Pediatric Inflammatory Bowel Disease

Foreword
Preface
Contents
Contributors
Part I: Etiology and Pathogenesis
1: Genetics of Inflammatory Bowel Diseases
	Introduction
	Genetic Epidemiology
		Ethnic and Racial Variations of Disease
		Family Studies
		Twin Studies
	NOD2 Gene and Crohn Disease
		Epidemiology of NOD2 Mutations
	Human Leukocyte Antigens in Ulcerative Colitis
	Genome-Wide Association Studies in IBD
		IL23R Polymorphisms in Crohn Disease and Ulcerative Colitis
		Association of the ATG16L1 Autophagy Gene with Crohn Disease
		Non-Coding Variation
		Meta-Analysis
		GWAS Meta-Analysis in Ulcerative Colitis
		Association of TNFRSF6B and IL27 with Pediatric Age of Onset IBD
		Impact of the Immunochip
		Trans-ancestry Association Studies
	Next-Generation Sequencing
		Sequencing in High-Risk Individuals and Families
		Next-Generation Sequencing in Research
	Risk Prediction
	Genotype-Phenotype Correlations in Pediatric IBD
		Genetic Sharing Between Pediatric Age of Onset IBD and Other Autoimmune Diseases
	Summary
	References
2: Immunologic Regulation of Health and Inflammation in the Intestine
	Introduction
	The Anatomy of the Intestinal Immune System
	The Intestinal Epithelium: Structure and Functional Subsets
	Epithelial Cell Function: Interlinked Connection with Microbiome and Dysfunction in IBD
	Gut-Associated Lymphoid Tissues
	Compartmentalized Gut Lymph Node Drainage
	Innate Immune Cell-Dependent Regulation of Intestinal Health
	Dendritic Cells
	Macrophages
	Granulocytes: Neutrophils, Eosinophils, Basophils, and Mast Cells
	Adaptive Immunity and Their Contribution to Intestinal Health and Inflammation
	T-cells
	B-cells
	Essential Immunologic Pathways that Regulate Intestinal Health
	Innate Lymphoid Cell-Dependent Regulation of Intestinal Health
	Causes and Immunologic Drivers of Intestinal Inflammation in Humans
	Understanding Intestinal Immunity and IBD in Children
	Summary
	References
3: Cytokines and Inflammatory Bowel Disease
	Introduction
	Pro-Inflammatory Cytokines
		Tumor Necrosis Factor-Alpha
		Interferon-gamma
		Interleukin-1
		Interleukin-2
		Interleukin-6
		Interleukin-12
		Interleukin-17
		Interleukin-23
		Interleukin-18
		Interleukin-13
		Interleukin-33
		Interleukin-37
		Interleukin-9
		Tumor Necrosis Factor-Like Ligand (Tl1a)
	Anti-Inflammatory Cytokines
		Transforming Growth Factor-Beta
		Interleukin-4
		Interleukin-10
		Interleukin-22
	Summary
	References
4: The Gut Microbiota and Inflammatory Bowel Disease
	Introduction
	Characteristics of the Gut Microbiome
	Characteristics of the Gut Metabolome
	Diet and the Gut Microbiome
	Gut Microbiota–Host Interactions at the Mucosal Interface
		The Innate Immune System
		The Adaptive Immune System
		The Intestinal Epithelium
	IBD and the Human Gut Microbiome
	Diet, IBD, and the Gut Microbiome
	The Gut Microbiota as a Therapeutic Strategy
		Probiotics and Prebiotics
		Enteral Nutrition Therapy
		Bacterial Engineering
		Fecal Transplantation
	Conclusions
	References
5: Immune Dysregulation Associated with Very Early-Onset Inflammatory Bowel Disease
	Introduction
	Genomics and VEO-IBD
	Clinical Presentation of Very Early-Onset (VEO) IBD
	Genetic Variants Associated with VEO-IBD and Their Immunologic Consequences
		Genetic Variants Influencing Intestinal Epithelial Barrier Function
		Genetic Variants Impairing Development of the Adaptive Immune System
		Genetic Variants Impairing Regulatory T cells
		Genetic Variants in the IL-10-IL-10R Pathway and Related Cytokine Family Members
		Genetic Variants Influencing Bacterial Recognition and Clearance
		Autoimmune and Autoinflammatory Disorders
	Immunologic Considerations
	Perspective and Future Directions in Genetic and Immunologic Analyses of VEO-IBD
	References
Part II: Epidemiology and Clinical Features
6: The Epidemiology of Pediatric Inflammatory Bowel Disease
	Introduction
	Incidence and Prevalence
		Changes in Incidence and Prevalence Over Time
		Projecting the Future Epidemiology of Pediatric Inflammatory Bowel Disease
	Changing Age at Inflammatory Bowel Disease Diagnosis
	Ethnocultural Differences in the Epidemiology of Inflammatory Bowel Disease
	Environmental Risk Factors
		The Hygiene Hypothesis
		Breastfeeding
		Cesarean Section
		Infectious Diseases and Antibiotic Use
		Exposure to Cigarette Smoke
		Urban Environments, Air Pollution, and Residential Greenspace
		Diet
		Association vs. Causation
	Gaps in Knowledge and Challenges in Determining the Global Epidemiology of Pediatric Inflammatory Bowel Disease
	Conclusions
	References
7: The Natural History of Crohn Disease in Children
	Introduction
	Disease Activity
	Evolution of Disease Phenotype
	Growth
	Corticosteroid Dependence
	Surgery
	Postoperative Recurrence
	Cancer Risk
	Quality of Life
	References
8: Natural History of Ulcerative Colitis in Children
	Introduction
	Overview
	Aminosalicylates
	Corticosteroids
	Immunomodulators
	Biologics
	Small Molecules
	Antibiotics
	Can We Predict the Course of Disease?
