IBD Book

Introduction

Inflammatory bowel disease (IBD) is an immune mediated disorder that affects the intestine and has extra intestinal manifestations as well. The first description of ulcerative colitis was in 18591. Cases resembling Crohn’s disease have been described since 1612 but the classical publication describing Crohn’s disease was in 1913 [1]. Management of patients with IBD has remarkably advanced from initial use of steroid, Sulfasalazine, and Azathioprine till the complete shift after the approval of first Anti-Tumor Necrosis Factor (TNF) (Infliximab) by the United States Food and Drug Authority (FDA) in 1998 [2]. Since then, there have been numerous medications targeting various pathways have been introduced to market.

IBD encompasses Crohn’s disease, ulcerative colitis and indeterminant colitis. Ulcerative colitis is confined to the colon and might involve the most distal part of the small bowel (Backwash ileitis), while Crohn’s disease can involve any part of the gastrointestal tract. In a small proportion of IBD patients (5 to 15%) it is not clear whether the patient has Crohn’s disease or ulcerative colitis and with time the disease might declare itself [3]. Also, the disease is characterized by periods of flares and remissions and there is an accelerative amount of bowel damage that happens with each flare of attack.

In Saudi Arabia one of the first publications describing IBD was in 1998 [4] and since then multiple studies have described the phenotypic characteristics and disease behavior and response to therapies in the Saudi population and more recently numerous national guidelines have been published that details the management of IBD in general [5] and special populations as well [6,7].

Multiple elements have been proposed as a cause for the development of IBD and these include factors like genetics, environmental exposures either early in life (breastfeeding and antibiotic exposure) or latter (medications, stress, smoking, infections) [8] (Figure 1). It is this interplay between genetics, environment and microbiome that cause the disease and is evident by the increasing incidence in areas where the disease was not prevalent in the past as well as the development of IBD in immigrant populations and with the industrialization of societies.

Also, the direct (medical) and indirect (societal) costs associated with the disease or not insignificant and with the increased therapeutic options have become an area of active research to achieve the best possible outcome with a reasonable amount of healthcare resources [9].

Chapter 1: Epidemiology and disease burden

Improved diagnostics, therapeutics, and updated management targets have improved patients’ survival and quality of life. In addition to this, due to decreased mortality and the ageing of populations this has contributed to the increased prevalence of the disease [10].

The prevalence of IBD has increased over the years mostly in industrialized countries and is most prevalent in North America and Europe and is least prevalent in Sub-Saharan Africa (Figure 2). Although IBD is not very prevalent, it remains a cause of significant morbidity or mortality in a younger population, effects their quality of life, is associated with an increase in the sum of the years of life lost (YLL) to due to premature mortality, in years lived with a disability (YLD) as well as an increase in disability-adjusted life years (DALYs)[11] (Figure 3).

As expected, due to the higher prevalence of IBD in North America and Europe, these areas have the highest burden related to disease associated life years (Figures 4 A & B), but in terms of years of life lost areas with a low sociodemographic index (SDI) like the geographical area of Sub-Saharan Africa are disproportionally affected. This might reflect limited access to care and diagnostic and therapeutic interventions.

The disease effects both males and females in almost identical proportions [12,13]. Also, the age distribution that both diseases effect is almost similar with a tendency for UC to effect those above the age of 40 years more frequently then Crohn’s disease.

The disease distribution for both diseases and the behavior of Crohn’s disease and severity of ulcerative colitis vary (Chapter 3).

There is also a risk of developing Crohn’s disease or ulcerative colitis base on the family history of IBD [14] is shown in table 1 as well as figures 5 A & B. Also, the relative risks associated with developing both Crohn’s disease or ulcerative colitis from some environmental exposures [15] is shown as a heatmap in Figure 6.

Figure 1. Various factors that have been associated with inflammatory bowel disorder. (Adapted from Ananthakrishnan A.N.[8])

Figure 2. Prevalence per 100,000 population of inflammatory bowel disease by geographic region (adapted from Piovani D. et al.[11]).

Figure 3. The burden of IBD on populations in terms of Disease Associated Life Years (DALYs), Years Lived with a Disability (YLD), and Years of Life Lost (YLL) by geographic region (adapted from Piovani D. et al.[11]).

Figure 4 A. Disease Associated Life Years (DALYs) associated with inflammatory bowel disease by geographic region (adapted from Piovani D. et al.[11]).

Figure 4 B. Years lived with a disability from inflammatory bowel disease by geographic region (adapted from Piovani D. et al.11). (adapted from Piovani D. et al.[11]).

Figure 4 C. Years of life lost to due to premature mortality (YLLs) from inflammatory bowel disease by geographic region (adapted from Piovani D. et al.[11]).

Table 1. The 10-year risk of developing Crohn’s disease or ulcerative colitis based on the family history and the current age of the individual (Adapted from Moller FT et al.[14]).

