. Quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. We developed statements through an iterative online platform and then finalized and voted on them. RESULTS The consensus includes 25 statements focused on medical treatment options. Consensus was not reached, and no recommendations were made, for 14 additional statements, largely due to lack of evidence. The group suggested corticosteroid therapies (including budesonide for mild to moderate disease). The group suggested exclusive enteral nutrition for induction therapy and biologic tumor necrosis factor antagonists for induction and maintenance therapy at diagnosis or at early stages of severe disease, and for patients failed by steroid and immunosuppressant induction therapies. The group recommended against the use of oral 5-aminosalicylate for induction or maintenance therapy in patients with moderate disease, and recommended against thiopurines for induction therapy, corticosteroids for maintenance therapy, and cannabis in any role. The group was unable to clearly define the role of concomitant immunosuppressants during initiation therapy with a biologic agent, although thiopurine combinations are not recommended for male patients. No consensus was reached on the role of aminosalicylates in treatment of patients with mild disease, antibiotics or vedolizumab for induction or maintenance therapy, or methotrexate for induction therapy. Patients in clinical remission who are receiving immunomodulators should be assessed for mucosal healing within 1 year of treatment initiation. CONCLUSIONS Evidence-based medical treatment of Crohn's disease in children is recommended, with thorough ongoing assessments to define treatment success.
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Affiliation(s)
- David R Mack
- Children's Hospital of Eastern Ontario Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada; Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada
| | - Eric I Benchimol
- Children's Hospital of Eastern Ontario Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada; Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Jeff Critch
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; Faculty of Medicine, Memorial University, St John's, Newfoundland and Labrador, Canada
| | - Jennifer deBruyn
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; Section of Pediatric Gastroenterology, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
| | - Frances Tse
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Paul Moayyedi
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Peter Church
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; IBD Centre, Department of Paediatrics, SickKids Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Colette Deslandres
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Centre Hospitalier Universitaire, Sainte-Justine, Montréal, Quebec, Canada
| | - Wael El-Matary
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; Section of Pediatric Gastroenterology, Department of Pediatrics, Health Sciences Centre, Winnipeg, Manitoba, Canada
| | - Hien Huynh
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; Department of Pediatrics (Gastroenterology), Stollery Children's Hospital, Edmonton, Alberta, Canada
| | - Prévost Jantchou
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Centre Hospitalier Universitaire, Sainte-Justine, Montréal, Quebec, Canada
| | - Sally Lawrence
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Anthony Otley
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; Division of Gastroenterology and Nutrition, IWK Health Centre, Halifax, Nova Scotia, Canada
| | - Mary Sherlock
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; Division of Pediatric Gastroenterology, McMaster University, Hamilton, Ontario, Canada
| | - Thomas Walters
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; IBD Centre, Department of Paediatrics, SickKids Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Michael D Kappelman
- Division of Pediatric Gastroenterology, University of North Carolina, Hospital-Children's Specialty Clinic, Chapel Hill, North Carolina
| | - Dan Sadowski
- Division of Gastroenterology, Royal Alexandra Hospital, Edmonton, Alberta, Canada
| | - John K Marshall
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Anne Griffiths
- Ch.I.L.D. Foundation Canadian Children IBD Network, Vancouver, British Columbia, Canada; IBD Centre, Department of Paediatrics, SickKids Hospital, University of Toronto, Toronto, Ontario, Canada.
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Panaccione R, Steinhart AH, Bressler B, Khanna R, Marshall JK, Targownik L, Afif W, Bitton A, Borgaonkar M, Chauhan U, Halloran B, Jones J, Kennedy E, Leontiadis GI, Loftus EV, Meddings J, Moayyedi P, Murthy S, Plamondon S, Rosenfeld G, Schwartz D, Seow CH, Williams C, Bernstein CN. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Luminal Crohn's Disease. Clin Gastroenterol Hepatol 2019; 17:1680-1713. [PMID: 30853616 DOI: 10.1016/j.cgh.2019.02.043] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 02/21/2019] [Accepted: 02/25/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Crohn's disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. METHODS We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. RESULTS The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. CONCLUSIONS Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.