	Summary
	References
9: Pediatric Inflammatory Bowel Disease: Unclassified
	Introduction
	Definition
	Epidemiology
		Diagnosis
			Clinical Features
			Endoscopic Evaluation
			Small Bowel Imaging
		Medical Management
		Surgical Management
	Conclusion
	References
10: Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease
	Introduction
	Growth Failure
	Joint Manifestations
	Bone Disease
	Oral Lesions
	Skin Lesions
	Eye Lesions
	Liver Disease
	Other Extraintestinal Manifestations
	Hematologic Abnormalities
	Vascular
	Pancreatitis
	Renal
	Pulmonary
	Neurologic
	Cardiac
	Summary
	References
11: Liver Disease in Pediatric Inflammatory Bowel Disease
	Introduction
	Abnormal Liver Chemistry
	Primary Sclerosing Cholangitis
		Epidemiology and Pathogenesis
		Primary Sclerosing Cholangitis and IBD
			Diagnosis
			Outcomes
			Treatment
	Other Autoimmune Liver Diseases
		Autoimmune Hepatitis
			Epidemiology and Pathogenesis
			Diagnosis
			Outcomes and Treatment
		Autoimmune Sclerosing Cholangitis
			Epidemiology and Pathogenesis
			Diagnosis
			Outcomes and Treatment
	IgG4-Associated Cholangitis
		Drug Hepatotoxicity (Table 11.2)
		Methotrexate
		Thiopurines
		Antitumor Necrosis Factor-α (Anti-TNFα)
	Other Biologics and Small Molecules
		Sulfasalazine and Mesalamine
		Glucocorticoids
		Hepatosplenic T-Cell Lymphoma
	Other Liver Diseases and IBD
		Cholelithiasis
		Liver Abscess
		Portal Vein Thrombosis and Budd-Chiari Syndrome
		Non-Alcoholic Fatty Liver Disease
		Granulomatous Hepatitis
		Hepatic Amyloidosis
	A Clinical Approach to Children with IBD and Liver Abnormalities
	References
12: Growth Impairment in Pediatric Inflammatory Bowel Disease
	Normal Growth and Pubertal Development
		Normal Growth Patterns
		Normal Growth Physiology
			The GH/IGF-1 Axis
				The Somatomedin Hypothesis
				Growth Hormone and IGF-1
				Gender Differences in the GH/IGF-1 Pathway
				Insulin-Like Growth Factor Binding Proteins (IGFBPs)
			Growth Plate Proliferation, Senescence, and Fusion
		Monitoring and Assessment of Growth
		Definitions of Impaired Growth
	Growth in Pediatric IBD
		Prevalence of Growth Impairment in IBD
			Crohn Disease
			Ulcerative Colitis
			Sex Differences in Linear Growth Impairment
		Pathophysiology of Growth Impairment in IBD
			Chronic Caloric Insufficiency
			Direct Cytokine Effects
				Disruption of the GH/IGF-1 Axis
				IGF-1 Independent Mechanisms
				The Role of IL-6 in Growth Impairment
			The Interplay Between Nutrition And Cytokines
			Disruption of the GH/IGF-1 Axis by Cytokine-Independent Molecular Pathways
				Interaction Between the Gut Microbiome and the GH/IGF-1 Axis
			Corticosteroid Suppression of Linear Growth
			The Pathogenesis of Pubertal Delay and Its Influence on Growth Impairment
			Influence of Genetic Factors
	Facilitation of Normal Growth in IBD
		The Importance of Prompt Recognition of IBD
		The Importance of Monitoring Growth
		Psychosocial Impact of Impaired Growth
		General Principles of Management
		Anti-Inflammatory Treatments and Effects on Growth
			Enteral Nutrition
			Corticosteroids
			Immunomodulatory Drugs
			Anti-Tumor Necrosis Factor-Alpha (Anti-TNFα)
			Surgery
			Hormonal Interventions
	Summary
	References
13: Inflammatory Bowel Diseases and Skeletal Health
	Introduction
	Growth and Bone Modeling and Remodeling
	Measurement of Bone Mass
	Bone Cells and Inflammation
		Osteocytes
		Osteoclasts and the RANKL/OPG System
		Osteoblasts
		T-Cells and Bone Loss
	Novel Pathogenic Pathways in IBD: Osteoimmune Connections
	The Gut Microbiome and Bone Health
	Effects of Intestinal Inflammation on Bone
		Animal Models
		Human Studies
		Osteoporosis and Fractures in Pediatric IBD
		Treatment
	Conclusions
	References
14: Puberty and Pediatric-Onset Inflammatory Bowel Disease
	The Pubertal Process in Healthy Children and Adolescents
	The Influence of IBD on Puberty
	Potential Causes of Pubertal Delay in IBD
		Nutritional Causes of Pubertal Delay
		Endocrine Aspects of Pubertal Delay
		Proinflammatory Cytokines–Endocrine Interactions
	Psychosocial Issues and Puberty
	Therapeutic Approach to Addressing Pubertal Issues in IBD
	References
15: Classification of Pediatric Inflammatory Bowel Disease
	Introduction
	Phenotypic Classification of IBD: A Historical Perspective
	The Vienna Classification [14]
	The Montreal Classification [15]
	The Paris Modification of the Montreal Classification for Pediatric IBD [10]
		Novel Features of the Paris Classification
	The Porto Criteria and the Revised Porto Criteria
	IBD-unclassified (IBD-U) and PIBD Classes
	Special Considerations
	Evolution of Disease Phenotype
	Future Directions
	References
Part III: Diagnosis
16: The History and Physical Exam
	Introduction
	History
	Physical Exam
	Summary
	References
17: Differential Diagnosis of Inflammatory Bowel Disease
	Acute Onset Diarrhea
		Intestinal Infection
		Food Allergy
		Acute Appendicitis
	Chronic or Recurrent Intestinal Symptoms