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Figure 5 A. Heat map of the 10-year risk of developing Crohn’s disease based on the family history and the current age of the individual (Adapted from Moller FT et al.[14]).

Figure 5 B. Heat map of the 10-year risk of developing ulcerative colitis based on the family history and the current age of the individual (Adapted from Moller FT et al.[14]).

Figure 6. Heatmap of the relative risk of developing ulcerative colitis or Crohn’s disease based on environmental factors (Adapted from Piovani D et al.[15]).

References

1. Kirsner JB. Historical origins of current IBD concepts. World J Gastroenterol. Apr 2001;7(2):175-84. doi:10.3748/wjg.v7.i2.175
2. Melsheimer R, Geldhof A, Apaolaza I, Schaible T. Remicade((R)) (infliximab): 20 years of contributions to science and medicine. Biologics. 2019;13:139-178. doi:10.2147/BTT.S207246
3. Venkateswaran N, Weismiller S, Clarke K. Indeterminate Colitis - Update on Treatment Options. J Inflamm Res. 2021;14:6383-6395. doi:10.2147/JIR.S268262
4. Isbister WH, Hubler M. Inflammatory bowel disease in Saudi Arabia: presentation and initial management. J Gastroenterol Hepatol. Nov 1998;13(11):1119-24. doi:10.1111/j.1440-1746.1998.tb00587.x
5. Mosli MH, Almudaiheem HY, AlAmeel T, et al. Saudi Arabia consensus guidance for the diagnosis and management of adults with inflammatory bowel disease. Saudi J Gastroenterol. Nov 21 2022;29(Suppl 1):S1-S35. doi:10.4103/sjg.sjg_277_22
6. Azzam NA, Almutairdi A, Almudaiheem HY, et al. Saudi consensus guidance for the management of inflammatory bowel disease during pregnancy. Saudi J Gastroenterol. Dec 15 2023;30(4):181-97. doi:10.4103/sjg.sjg_318_23
7. Saadah OI, AlAmeel T, Al Sarkhy A, et al. Saudi consensus guidance for the diagnosis and management of inflammatory bowel disease in children and adolescents. Saudi J Gastroenterol. Aug 30 2024;doi:10.4103/sjg.sjg_171_24
8. Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. Apr 2015;12(4):205-17. doi:10.1038/nrgastro.2015.34
9. AlRuthia Y, Alharbi O, Aljebreen AM, et al. Drug utilization and cost associated with inflammatory bowel disease management in Saudi Arabia. Cost Eff Resour Alloc. 2019;17:25. doi:10.1186/s12962-019-0194-3
10. Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. Jan 2021;18(1):56-66. doi:10.1038/s41575-020-00360-x
11. Piovani D, Danese S, Peyrin-Biroulet L, Bonovas S. Inflammatory bowel disease: estimates from the global burden of disease 2017 study. Aliment Pharmacol Ther. Jan 2020;51(2):261-270. doi:10.1111/apt.15542
12. Aljebreen AM, Alharbi OR, Azzam NA, Almalki AS, Alswat KA, Almadi MA. Clinical epidemiology and phenotypic characteristics of Crohn’s disease in the central region of Saudi Arabia. Saudi J Gastroenterol. May-Jun 2014;20(3):162-9. doi:10.4103/1319-3767.132993
13. Alharbi OR, Azzam NA, Almalki AS, et al. Clinical epidemiology of ulcerative colitis in Arabs based on the Montreal classification. World J Gastroenterol. Dec 14 2014;20(46):17525-31. doi:10.3748/wjg.v20.i46.17525
14. Moller FT, Andersen V, Wohlfahrt J, Jess T. Familial risk of inflammatory bowel disease: a population-based cohort study 1977-2011. Am J Gastroenterol. Apr 2015;110(4):564-71. doi:10.1038/ajg.2015.50
15. Piovani D, Danese S, Peyrin-Biroulet L, Nikolopoulos GK, Lytras T, Bonovas S. Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses. Gastroenterology. Sep 2019;157(3):647-659 e4. doi:10.1053/j.gastro.2019.04.016

Chapter 2: Etiology and pathogenesis

Inflammatory bowel disease (IBD) etiology may involve the host immune system dysregulation, genetic predisposition, gut microbiota dysbiosis, and environmental triggers [1].

The intestinal mucosa consists of epithelial cells, goblet cells, Paneth cells, stroma, and immune cells. The intestinal epithelium includes epithelial cells closely bound by tight junctions. The intestine is structured with a villi and invaginations called crypts of Lieberkühn. The goblet and Paneth cells produce mucus and antimicrobial peptides respectively, thus limiting the spread of luminal microorganisms [2].