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Affiliation(s)
- Remo Panaccione
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
| | - A Hillary Steinhart
- Division of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Brian Bressler
- Department of Medicine, Division of Gastroenterology, St Paul's Hospital, Vancouver, British Columbia, Canada
| | - Reena Khanna
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
| | - John K Marshall
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Laura Targownik
- Section of Gastroenterology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Waqqas Afif
- Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Alain Bitton
- Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Mark Borgaonkar
- Faculty of Medicine, Memorial University, St John's, Newfoundland, Canada
| | - Usha Chauhan
- Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Brendan Halloran
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
| | - Jennifer Jones
- Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Erin Kennedy
- Division of General Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Grigorios I Leontiadis
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Jonathan Meddings
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Paul Moayyedi
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Sanjay Murthy
- Division of Gastroenterology, University of Ottawa, Ottawa, Ontario, Canada
| | - Sophie Plamondon
- Department of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada
| | - Greg Rosenfeld
- Division of Gastroenterology, Pacific Gastroenterology Associates, Vancouver, British Columbia, Canada
| | - David Schwartz
- Inflammatory Bowel Disease Center, Vanderbilt University, Nashville, Tennessee
| | - Cynthia H Seow
- Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | | | - Charles N Bernstein
- Section of Gastroenterology, University of Manitoba, Winnipeg, Manitoba, Canada
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Wright EK, Ding NS, Niewiadomski O. Management of inflammatory bowel disease. Med J Aust 2019; 209:318-323. [PMID: 30257634 DOI: 10.5694/mja17.01001] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 08/03/2018] [Indexed: 12/13/2022]
Abstract
Australia has one of the highest incidence rates of inflammatory bowel disease (IBD) in the world. Early diagnosis and treatment for IBD is critical. For Crohn disease, in particular, this may change the natural history of disease and reduce disability. Faecal calprotectin is a sensitive test that can be used by primary care physicians to assist in determining which patients with gastrointestinal symptoms may have IBD. This allows for prompt identification of patients who may benefit from endoscopy. Regular re-evaluation of disease status with strategies that can safely, readily and reliably detect the presence of inflammation with faecal biomarkers and imaging is important. To avoid the risks of cumulative radiation exposure, magnetic resonance imaging and/or intestinal ultrasound, rather than computed tomography scanning, should be performed when possible. Drug treatments for IBD now include five biological drugs listed by the Pharmaceutical Benefits Scheme: adalimumab, infliximab, golimumab, vedolizumab and ustekinumab. Such developments offer the possibility for improved disease control in selected patients.
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Affiliation(s)
| | - Nik S Ding
- St Vincent's Hospital Melbourne, Melbourne, VIC
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Feuerstein JD, Moss AC, Farraye FA. Ulcerative Colitis. Mayo Clin Proc 2019; 94:1357-1373. [PMID: 31272578 DOI: 10.1016/j.mayocp.2019.01.018] [Citation(s) in RCA: 259] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 11/02/2018] [Accepted: 01/22/2019] [Indexed: 02/07/2023]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that can involve any aspect of the colon starting with mucosal inflammation in the rectum and extending proximally in a continuous fashion. Typical symptoms on presentation are bloody diarrhea, abdominal pain, fecal urgency, and tenesmus. In some patients, extraintestinal manifestations may predate the onset of gastrointestinal symptoms. A diagnosis of UC is made on the basis of presenting symptoms consistent with UC as well as endoscopic evidence showing continuous and diffuse colonic inflammation that starts in the rectum. Biopsies of the colon documenting chronic inflammation confirm the diagnosis of UC. Most cases are treated with pharmacological therapy to first induce remission and then to maintain a corticosteroid-free remission. There are multiple classes of drugs used to treat the disease. For mild to moderate UC, oral and rectal 5-aminosalycilates are typically used. In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors. However, in up to 15% of cases, patients in whom medical therapy fails or who have development of dysplasia secondary to their long-standing colitis will require surgical treatment. Finally, to minimize the complications of UC and adverse events from medications, a working collaboration between primary care physicians and gastroenterologists is necessary to make sure that vaccinations are optimized and that patients are screened for colon cancer, skin cancer, bone loss, depression, and other treatable and preventable complications.
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Affiliation(s)
- Joseph D Feuerstein
- Department of Medicine and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
| | - Alan C Moss
- Department of Medicine and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Francis A Farraye
- Department of Medicine and Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, MA
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Lin SC, Goldowsky A, Papamichael K, Cheifetz AS. The Treatment of Inflammatory Bowel Disease in Patients With a History of Malignancy. Inflamm Bowel Dis 2019; 25:998-1005. [PMID: 30590558 PMCID: PMC7534371 DOI: 10.1093/ibd/izy376] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Indexed: 12/13/2022]
Abstract
As patients with inflammatory bowel disease (IBD) are living longer and our medical armamentarium expands, gastroenterologists are more frequently faced with treatment decisions about patients with IBD who also have a history of malignancy. This review aims to summarize the current literature on IBD, the inherent risk of developing gastrointestinal and extra-intestinal malignancies, and the risk of malignancies associated with available biologic and immunomodulatory therapies and to discuss the overall treatment strategy for a patient with a history of malignancy.