		Intestinal Infection
		Celiac Disease
		Eosinophilic Gastroenteropathy
		Primary or Acquired Immunodeficiency Diseases
		Intestinal Neoplasm
		Vasculitis Disorders
	Abdominal Mass
	Isolated Esophagogastroduodenal Involvement
	Isolated Perineal Disease
	References
18: Laboratory Evaluation of Inflammatory Bowel Disease
	Introduction
	Blood Tests
	Anemia
	Acute Phase Reactants: Platelets
	Acute Phase Reactants: Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) and Other Markers
	Other Laboratory Evaluations
	Specific Blood Tests: Inflammatory Bowel Disease Serologies
	Stool Evaluation
	Fecal Calprotectin
	Summary
	References
19: Fecal Markers in Inflammatory Bowel Disease
	Introduction
	Overview of Stool Tests
	Introduction to Calprotectin
	Fecal Calprotectin Collection
	Cuffoff Levels
	Reliability, Sensitivity, and Specificity
	Fecal Calprotectin as a Screening Tool
	Fecal Calprotectin Comparison to Endoscopy
	Fecal Calprotectin and Comparison to MRI
	Fecal Calprotectin and Disease Location
	Fecal Calprotectin Use to Monitor Pediatric Inflammatory Bowel Disease
	Fecal Calprotectin to Evaluate Post-Operative Recurrence
	Fecal Calprotectin to Evaluate for Pouchitis
	Fecal Calprotectin to Predict Mucosal Healing
	Fecal Calprotectin to Predict Histologic Remission
	Fecal Calprotectin to Predict Relapse
	Fecal Calprotectin as a Marker of Tight Control—CALM Study
	Fecal Calprotectin Recommendations in Clinical Guidelines (Table 19.3)
	Summary
	References
20: Radiologic Evaluation of Pediatric Inflammatory Bowel Disease
	Introduction to Imaging
	Crohn Disease
	Ulcerative Colitis
		Radiographs
		Fluoroscopic Examinations
		Ultrasound and Contrast-Enhanced Ultrasound of the Bowel
		Computed Tomography Enterography (CTE)
			CTE Features of CD
			CTE Features of UC
		Magnetic Resonance Enterography (MRE)
			MRE Features of CD
			MRE Features of UC
	Nuclear Medicine Imaging Studies
		White Blood Cell Scans
		PET and PET-MR Examinations
	Imaging of Complications
		Perianal Disease
		Stricture
		Penetrating Disease—Intraabdominal Abscesses and Enteric Fistulas
		Toxic Megacolon
		Bowel Obstruction/Perforation
	Imaging of Extraintestinal Manifestations
		Musculoskeletal System
		Hepatobiliary Disease
		Urolithiasis
	Interventional Radiology in IBD
		Percutaneous Abscess Drainage
		Additional Applications of Interventional Radiology
	Conclusion
	References
21: Endoscopy and Inflammatory Bowel Disease
	Introduction
	Endoscopy: Background History
	Patient Preparation
	Antibiotic Prophylaxis
	Bowel Preparation
	Monitoring and Sedation
	Endoscopic Techniques in Inflammatory Bowel Disease
		Upper Gastrointestinal Endoscopy
		Ileocolonoscopy
			Equipment
	Ileocolonoscopy Basic Technique
		Getting Started and Patient Positioning
		Practical Tips in Ileocolonoscopy
	Rectal Intubation
	Sigmoid and Descending Colon
	Splenic Flexure and Transverse Colon
	Hepatic Flexure and Ascending Colon
	Cecum
	Ileal Intubation and Its Importance
	Ileum
	Endoscope Withdrawal
	Dilatation of Strictures
		Complications of Ileocolonoscopy
	Small Bowel Assessment
		Wireless Capsule Endoscopy
	Enteroscopy
	Push Enteroscopy
	Instruments and Technique
		Double-Balloon Enteroscopy
	Instruments and Technique
		Endoscopic Findings in Inflammatory Bowel Disease
	Ulcerative Colitis
	Crohn Disease
	Inflammatory Bowel Disease-Undefined (IBD-U)
	Follow-Up and Surveillance Ileocolonoscopy
	Treatment Targets
	Scoring Systems for Endoscopic PIBD Disease Activity
	Endosonography
	New Endo-Diagnostic Methods
		High-Magnification Chromoscopic Colonoscopy (HMCC)
		Confocal Laser Endomicroscopy
		Therapeutic Endoscopy in IBD
		Colon Capsule Endoscopy
	Conclusions
	References
22: The Pathology of Chronic Inflammatory Bowel Disease
	Major Histologic Features Noted in Mucosal Specimens
		Preparation and Procedure-Induced Artifacts
		Histologic Patterns in Colitis
		Acute Self-Limited Colitis and its Distinction from IBD
		Histologic Features of Early IBD
			Very Early-Onset IBD
		Characteristic Features of Ulcerative Colitis and Crohn Disease
	“Atypical” Features in the Diagnosis of Ulcerative Colitis
		Rectal Sparing and Patchiness
		Backwash Ileitis
		Upper GI Tract Involvement in UC
		Periappendiceal Inflammation in Ulcerative Colitis
		Fulminant and Indeterminate Colitis
		Pouchitis
	References
23: Capsule Endoscopy in Pediatric Inflammatory Bowel Disease
	Introduction
	Indications
	Small Bowel Capsule Endoscopy in IBD
		Inflammatory Bowel Disease Undetermined and Ulcerative Colitis
	Pan-Enteric Capsule Endoscopy
	Monitoring the Mucosa
	Capsule Topics of Interest
		Contraindications to Capsule Endoscopy
		Swallowing the Capsule/Endoscopic Placement for Those Who Cannot Swallow
		Bowel Preparation
		Interpretation and Scoring Methods
		Capsule Retention and Incomplete Procedures
			Patency Capsule
	Conclusion
	References
24: Bone Health in Pediatric Inflammatory Bowel Disease
	Introduction