A loss of mucus layer thickness by marked reduction in goblet cell numbers has been linked to Crohn’s disease [3], and abnormal mucus composition has been reported in UC [4]. The lamina propria, contains stromal cells, including fibroblasts, myofibroblasts, and perivascular pericytes which serve the function of fibrosis and wound healing [2], and may be related to the aggravation of UC through their capacity to produce chemokines, including chemokine (C-C motif) ligand (CCL)19, CCL21, and the immune-system regulator interleukin (IL)-33 [5]. Plasma cells release immunoglobulin (Ig)A that inhibit the infiltration of pathogenic microorganisms and help in sustaining a homeostatic equilibrium between the host and commensal microbiota.

Both the epithelium and other non-immune intestinal components are important mediators of intestinal homeostasis and IBD pathophysiology, [6,7]. Some of the functions of these non-immune cells are mediated through interaction with components of the immune system.

Immune system dysregulation

The mucosal immune system is the most extensive part of the immune system. intestinal immune cells are involved in a highly balanced immune response aimed at controlling pathogen invasion, while stopping an excessive immune responses against innocuous food antigens and commensal microbes that could risk unintentional tissue injury (Figure 1).

The immune system confers host defense against pathogens and provides anti-tumor protection. At the same time, regulatory mechanisms counterbalance these responses to prevent reactions against self and innocuous external antigens, thus promoting a state of tolerance.

The immune system can be classified into innate and adaptive immunity. Innate immunity that is composed of myeloid cells, initiates rapid responses to conserved structural motifs on microorganisms. Innate immune cells (IIC) express pattern recognition receptors (PRRs), such as toll-like receptors (TLRs) and Nod-like receptors (NLR), allowing them to distinguish pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).

IIC provide host defense and inflammation by generating cytokines and chemokines, triggering the complement cascade and phagocytosis, or stimulating adaptive immunity by presenting antigens. IIC include neutrophils, monocytes, macrophages, and dendritic cells (DCs) [8,9].

Figure 1 damage to the intestinal barrier triggers the recruitment of neutrophils from the circulation to the inflamed tissue along a chemotactic gradient formed by cytokines (IL-1β, IL-6, TNF-α), chemokines (CCL8, CXCL10, MIP-2), and growth factors (GM-CSF, G-CSF). Neutrophil recruitment is also mediated by bacteria-derived molecules such as formyl-methionyl-leucyl- phenylalanine (fMLP) and short-chain fatty acids (SCFAs). The recruited neutrophils participate in the elimination of microorganisms through phagocytosis, degranulation, reactive oxygen species (ROS) generation, and the release of neutrophil extracellular traps (NETs). Once their functions are completed, neutrophils undergo apoptosis and efferocytosis, facilitating the resolution of inflammation, tissue repair, and a return to normal tissue homeostasis. The participation of neutrophils and NETs in IBD is a double-edged sword.

Some intestinal cell populations can adjust their functions to the needs of the intestinal microenvironment under steady state. This adaptation can be harmful in IBD, but is also a potential therapeutic target for the treatment of the disease.

Neutrophils are the most numerous immune cells in the human circulation and are quickly recruited to sites of infection or inflammation [10]. It plays a role in intestinal homeostasis and inflammation, playing an essential role in gut defense but also being an important mediator of tissue damage in the inflamed mucosa upon excessive recruitment. Several studies demonstrate the effect of neutrophils on other components of the intestinal mucosa in IBD, such as other immune cells and epithelial cells and other non-immune cells [11].

Intestinal macrophages, which restrain their robust proinflammatory potential through a natural resistance to producing inflammatory mediators in response to pattern-recognition molecules, while also retaining several of their homeostatic abilities, including phagocytosing bacteria, preserving Tregs and maintaining tolerance, and promoting epithelial cell renewal [12]. In the intestinal microenvironment, macrophages adapt their functions to the context. For example, CX3CR1 high macrophages can distinguish harmful from commensal bacteria via TLR and NLR recognition. In the intestinal microenvironment, CX3CR1 high macrophages are excellent phagocytes, but produce low levels of pro-inflammatory cytokines and maintain tolerance through the production of anti-inflammatory cytokines such as IL-10 [13]. CX3CR1 high intestinal macrophages sense and take up bacterial antigen from the intestinal lumen via their transepithelial dendrites [14-19]. In homeostasis, the intestinal microbiota inhibits the migration of antigen-loaded CX3CR1 high intestinal macrophages to mesenteric lymph nodes, thereby also inhibiting antigen presentation to T cells, and effectively sustaining tolerance towards commensal bacteria.

The etiology of IBD remains unknown, but IBD appears to be sustained in genetically susceptible individuals by an impaired immune response against intestinal microorganisms. This abnormal immune response is associated with dysregulation of both innate and adaptive immune responses.

IBD is characterized by penetration of the epithelial barrier of the intestine, and non-resolving mucosal damage is a major component of the disease [20]. While generally unknown, the cause of this damage could be related to an infectious agent [21], a chemical compound [1], or a metabolic alteration probably related to diet-mediated dysbiosis [22]. Unsuccessful resolution of inflammation is supported by disruption of tolerance towards commensal microorganisms or autologous signals of tissue damage [23].