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Affiliation(s)
- Steven C Lin
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Alex Goldowsky
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Adam S Cheifetz
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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Nagarajan P, Asgari MM, Green AC, Guhan SM, Arron ST, Proby CM, Rollison DE, Harwood CA, Toland AE. Keratinocyte Carcinomas: Current Concepts and Future Research Priorities. Clin Cancer Res 2019; 25:2379-2391. [PMID: 30523023 PMCID: PMC6467785 DOI: 10.1158/1078-0432.ccr-18-1122] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 10/08/2018] [Accepted: 12/03/2018] [Indexed: 12/12/2022]
Abstract
Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are keratinocyte carcinomas, the most frequently diagnosed cancers in fair-skinned populations. Ultraviolet radiation (UVR) is the main driving carcinogen for these tumors, but immunosuppression, pigmentary factors, and aging are also risk factors. Scientific discoveries have improved the understanding of the role of human papillomaviruses (HPV) in cSCC as well as the skin microbiome and a compromised immune system in the development of both cSCC and BCC. Genomic analyses have uncovered genetic risk variants, high-risk susceptibility genes, and somatic events that underlie common pathways important in keratinocyte carcinoma tumorigenesis and tumor characteristics that have enabled development of prediction models for early identification of high-risk individuals. Advances in chemoprevention in high-risk individuals and progress in targeted and immune-based treatment approaches have the potential to decrease the morbidity and mortality associated with these tumors. As the incidence and prevalence of keratinocyte carcinoma continue to increase, strategies for prevention, including effective sun-protective behavior, educational interventions, and reduction of tanning bed access and usage, are essential. Gaps in our knowledge requiring additional research to reduce the high morbidity and costs associated with keratinocyte carcinoma include better understanding of factors leading to more aggressive tumors, the roles of microbiome and HPV infection, prediction of response to therapies including immune checkpoint blockade, and how to tailor both prevention and treatment to individual risk factors and needs.
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Affiliation(s)
| | - Maryam M Asgari
- Department of Dermatology, Massachusetts General Hospital, and Department of Population Medicine, Harvard Medical School, Boston, Massachusetts
| | - Adele C Green
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- Cancer Research UK Manchester Institute and Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom
| | - Samantha M Guhan
- Department of Dermatology, Massachusetts General Hospital, and Department of Population Medicine, Harvard Medical School, Boston, Massachusetts
| | - Sarah T Arron
- Department of Dermatology, University of California, San Francisco, San Francisco, California
| | - Charlotte M Proby
- Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom
| | - Dana E Rollison
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Catherine A Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University, London, United Kingdom
| | - Amanda Ewart Toland
- Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Huang SZ, Liu ZC, Liao WX, Wei JX, Huang XW, Yang C, Xia YH, Li L, Ye C, Dai SX. Risk of skin cancers in thiopurines-treated and thiopurines-untreated patients with inflammatory bowel disease: A systematic review and meta-analysis. J Gastroenterol Hepatol 2019; 34:507-516. [PMID: 30393891 DOI: 10.1111/jgh.14533] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/23/2018] [Accepted: 10/26/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIM The thiopurines are effective in the management of patients with inflammatory bowel disease (IBD), but the association between thiopurines use and the risk of skin cancer (including nonmelanoma skin cancer [NMSC] and melanoma skin cancer) has already been sufficiently reported. However, the results of these studies are inconsistent, and thus, the objective of our analysis was to explore whether thiopurines can lead to an excess risk of skin cancer in IBD patients. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched to identify relevant studies that evaluated the risk of skin cancer in IBD patients treated with thiopurines. A random effects meta-analysis was conducted to calculate the pooled incidence rate ratios as well as risk ratios (RRs). Subgroup analysis was performed to explore the potential source of heterogeneity. RESULTS Thirteen studies comprising 149 198 participants were included. The result suggested that thiopurines significantly increased the risk of overall skin cancer in IBD patients (random effects: RR = 1.80, 95% confidence interval [CI] 1.14-2.87, P = 0.013), among which NMSC showed an excess risk associated with thiopurines use (random effects: RR = 1.88, 95% CI 1.48-2.38, P < 0.001) while no increased risk was observed with respect to melanoma skin cancer (random effects: RR = 1.22, 95% CI 0.90-1.65, P = 0.206). Subgroup analysis regarding sample size and geographic distribution in skin cancer and follow-up duration in NMSC reached statistical significance, while other subgroups showed no significance. CONCLUSION Exposition of thiopurines in patients with IBD is associated with a higher risk of skin cancer. Routine skin screening and daily skin protective practice are recommended for these patients.
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Affiliation(s)
- Shao-Zhuo Huang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhi-Cheng Liu
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Wei-Xin Liao
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Jun-Xiao Wei
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiao-Wen Huang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Chen Yang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Yu-Han Xia
- Basic Medical College, Southern Medical University, Guangzhou, Guangdong, China
| | - Lu Li
- Department of Plastic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Chao Ye
- Basic Medical College, Navy Medical University, Shanghai, China
| | - Shi-Xue Dai
- Department of Gastroenterology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, South China University of Technology, Guangzhou, Guangdong, China.,Guangdong Geriatrics Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, South China University of Technology, Guangzhou, Guangdong, China
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