	Skeletal Modeling and Bone Accrual During Childhood
	Changes in Cortical and Trabecular Bone with Growth
	Biochemical Markers of Bone Metabolism
	Potential Threats to Bone Health in Pediatric IBD
	Malnutrition
	Decreased Muscle Mass and Biomechanical Loading of the Skeleton
	Glucocorticoid-Induced Osteopenia
	Inflammation and Bone Loss
	Assessment of Bone Status in Children and Adolescents
		Classification of Bone Health and Relation to Fracture Risk
		Limitations of DXA in Children and Adolescents
		Peripheral Quantitative Computed Tomography
	Clinical Studies of Bone Health in Pediatric IBD
		Accounting for Body Size Differences
		Glucocorticoid Effect
		Impact of Disease Activity
		Longitudinal Studies
	Potential Therapies for Bone Health in Pediatric IBD
		Physical Activity
		Vitamins and Minerals
		Bisphosphonates
	Summary
	References
Part IV: Medical Therapy
25: 5-Aminosalicylate Therapy
	Introduction
	Mechanism of Action
	Pharmacokinetics
	Indications and Efficacy
		Ulcerative Colitis
		Crohn Disease
		Surgically Induced Remission of Crohn Disease and Prevention of Postoperative Recurrence
		Chemoprevention of Colorectal Carcinoma
		Side Effects
	Adherence
	Conclusion
	References
26: Antibiotic Therapy
	Introduction
	Antibiotic Use in Crohn Disease
	Active Crohn Disease
	Anti-MAP Therapies
	Perianal Disease
	Postoperative Recurrence of Crohn Disease
	Antibiotics in Active Ulcerative Colitis
	Antibiotics in Extra-Intestinal Manifestations of IBD
	Additional Considerations
	Summary
	References
27: Nutritional Management of Inflammatory Bowel Disease
	Introduction
	Nutritional Impairment in Pediatric Inflammatory Bowel Disease
	Dietary Intake and Body Composition in Children with IBD
		Dietary Intake
		Body Composition
		Micronutrient Deficiencies
		Elevated Body Mass Index in Inflammatory Bowel Disease
	General Management of Nutrition in Inflammatory Bowel Disease
		Monitoring Nutritional Status
		History of the Use of EEN in CD
		Postulated Mechanisms of Action of EEN in CD
		The Intestinal Microbiota
		Anti-Inflammatory Activities of Enteral Formulae
		Epithelial Barrier Function
	Effectiveness of Exclusive Enteral Nutrition Therapy in Crohn Disease
		Induction of Remission
		Comparative Effectiveness of Nutritional and Biological Therapy
		Maintenance of Remission
		Maintenance of Remission with EN in Adults
		Maintenance of Remission with EN in Pediatrics
		EN in Combination with Medical Therapy
		Repeated EEN and Long-Term Outcomes of Therapy
	Additional Effects and Proof of Efficacy of EEN
		EEN and Mucosal Healing
		EEN and Changes in Fecal Markers of Inflammation
		EEN: Nutritional Status and Growth
		EEN and Bone Health
		EEN and Quality of Life
		Pre-/Postoperative Effects
		Adverse Effects of Enteral Nutrition
	Factors Affecting Response to EEN
		Disease-Related Factors
			Disease Duration
			Disease Location
		EEN-Related Factors
			Polymeric Versus Elemental/Semi-Elemental Diets
			Fat Composition
			Exclusive Versus Partial EN (PEN)
			Duration of Therapy
			Predicting the Response to EEN
		Delivery of EEN
			Route of Administration of EEN
			Approach to Reintroduction of Normal Diet
			Geographic Variability and Barriers to Utilization of EEN
	Conclusion
	References
28: 2021 Corticosteroids
	Introduction
	The Working Mechanism of Corticosteroids
	Systemic Corticosteroids
	Topical Corticosteroids
	Pharmacokinetics
	Topical Steroid Formulations
		Efficacy of Oral Budesonide Treatment in Crohn Disease
	Side Effects of Budesonide in Children
	Maintenance Treatment in Crohn Disease
	Budesonide in Ulcerative Colitis
	Conclusion
	References
29: Mercaptopurine Therapy
	Introduction
	6-Mercaptopurine Metabolism
	Efficacy of Thiopurines in Crohn Disease
	Efficacy of Thiopurines in Ulcerative Colitis
	Thiopurines and Mucosal Healing
	Clinical Indication
	Thiopurines in Combination with Anti-TNF
	Postoperative Prophylaxis
	Testing for TPMT Deficiency
	Monitoring of Thiopurine Metabolite Levels
	Thiopurine Toxicity
	Thiopurines and Risk of Malignancy
	Conclusion
	References
30: Methotrexate
	Introduction
	Mechanism of Action
	Efficacy
	Dose and Administration
	Toxicity and Monitoring
	References
31: Infliximab Therapy for Pediatric Crohn Disease and Ulcerative Colitis
	Introduction
	Crohn Disease
	Infliximab Is Within REACH for Pediatric CD
	Early Use of Infliximab
	Combination Therapy Versus Infliximab Monotherapy
	Proactive Therapeutic Drug Monitoring and Treat-to-Target in CD
	Infliximab Concentration Detection Methods
	Incidence of Primary and Repeat Abdominal Surgeries in the Infliximab Era
	Ulcerative Colitis
	Infliximab in Moderate to Severe UC
	Infliximab in Refractory UC
	Therapeutic Drug Monitoring and UC
	Infliximab and the Incidence of Surgery in Pediatric UC
	Infliximab Biosimilars
	Infliximab Safety Profile
		Infusion Reactions
		Rapid (One-Hour) Infusions
		Infections
		Vaccination
		Malignancy
		Mortality
	Summary