Genetic predisposition

Comparison of first-degree relatives of IBD patients with the general population reveals a heritable risk of CD and UC [23-24]. Genome wide association studies (GWAS) have identified more than 240 risk variants associated with IBD. These variants are found in genes related to bacteria recognition (e.g., NOD2), autophagy (e.g., ATG16L1 and IRGM), regulation of epithelial barrier (e.g., ECM1), and innate and adaptive immunity (e.g., IL-23R, IL-10, ITGAL, and ICAM1 variants) [25,26]. Based on that, it has been possible to uncover fundamental molecular features underlying the disease and to identify genes and signaling pathways that represent potential therapeutic targets or biomarkers. However, only a small percentage of the disease variance in CD and UC can be linked to recognized IBD risk loci [27].

To resolve this limitation, new techniques have allowed the study of single-cell-specific transcriptional profiles. For example, single-cell RNA sequencing (scRNA-seq) and high-dimensional protein analyses, such as mass cytometry and multichannel spectral cytometry, have defined IBD-linked profiles and detected cell sub-populations that are elevated or diminished in IBD, particularly populations of fibroblasts [5], epithelial cells [4], and immune cells [28-31].

A complementary approach to GWAS is through transcriptome wide association studies (TWAS), which associate gene expression with genetic susceptibility to disease, providing functional insight into risk loci [32]. TWAS findings have provided understanding of tissue-specific molecular events underlying genetic susceptibility to IBD. Associated genes are potential targets for new treatments and could be prioritized in functional studies.

Intestinal microbial dysbiosis

The gut microbiota is an important physical, chemical, and immunological interface between the environment and host; thus, any dysregulation or breakdown of this barrier can contribute to disease states (Figure 2). For example, altered physical epithelial barrier function, a thinner mucus layer, and altered responses to endoplasmic reticulum stress (via mutations in MUC19, ITLN1, FUT2, and XBP1) have all been identified as risk factors for IBD [33-35].

Currently, the pathogenesis of human IBD is believed to involve inappropriate activation of the immune system when genetically susceptible individuals are exposed to gut antigens, such as microbiome components [36]. Although alterations in the gut microbiome have been proposed to be critical in IBD pathogenesis, it is not yet clear how this process occurs and whether dysbiosis is a central cause or a common consequence of the disease [37].

In healthy individuals, 99% of gut bacterial are Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Firmicutes and Bacteroidetes account for approximately 90% of the total microbiome composition. These phyla are critically important in maintaining gut homeostasis and produce short-chain fatty acids (SCFAs), especially butyrate and propionate, from the fermentation of dietary components such as indigestible fibers. SCFAs are important energy sources for colonic mucosa cells but have also been shown to play key roles in regulating immune homeostasis [38].

Dysbiosis is defined as an alteration in gut microbiota composition and diversity and a shift in the balance between commensal and potentially pathogenic microorganisms [39]. Several pieces of evidence support the role of the microbiome and dysbiosis in IBD development. For example, experimental mice subjected to germ free conditions develop attenuated colitis [40]. In studies using mouse models, the transfer of bacterial strains associated with IBD induces intestinal inflammation in genetically susceptible mice [41]. Similarly, fecal transplantation from human IBD donors to germ-free mice stimulates proinflammatory responses, with increased Th17 cell infiltration and proinflammatory mediators compared with transplants from healthy human donors [42].

Extensive research focuses on determining the groups of microbes that are related to the development of intestinal inflammation. Patients with IBD tend to present several changes, not only in composition, but also in the diversity of their microbiome populations when compared to healthy individuals. Evidence shows that alterations in microbiome components can also be involved in different IBD phenotypes [43]. The IBD microbiota has been characterized by an increase in the Bacteroidetes and Proteobacteria and a decrease in Firmicutes compared to control individuals. Specifically, levels of Faecalibacterium prausnitzii, a highly metabolically active commensal bacterium, are reduced in individuals with IBD [44]. Patients with IBD have reduced microbiome diversity (mostly a decrease in the Firmicutes) and an increase in the presence of Proteobacteria, such as Enterobacteriaceae and Bilophila, and certain members of Bacteroidetes [45]. Dysbiosis can potentially lead to a reduction in key functions necessary for maintaining intestinal barrier integrity and gut homeostasis. Therefore, alterations in the immune response and proinflammatory activity could be due to a dysbiotic microenvironment.

Figure 2: The role of gut dysbiosis in the pathogenesis of IBD. Gut microbiota reflect an interaction of host genetics with dynamic exposure to innumerable stimuli from the exposome. Crosstalk amongst these factors results in long-standing consequences to the gut microbiota and epigenetic modifications in a multidirectional fashion, potentially affecting and epigenetic modifications in a multidirectional fashion, potentially affecting susceptibility to diseases. The prevalence of either regulatory (eubiosis) or inflammatory (dysbiosis) species within the gut microbial community determines the respective predominant immune response. Treg, regulatory response. Treg, regulatory T-cell; Breg, regulatory B-cell; ILC, innate lymphoid cell; IgA, T-cell; Breg, regulatory B-cell; ILC, innate lymphoid cell; IgA, immunoglobulin A; MØ, macrophage; immunoglobulin A; MØ, macrophage; TSLP, thymic stromal lymphopoietin. TSLP, thymic stromal lymphopoietin.

Environmental triggers

Epidemiologic data suggest a strong role of the environment [46-48]. Disease concordance in monozygotic twins approaches 50% at best, with many studies suggesting that the estimates may be lower. The risk of IBD in the immigrant population resembles that of country of residence rather than the country of origin [49].

Also, countries that have witnessed a rapidly changing environment and lifestyle have seen an increase in the incidence of IBD over the past few decades at a rate of change that outpaces what could be attributed solely to genetics [50]. Many environmental triggers for IBD include smoking, Vitamin D deficiency, medications including antibiotics, stress, diet, and air pollution.

Smoking remains the most widely studied and replicated environmental trigger for CD and UC. the first described protective association between UC and smoking was in 1982, subsequent studies confirmed the inverse effect of current smoking on the development of UC, lower rate of relapse, and reduced need for colectomy in current smokers [51-54]. However, cessation of smoking is associated with an increase in risk of UC within 2–5 years of cessation. On the other hand, smoking increases the risk of developing CD two-fold [55-56], increases risk of disease flares, need for steroids and is associated with a higher rate of post-operative disease recurrence [56-58]. Despite strong epidemiologic data, the mechanism how smoking impacts IBD remains unclear as does the reason for its protective effect in UC but deleterious impact on CD.

There has been increasing recognition of the immunologic role of vitamin D [59-61]. Many studies suggest that the role of vitamin D is fairly varied and associated with a diverse spectrum of diseases. A deficiency of vitamin D could be a consequence of IBD itself with reduced physical activity, sunlight exposure, malnutrition, inadequate dietary intake of vitamin D, or lower bioavailability, all contributing to the deficiency [62-64]. However, vitamin D deficiency is common even in newly diagnosed IBD patients suggesting that low vitamin D itself can contribute to increased risk of IBD [65].

Medications adverse effects like aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are well recognized. However, while their potential effect in triggering onset or relapse of IBD has been clinical suspected, limited high quality evidence is available to support this. Most studies where case-controls where confounding by indication is a possibility, identifying use of aspirin or NSAIDs to treat pre-diagnosis symptoms of CD and UC, and differentiating NSAID enteritis or colitis from true idiopathic IBD have been difficult to achieve. high dose, prolonged duration, and frequent use of NSAIDs was associated with an increased risk of CD and UC [66]. Antibiotics probably influence the risk of developing disease through their effect on the microbiome. Whether early life flora acquired during birth and infancy is critical, or whether an individual at risk for IBD remains susceptible to dynamic changes in flora associated with dietary patterns or other lifestyle factors [67].

Stress is thought to play a role in the pathogenesis of CD and UC, and to mediate disease flares [68-70]. Mood components of perceived stress including depression and anxiety may play a role in mediating or exacerbating disease related to stress [71]. A prospective study using the Nurses’ Health Study found that both recent and remote depressive symptoms were associated with increased risk of CD but not UC [72]. The effect of recent depressive symptoms within 4 years of diagnosis was more prominent than that of remote depression. There is limited high-quality data on whether interventions to treat depression or stress can modify its effect on disease.

One of the environmental triggers most commonly reported by patients, but yet one where there is a significant gap in data is diet [73-74]. A majority of prior studies have been limited by factors including retrospective ascertainment of diet, allowing for both recall bias as well as modifications in diet that may have occurred since the onset of disease symptoms, and the small number of incident cases limiting power. There are far fewer data examining the role of diet in triggering disease flare. In a survey of 244 IBD patients in France, over half the participants reported belief that diet played a role in disease relapse [75]. However, the spectrum of foods that patients reported excluding to prevent relapse was distributed among the different food groups, suggesting that there may not be uniform dietary triggers to relapses.

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33. Turpin, W.; Goethel, A.; Bedrani, L.; Croitoru Mdcm, K. Determinants of IBD Heritability: Genes, Bugs, and More. Inflamm. Bowel. Dis. 2018, 24, 1133–1148.
34. Kaser, A.; Lee, A.H.; Franke, A.; Glickman, J.N.; Zeissig, S.; Tilg, H.; Nieuwenhuis, E.E.; Higgins, D.E.; Schreiber, S.; Glimcher, L.H.; et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008, 134, 743–756.
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Chapter 3: Clinical presentation and classification

CD and UC share several clinical features and overlapping treatment strategies, yet each presents with distinct pathological and phenotypic characteristics. This section provides an overview of their classification, clinical presentation, and specific phenotypes, such as upper gastrointestinal and perianal CD.