	References
32: Anti-TNF Therapies Other Than Infliximab for the Treatment of Pediatric Inflammatory Bowel Disease
	Introduction
	Therapeutic Efficacy and Pivotal Trials
		Adalimumab
			Efficacy of Adalimumab in Pediatric CD Patients
			Efficacy of Adalimumab in Pediatric UC Patients
			Efficacy of Adalimumab in Pediatric Patients Exposed to Infliximab
		Efficacy of Adalimumab in Adult Patients
		Certolizumab
			Efficacy of Certolizumab in Pediatric Patients
			Efficacy of Certolizumab in Adult Patients
			Efficacy of Certolizumab in Adult Patients with Previous Infliximab Exposure
		Golimumab
			Efficacy of Golimumab in Pediatric Patients
			Efficacy of Golimumab in Adult Patients
	Additional Clinical Endpoints
		Growth and Bone Health
		Quality of Life
		Postoperative Prophylaxis
	Optimizing the Use of Adalimumab, Certolizumab Pegol, and Golimumab
		Treat to Target
		Combination Therapy
		Therapeutic Drug Monitoring
		Comparative Effectiveness
	Safety Data
		Malignancy
		Infection
		Postoperative Infections
		Novel Viral Infections
		Immune Reactions (TNFα-Induced Psoriasis, Drug-Induced Lupus, Auto-Immune Hepatitis)
	Biosimilars
	Future Directions
	References
33: Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease
	Introduction
	Thiopurine Monitoring
	Anti-TNF Drug Concentrations
	Anti-TNF Drug Antibodies and Outcomes
	Immunomodulator Use with Anti-TNF Agents
	Proactive Dose Optimization
	Practical Use of TDM with Anti-TNF Agents
	TDM with Vedolizumab and Ustekinumab
		Vedolizumab
		Ustekinumab
	Conclusion
	References
34: New Non-anti-TNF-α Biological Therapies for the Treatment of Inflammatory Bowel Disease
	Introduction
	Cytokine Targets
		IL-12/IL-23
			Ustekinumab
			Pediatric Data
			Safety
			Briakinumab
		Selective IL23 Inhibition
			Brazikumab
			Pediatric Data
			Safety
			Risankizumab
			Pediatric Data
			Safety
			Mirikizumab
			Pediatric Data
			Safety
			Guselkumab
		IL-6
			Pediatric Data
			Safety
		IL-13
			Tralokinumab
			Pediatric Data
			Safety
			Dectrekumab
			Pediatric Data
			Bertilimumab
			Pediatric Data
		IL-17
			Vidofludimus
			Pediatric Data
			Safety
		IL-21
			ATR-107
			NNC0114-0006
			Pediatric Data
	Blockade of the Downstream Signaling Pathways Mediated by Cytokines
		JAK/STAT Pathway
			Tofacitinib
			Pediatric Data
			Safety
			Filgotinib
			Pediatric Data
			Safety
			Upadicitinib
			Pediatric Data
			Safety
			Peficitinib
			Pediatric Data
			Safety
			TD-1473
		TGF-β
			Mongersen
			Pediatric Data
			Safety
	Targeting Chemokines
		Anti CXCR3/CXCL10
		BMS936557 (MDX-1100, Eldelumab)
		Pediatric Data
		Safety
		Anti CCR9/CCL25
		Vercirnon (CCX282-B)
		Pediatric Data
		Safety Data
	Antiadhesion Molecules
		Natalizumab
		Pediatric Data
		Safety
		Vedolizumab (MLN-002, MLN-02, Entyvio®)
		Pediatric Data
		Safety
		Etrolizumab (rhuMAb β7)
		Pediatric Data
		Safety
		Ontamalimab
		Pediatric Data
		Safety
		AJM300
		Pediatric Data
		Safety
		Alicaforsen
		Pediatric Data
		Safety
		Abrilumab
		Pediatric Data
		Firategrast
		Pediatric Data
		TRK-170
		Pediatric Data
		GLPG0974
		Pediatric Data
	Administration of Anti-Inflammatory Cytokine
		Interleukin-10 (IL-10)
			Pediatric Data
			Safety
	Blockade of T Cell Stimulation and Induction of Apoptosis
		Laquinimod
			Pediatric Data
			Safety
			Cobitolimod (DIMS0150)
			Safety Data
			Pediatric Data
		Monarsen
		Pediatric Data
		Safety
	Sphingosine-1-Phosphate Receptor Modulators
		Etrasimod
			Pediatric Data
			Safety
		Ozanimod
			Pediatric Data
			Safety
	Oligonucloetides
		GATA3 DNAzyme
		STNM01
	Miscellaneous Agents
		Apremilast (CC-10004)
		RDP58 (Delmitide Acetate)
		LT02
		LYC-30937-EC
		TOP-1288
		GSK2982772
		Rosiglitazone
		VB-201
	Summary
	References
35: Medical Treatment of Perianal Crohn Disease
	Background
		Case
		Classification
		Pathogenesis
		Natural History
		Diagnosis
	Medical Therapy of Fistulas
		5-Aminosalicylic Acid Derivatives
		Corticosteroids
		Antibiotics
		Azathioprine/6-Mercaptopurine/Methotrexate
		Tacrolimus
		Cyclosporin A
		Infliximab
		Adalimumab and Certolizumab Pegol
		Other Anti-TNF-α Agents
		Vedolizumab
		Other Therapies
	Conclusions
	References
36: Treatment of Acute Severe Ulcerative Colitis
	Case
	Introduction
	Initial Management
	Monitoring Response to Corticosteroids
	Medical Rescue Therapy
	Surgery
	Future Directions/Conclusions
	References
37: Dietary Therapies for Inflammatory Bowel Disease
	Introduction
	Diet and Worldwide Trends in IBD
	Diet and the Gut Microbiota
	Dietary Components and IBD
	Macronutrients
		Fat
		Carbohydrates
	Micronutrients and Trace Minerals
	Food Additives
	Oral Supplements
		Curcumin
		Iron
		Probiotics
	Structured Diets
		Exclusive Enteral Nutrition
		Partial Enteral Nutrition
		Parenteral Nutrition
		Exclusion Diets
			CD-TREAT: Crohn Disease Treatment-with-EATing
			Specific Carbohydrate Diet
			IBD Anti-inflammatory Diet
			Crohn Disease Exclusion Diet
			Semi-Vegetarian Diet