Classification of Crohn’s disease

CD is classified using the Montreal classification system, which considers age at diagnosis, disease location, and behavior. This system helps improve diagnostic precision and guides individualized management strategies [1].

Age at diagnosis

• A1: ≤16 years
• A2: 17–40 years
• A3: >40 years

Location of disease

• L1: Terminal ileum
• L2: Colon
• L3: Ileocolon
• L4: Upper GI (may coexist with L1–L3)

Disease behavior

• B1: Non-stricturing, non-penetrating
• B2: Stricturing
• B3: Penetrating
• Perianal modifier (p)

Figure 1. The phenotype of Crohn’s disease in Saudi Arabia as per Montreal Classification for Age (A), Behaviour (B), and Location (L) (adapted from Aljebreen A. M. et al.[2]).

Clinical presentation of Crohn’s disease

Clinical evaluation has always been fundamental in diagnosing diseases, and this holds especially true in IBD. CD presents with a wide range of intestinal and extraintestinal symptoms, reflecting its complex and systemic nature. Understanding the phenotypic classification helps clinicians tailor treatment and improve patient outcomes. Early recognition of these features remains critical to effective long-term disease management.

Gastrointestinal symptoms

Abdominal pain and diarrhea

Abdominal pain, particularly in the lower right quadrant, is a common early symptom (80-85%). It may be accompanied by bloating, flatulence, and distension. Diarrhea is another hallmark symptom—often non-bloody (65%), but can be bloody depending on disease location. Visible blood in the stool is less frequent than in UC but not uncommon [3].

Oral manifestations

Recurrent aphthous ulcers (canker sores) may appear, though their direct association with CD remains debated, as they are also common in the general population. Other findings may include nodular swelling, a cobblestone appearance in the oral mucosa, granulomatous ulcers, or pyostomatitis vegetans. Medications used in CD, including sulfasalazine and corticosteroids, can lead to oral side effects such as lichenoid reactions. Oral fungal infections like candidiasis could develop due to immunosuppressive therapy. Anemia-related signs such as pallor, angular cheilitis, and glossitis could develope due to malabsorption.

Systemic Symptoms

Growth delay in children

Is a notable concern in pediatric CD. It may be the presenting sign, particularly during puberty, with up to 30% of affected children showing delayed growth.

Fever and weight loss

Fever, when present, usually indicates complications like abscesses. Weight loss is common, especially in adults, due to decreased food intake and malabsorption. Patients may avoid eating to reduce symptoms. Extensive small bowel involvement may impair absorption of key nutrients, exacerbating weight loss [4].

Extraintestinal manifestations

These include arthritis, erythema nodosum (tender red nodules) and pyoderma gangrenosum (ulcerative lesions), uveitis, and episcleritis. These will be covered in detail in Chapter 5.

Hepatobiliary

These include primary sclerosing cholangitis (less common in CD but can occur), especially in overlap cases with UC.

Distinct phenotypes of Crohn’s disease

Upper gastrointestinal CD

Including the stomach, duodenum, or esophagus is less common but clinically significant. Symptoms may include nausea, vomiting, epigastric pain, and dysphagia. Diagnostic evaluation often requires upper endoscopy, and treatment strategies may need to be adjusted to address the unique challenges of upper gastrointestinal disease.

Although isolated gastric involvement is rare (occurring in less than 0.07% of cases), upper gastrointestinal symptoms can be found in 13–16% of CD patients, usually following the onset of lower gastrointestinal symptoms. It commonly affects younger, non-smoking patients, and more frequently present with concomitant ileal involvement and a stenosing behavior [5].

Perianal Crohn’s Disease

Perianal involvement is among the most complex and debilitating manifestations of CD. Patients may present with pain, itching, or discharge due to fistulas, fissures, abscesses, or skin tags. Incontinence can also occur. Management often requires a multidisciplinary approach combining medical therapy and surgical interventions aimed at fistula healing and symptom control [6].

Classification of ulcerative colitis

UC is classified based on the anatomical extent of colonic involvement, which guides both clinical decision-making and therapeutic strategies

Age at diagnosis

• A1: ≤16 years
• A2: 17–40 years
• A3: >40 years

Disease extent

• E1 (Ulcerative Proctitis): Inflammation limited to the rectum
• E2 (Left-sided Colitis): Involvement distal to the splenic flexure (rectum, sigmoid, and descending colon)
• E3 (Extensive Colitis / Pancolitis): Inflammation extending proximal to the splenic flexure and potentially involving the entire colon

Disease severity

• S1: Clinical remission
• S2: Mild ulcerative colitis
• S3: Moderate ulcerative colitis
• S4: Severe ulcerative colitis

Figure 2. The phenotype of ulcerative colitis disease in Saudi Arabia as per Montreal Classification for Age (A), Extent (E), and Severity (S) (adapted from Alharbi O. et al.[7]).

Clinical presentation of ulcerative colitis

UC is a chronic inflammatory condition of the colon, characterized by continuous mucosal inflammation that begins in the rectum and extends proximally in a contiguous fashion. Unlike CD, UC is confined to the colon and does not exhibit skip lesions or transmural inflammation. The clinical presentation of UC depends on both the extent and severity of inflammation, influencing gastrointestinal as well as extraintestinal manifestations.

Chronic inflammation in UC may lead to long-term complications, including iron deficiency anemia and an increased risk of colorectal cancer. These risks emphasize the importance of routine surveillance colonoscopy and proactive disease management.

Gastrointestinal Manifestations

Diarrhea and rectal bleeding

The hallmark symptom of UC is diarrhea, often accompanied by visible blood, mucus, or pus in the stool. The frequency of bowel movements varies, ranging from mild to debilitating. Rectal bleeding is a dominant feature, present in approximately 90–95% of patients. The severity of bleeding is proportional to the extent of mucosal involvement, and in some cases, may lead to iron deficiency anemia [8].

Abdominal pain and cramping

Lower abdominal pain, typically cramping in nature, is common and often coincides with bowel movements.

Urgency and tenesmus

Patients frequently report urgency and tenesmus (the persistent sensation of needing to defecate despite an empty rectum).

Systemic manifestations

Fever and fatigue

During active disease flares, systemic inflammation may result in low-grade fever and persistent fatigue, significantly impacting quality of life.

Weight Loss

Ongoing diarrhea, anorexia, and the metabolic burden of inflammation contribute to weight loss and, in some cases, malnutrition—particularly in patients with extensive disease or frequent relapses [9].

Table 1. summary of the key important clinical and histological difference between Crohn’s disease and ulcerative colitis

library(knitr)
library(kableExtra)

# Data from the provided table
comparison_data <- data.frame(
  Feature = c("Location", "Distribution", "Depth of inflammation", "Rectal involvement", 
              "Ileal involvement", "Perianal Disease", "Fistulas and abscesses", "Strictures", 
              "Bleeding", "Diarrhea", "Abdominal Pain", "Weight Loss/Malnutrition", "Surgery Recurrence"),
  `Crohns Disease` = c("Any part of the gastrointestinal tract (mouth to anus)", "Patchy, skip lesions", 
                            "Transmural", "Often spared", "Common", 
                            "Common (fistula, abscess)", "Common", "Common", "Less common, mild", 
                            "Often non-bloody", "Common", 
                            "Common", "High recurrence post-resection"),
  `Ulcerative Colitis` = c("Colon and rectum only", "Continuous from rectum proximally", 
                               "Mucosal and submucosal only", "Almost always involved", "Occasional 15% (backwash ileitis) not more than 10 cms", 
                               "Rare", "Rare", "Rare", "Common, may be severe", "Typically bloody diarrhea", 
                               "Cramps with urgency", "Less common", 
                               "Low after ileal pouch-anal anastomosis ")
)

kable(comparison_data, align = 'c') %>%
  kable_styling(bootstrap_options = c("striped", "hover", "condensed"), 
                full_width = FALSE, font_size = 12, position = "center") %>%
  column_spec(1, bold = TRUE, background = "#f2f2f2", color = "#333333") %>%
  row_spec(0, background = "#d3d3d3", color = "#000000", bold = TRUE) %>%
  row_spec(1:nrow(comparison_data), extra_css = "border-bottom: 1px solid #dddddd;") %>%
  scroll_box(width = "100%", height = "auto")

Feature	Crohns.Disease	Ulcerative.Colitis
Location	Any part of the gastrointestinal tract (mouth to anus)	Colon and rectum only
Distribution	Patchy, skip lesions	Continuous from rectum proximally
Depth of inflammation	Transmural	Mucosal and submucosal only
Rectal involvement	Often spared	Almost always involved
Ileal involvement	Common	Occasional 15% (backwash ileitis) not more than 10 cms
Perianal Disease	Common (fistula, abscess)	Rare
Fistulas and abscesses	Common	Rare
Strictures	Common	Rare
Bleeding	Less common, mild	Common, may be severe
Diarrhea	Often non-bloody	Typically bloody diarrhea
Abdominal Pain	Common	Cramps with urgency
Weight Loss/Malnutrition	Common	Less common
Surgery Recurrence	High recurrence post-resection	Low after ileal pouch-anal anastomosis

Table 2. Histological differences between Crohn’s disease and Ulcerative Colitis:

library(knitr)
library(kableExtra)