			Low-FODMAP Diet
			Gluten-Free Diet
			The Paleolithic Diet
	Conclusion
	References
38: Integrative Health Therapies for Pediatric IBD
	Introduction
	Integrative Health Use in IBD
	Biologically Based Therapies for the Treatment of IBD
	Herbal Therapies
		Aloe Vera
		Triticum aestivium
		Andrographis paniculata
		Jian Pi Ling
		Oenothera biennis
		Curcumin
		Boswellia
		Artemisia absinthium
		Tripterygium wilfordii Hook F (TWHF)
		Belladonna
		Cannabis
		Indigo naturalis
	Non-herbal Therapies
		Fatty Acids
			Fish Oil (Omega-3 FFA)
			Blond psyllium
			N-Acetyl Glucosamine (NAG)
			Chitosan
			Bromelain
			Rutin
	Rectal Enema Therapies
		Kui Jie Qing (KJQ)
		Xilei-San
		Bovine Colostrum
		Dietary Therapy and Probiotics
	Mind Body Therapies for Pediatric IBD
		Yoga
		Mindfulness and Meditation
		Acupuncture and Moxibustion
		Exercise and Sleep
	Conclusion
	References
Part V: Surgical Therapy
39: Management of Intraabdominal Complications of Inflammatory Bowel Disease
	Introduction
	Intraabdominal and Pelvic Abscess
		Pathogenesis
		Evaluation
		Treatment
	Antimicrobial Therapy
	Percutaneous Interventional Drainage
	Surgical Intervention
	Percutaneous Versus Surgical Drainage
		Treatment of Phlegmon (Inflammatory Mass)
		Crohn Disease-Specific Therapy
		Nutritional Considerations
	Summary
	Other Complications from Internal Penetrating CD
		Perforation
		Small Bowel Obstruction
	Toxic Megacolon
	References
40: Surgical Management of Crohn Disease in Children
	Introduction
	History of Surgical Therapy
	Prognostic Indicators and Operative Indications
	Surgical Emergencies
	Elective Surgery
	Surgical Therapy
	Small Intestinal or Ileo-colonic Disease
	Stricturoplasty
	Laparoscopy
	Colonic Disease
	Perianal Disease
	Rectal Strictures
	Impact of Medical Therapy
	Post-operative Recurrence
		Early Recurrence Predictors
	Adjuvant Procedures
	References
41: Surgical Treatment of Ulcerative Colitis
	Indications for Surgical Intervention
	Surgical Procedures
	Surgical Decision Making
	Preparation for Surgery
	Outcomes of Surgery
	Functional Results
	Complications
	Pouchitis
	Carcinoma
	Current Trends and Future Considerations
	Summary
	References
42: Postoperative Surveillance and Management of Crohn Disease
	Risk and Diagnosis of Postoperative Crohn Disease
	Risk Factors for Postoperative Recurrence
	Risk Stratification for Postoperative Recurrence
	Nonbiologic Treatment Options for Preventing Postoperative Crohn Disease
	Anti-TNFs for Prevention of Postoperative Crohn Disease
	Safety of Postoperative Anti-TNFs
	Enteral Nutrition for Postoperative Crohn Disease
	Treating Postoperative Crohn Disease: Waiting for Endoscopic Recurrence
	Strategies for Postoperative Crohn Disease Management
	Conclusions
	References
43: Perioperative Immunosuppression in Inflammatory Bowel Disease
	Introduction
	Effects of Immunosuppression on Operative Outcomes in Pediatric Populations
		Glucocorticoids
		Immunomodulators
		Monoclonal Antibodies
	Clinical Recommendations
	Conclusion
	References
44: Pouchitis and Pouch-Related Complications
	Introduction
		Pouch Anatomy
		Pouch Function
	Pouchitis
		Definition and Incidence
	Etiology and Pathogenesis
		Fecal Stasis and Dysbiosis
		Immune Dysregulation
		Mucosal Ischemia
		Crohn Disease of the Pouch
		Extraintestinal Manifestations
		Cuffitis
		Smoking
	Diagnosis
	Classification
	Treatment
		Prophylaxis
		Acute Pouchitis
		Chronic Pouchitis
		Surgical
	Outcome
	Noninflammatory Pouch-Related Complications
		Irritable Pouch Syndrome
		Floppy Pouch Complex
		Fertility
	Summary
	References
45: Enteral Feeding Devices and Ostomies
	Gastrostomy
	Complications of Gastrostomy/Gastrojejunostomy Tubes
		Infection
		Tube Migration and Dislodgement
		Leakage, Stomal Erosion, and Peristomal Skin Breakdown
		Hypergranulation Tissue
		Tube Obstruction
		Fistula Formation
	Ostomy Education and Management
	References
Part VI: Research
46: Clinical Indices for Pediatric Inflammatory Bowel Disease Research
	Introduction
	Assessment of Instruments Used in Clinical Research
	Outcomes in Pediatric Inflammatory Bowel Disease
		Crohn Disease Activity Indices
		Perianal Crohn Disease
		Ulcerative Colitis Disease Activity Indices
		Patient-Reported Outcomes
	Gastrointestinal Endoscopy Indices
		Crohn Disease
	Ulcerative Colitis Endoscopic Assessment
	Quality of Life, Disability, and Other Related Instruments
	Radiographic Indices
	Summary of Clinical Outcome Measures
	Appendix 1
		Appendix 1.1: Pediatric Crohn Disease Activity Index [19] History (Recall, 1 week)
		Appendix 1.2: Weighted Pediatric Crohn Disease Activity Index (wPCDAI) [68] History (Recall, 1 week)
		Appendix 1.3: The MINI Index
	Appendix 2
		Appendix 2.1: Perianal Crohn Disease Activity Index [43]
		Appendix 2.2: Fistula Drainage Assessment [44]
		Appendix 2.3
	Appendix 3
		Appendix 3.1: Ulcerative Colitis Disease Activity Indices (Adult)
		Appendix 3.2: Pediatric Ulcerative Colitis Activity Index
	Appendix 4
		Appendix 4.1: Crohn Disease Endoscopic Index of Severity [93]
		Appendix 4.2: Simple Endoscopic Score for Crohn Disease [97]
		Appendix 4.3: Rutgeerts Score for Postoperative Endoscopic Disease Recurrence [101]
		Appendix 4.4: Ulcerative Colitis Endoscopic Index of Severity (UCEIS) [65]
		Appendix 4.5: Lewis Score [103]
	References
47: Clinical Trials (Clinical Perspective)
	Introduction
	Summary
	References
48: Global Regulatory Industry Perspective of Clinical Trials
	Key Stakeholders in Drug Development Process
	Regulatory Agencies
	Industry Sponsors
	Academic Researchers
	Investigators
	Regulations Guiding Pediatric Drug Development
	Sulfanilamide Tragedy 1937 and the Food, Drug, and Cosmetic Act of 1938
	Thalidomide Tragedy 1957–1961, the Kefauver–Harris Amendments of 1962, and the European Directive 65/65/EEC
	Orphan Drug Regulations
	Pediatric Drug Regulations (US)
	Pediatric Drug Regulations (EU)
	Pediatric Drug Regulations (Rest of World)
	Overview of Clinical Trials
		Phase I Clinical Trials
		Phase II Clinical Trials
		Phase III Clinical Trials
		Phase IV Clinical Trials
	Key Concepts in Clinical Trial Conduct
	Institutional Review Board (IRB)
	Informed Consent
	Pediatric Considerations
	Adverse Event Reporting
	Data Monitoring Committee
	Highlights of the Regulatory Review Process
	Regulatory Safeguards for Pediatric Patients Involved in Clinical Trials
	Criteria for IRB Approval of Pediatric Research
	Pediatric Extrapolation
	Pediatric-Specific Issues in IBD Trials
	References
Part VII: Special Considerations
49: Infectious Complications of Pediatric Inflammatory Bowel Disease
	Introduction
	Antibiotic Use for Treatment of IBD
	Infections Associated with Underlying IBD
		Clostridium difficile
		Cytomegalovirus
		Coronavirus 2019 (COVID-19)
	Increased Risk of Infections Secondary to Therapies
		Purine Analogues
		Corticosteroids
		Tumor Necrosis Factor Antagonists
	Conclusion
	References
50: Psychological Aspects of Inflammatory Bowel Disease in Children and Adolescents
	Introduction
	Health-Related Quality of Life
	Pain and Symptom Management
	Social Functioning and Peer Relationships
	Academic Functioning
	Body Image
	Emotional Functioning
	Family Functioning
	Adherence and Self-Management
	Self-Efficacy and Disease Knowledge
	Health Behaviors
	Psychotherapy and Other Resources
	Summary
	References
51: Measurement of Quality of Life in Pediatric Inflammatory Bowel Disease
	Introduction
	Quality of Life: Concepts/Definitions
	Why Measure Health-Related Quality of Life?
	Approaches to Health-Related Quality-of-Life Measurement
	Health-Related Quality-of-Life Assessment in Pediatrics
	Health-Related Quality-of-Life Assessment in Inflammatory Bowel Disease: Adult IBD Perspective
	Health-Related Quality-of-Life Assessment in Pediatric Inflammatory Bowel Disease
	IMPACT
		The Development of the Impact Questionnaire
		Description of the Instrument (IMPACT-III)
	Practical Issues for Use of IMPACT
		Administration and Instructions to Respondents
		Scoring
	Deficiencies in Current Knowledge and Areas for Future Research
		Identifying the Factors which Influence HRQOL
		Comparisons of HRQOL Between Patients with IBD, Patients with Other Chronic Pediatric Illnesses, and Healthy Peers
		Assessing Disease-Specific HRQOL in Pediatric IBD Patients Not Captured by IMPACT Questionnaire
		The Impact of Family on the Assessment of HRQOL in Pediatric IBD Patients
		Cross-Cultural Comparisons of HRQOL in Pediatric IBD
	References
52: Irritable Bowel Syndrome and Functional GI Disorders in Inflammatory Bowel Disease
	Epidemiology
	Clinical Features
	Pathophysiology
	Low-Grade Inflammation
	Gut Microbiota
	Altered Motility
	Biochemical Changes
	Genetics
	Psychological Factors
	Visceral Hypersensitivity and IBD
	Diagnosis
	Treatment
	“Irritable” Pouch Syndrome
	Summary
	References
53: Inflammatory Bowel Disease in Pregnancy
	Introduction
	Contraception
	Fertility
	Effect of IBD on Pregnancy
	Effect of Pregnancy on IBD
	Management of IBD During Pregnancy
		Clinical Assessment
		Medical Therapies
			Antidiarrheals
			Aminosalicylates
			Antibiotics
			Corticosteroids
			Immunosuppressants
				Immunomodulators
				Biologic Agents
				Anti-tumor Necrosis Factors (TNFs)
				Anti-integrins
				Interleukins 12 and 23
				Small Molecules (Janus Kinase Inhibitor)
		Breastfeeding
	Mode of Delivery
	Surgery and Pregnancy
	Transition of Care
	References
54: Pediatric Inflammatory Bowel Disease Care in Low- and Middle-Income Countries
	Introduction
	Diagnostic Evaluation
		Clinical Evaluation and PIBD Activity Indices
		Serological Tests
		Microbiological Investigations
		Fecal Calprotectin
	Imaging
	Endoscopic Evaluation
	Histopathology
	Pharmacological Therapy
	Nutritional Therapy
	Surgery
	Conclusion
	References
55: Immunizations in the Child with Inflammatory Bowel Disease
	Introduction
	Underimmunization
	Who and When to Immunize?
	Inactivated Vaccines in Children with IBD
	Immunizing the Child with IBD: Practical Aspects
	COVID-19 Infection and Vaccine Development: Relevance to Inflammatory Bowel Disease
	Summary
	References
56: Colitis-Associated Cancers
	Clinical Presentation of Colitis-Associated Cancers
	Pathogenesis and Genomic Alterations in Colitis-Associated Bowel Cancers
		Spectrum of Genomic Alterations in Colitis-Associated Cancer
	Epidemiology and Incidence
	Conditions Increasing the Risk of Colitis-Associated Cancers
	Duration of Colitis
	Age of Onset of Inflammatory Bowel Disease
	Anatomic Extent of Colitis
	Histologic Inflammation
	Primary Sclerosing Cholangitis
	Family History of Colorectal Cancer
	Prevention of Colitis-Associated Cancers
		Pharmacotherapy and Chemoprevention
		Sulfasalazine/5-Aminosalicylates
		Thiopurines
		Biologics/Small Molecule Agents
		Folic Acid
		Ursodeoxycholic Acid
	Screening, Surveillance, and Risk-Reducing Surgery
		Screening and Surveillance
		Endoscopic Detection
		Endoscopic Resection
		Risk-Reducing Surgery
		Biomarkers
	Systemic Therapy for Advanced Colitis-Associated Cancers
		Small-Bowel Adenocarcinoma in Crohn Disease Patients
	Other Malignancies
	Summary
	References
57: Quality Improvement in Inflammatory Bowel Disease
	Introduction
	Variation in Care
	The Chronic Illness Care Model
	The Need for Quality Improvement in IBD
	The Improvement Model
	Improvement Collaborative
	The ImproveCareNow Network
	Learning Health Network
	Maintaining Improvement
	Improvement Science in the Business of Health Care
	Conclusion
	References
58: Fostering Self-Management and Patient Activation
	Introduction
	Defining Self-Management
		Self-Management Tasks
		Self-Management Skills
	Self-Management for Kids
	Does Self-Management Really Matter?
	How to Cultivate Self-Management
	Parent and Patient Activation
	Co-production
		Pill Cases
		Shot Anxiety
			Spanish Language Educational Videos
	The Need for Reliable Education
	Conclusions
	References
59: Advocacy for Pediatric Patients with IBD
	Introduction
	Advocacy Directed at Schools
	Advocacy Directed at Insurance Companies
		Obtaining Health Insurance and the Options Your Patients Have
		Navigating Insurance Company Denials and Prior Authorizations
	Social Security Disability Benefits
	Family and Medical Leave for Caregivers
	Summary
	Appendix 1
	References
60: Advocacy for Pediatric Patients with Inflammatory Bowel Disease
	Introduction
	Advocacy Directed at Schools
		COVID-19 Considerations
	Advocacy Directed at Insurance Companies
	Social Security Disability
	Family and Medical Leave for Caregivers
	Restroom Access Act
	Summary
	Appendix 1: Sample Letter for Patient’s Student File Regarding Educational Accommodations Needed for an IBD Diagnosis
	Appendix 2: Preparing an Effective Insurance Company Letter of Medical Necessity
	Appendix 3: Letter of Medical Necessity for Ustekinumab
	Appendix 4: Sample Letter to Support Maintenance of Infusion at Infusion Center
	Appendix 5: Sample Letter for Appeal of Denial of Mental Health Benefits
	Appendix 6: Social Security Listing of Impairments for Children with IBD
	Appendix 7: Preparing an Effective Letter for Family Medical Leave Act provisions
61: Transition from Pediatric to Adult Care
	Introduction
	Background
	Challenges and Barriers to Transition for Adolescent IBD Patients
	Transition Steps
	Overview of the Transition Process
		Patients (Age 12–14)
			Skill Set 1
			Skill Set 2
		Parents/Family (Age 12–14)
		Pediatric Team (Age 12–14)
	Focus on Independence
		Patients (Age 14–17)
			Skill Set 3
			Skill Set 4
		Parents (Age 14–17)
		Pediatric Team (Age 14–17)
	Self-Management: Health and Lifestyles
		Patients (Age 17–18)
			Skill Set 5
			Skill Set 6
		Parents (Age 17–18)
		Pediatric Team (Age 17–18)
		Adult Team (Age 18+)
	Monitoring the Process
	Conclusion
	References
Index