# Data from the provided table
histopathology_data <- data.frame(
  Feature = c("Discrete mucosal ulcers", "Mucosal edema", "Fissures", "Granulomas", 
              "Abnormal crypt architecture", "Architectural distortion", "Lymphoid aggregates", 
              "Paneth cell metaplasia"),
  `Crohns Disease` = c("Common", "Common", "Present", "Often seen (non-caseating)", 
                            "Minimal", "Focal", "Frequent", "Absent"),
  `Ulcerative Colitis` = c("Absent (except in fulminant colitis)", "Usually absent", 
                               "Rare", "Absent, except in crypt rupturing", "Frequent", 
                               "Diffuse", "Rare", "Occasionally present")
)

kable(histopathology_data, align = 'c') %>%
  kable_styling(bootstrap_options = c("striped", "hover", "condensed"), 
                full_width = FALSE, font_size = 12, position = "center") %>%
  column_spec(1, bold = TRUE, background = "#f2f2f2", color = "#333333") %>%
  row_spec(0, background = "#d3d3d3", color = "#000000", bold = TRUE) %>%
  row_spec(1:nrow(histopathology_data), extra_css = "border-bottom: 1px solid #dddddd;") %>%
  scroll_box(width = "100%", height = "auto")

Feature	Crohns.Disease	Ulcerative.Colitis
Discrete mucosal ulcers	Common	Absent (except in fulminant colitis)
Mucosal edema	Common	Usually absent
Fissures	Present	Rare
Granulomas	Often seen (non-caseating)	Absent, except in crypt rupturing
Abnormal crypt architecture	Minimal	Frequent
Architectural distortion	Focal	Diffuse
Lymphoid aggregates	Frequent	Rare
Paneth cell metaplasia	Absent	Occasionally present

References

1. Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montre al classification of inflammatory bowel disease: Controversies, consensus, and implications. Gut. 2006; 55: 749-753.
2. Aljebreen AM, Alharbi OR, Azzam NA, Almalki AS, Alswat KA, Almadi MA. Clinical epidemiology and phenotypic characteristics of Crohn’s disease in the central region of Saudi Arabia. Saudi J Gastroenterol. May-Jun 2014;20(3):162-9. doi:10.4103/1319-3767.132993
3. Gomollón F, Dignass A, Annese V, Tilg H, Van Assche G, Lindsay JO, et al. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management. J Crohn’s Colitis. Oxford University Press; 2017 Jan 1; 11(1): 3–25.
4. Gajendran M, Loganathan P, Catinella AP, Hashash JG. A com prehensive review and update on Crohn’s disease. Disease-a Month. 2018; 64: 20-57.
5. Pimentel AM, Rocha R, Santana GO. Crohn’s disease of esophagus, stomach and duodenum. World J Gastrointest Pharmacol Ther 2019; 10(2): 35-49 [PMID: 30891327 DOI: 10.4292/wjgpt.v10.i2.35]
6. Juncadella AC, Alame AM, Sands LR, Deshpande AR. Perianal Crohn’s disease: a review. Postgrad Med. 2015 Apr;127(3):266-72.
7. Alharbi OR, Azzam NA, Almalki AS, et al. Clinical epidemiology of ulcerative colitis in Arabs based on the Montreal classification. World J Gastroenterol. Dec 14 2014;20(46):17525-31. doi:10.3748/wjg.v20.i46.17525
8. Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, et al. Third European Evidence based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders. J Crohn’s Colitis. Oxford University Press; 2017 Jun 1; 11(6): 649–70
9. Vavricka SR, Rogler G, Gantenbein C, Spoerri M, Prinz Vavricka M, Navarini AA, et al. Chronological Order of Appearance of Extraintestinal Manifestations Relative to the Time of IBD Diagnosis in the Swiss Inflammatory Bowel Disease Cohort. Inflamm Bowel Dis. 2015 Aug; 21(8): 1794–800.

Chapter 4: Incidental terminal ileitis

With the increasing use of colonoscopy for colorectal cancer (CRC) screening and surveillance, incidentally diagnosed terminal ileitis (IDTI) is being identified more frequently in otherwise asymptomatic individuals. However, its true prevalence, clinical significance, and long-term outcomes remain unclear. While IDTI can result from various causes, including NSAID use or early Crohn’s disease (CD), there is no clear consensus on how to manage these cases.

Prevalence and Long-Term Outcomes

Prevalence range from 0.04% to 6.77%, with significant variation in diagnostic criteria [1]. A pooled prevalence analysis estimated IDTI in about 0.7% of non-diagnostic colonoscopies. In some cohort studies the diagnostic work-up for CD the diagnosis was based on varying combinations of clinical, biomarkers, endoscopic, and radiological findings, The long-term follow-up of IDTI patients (median 13–84 months) suggests that most cases do not progress to overt CD. However, in some cases, particularly when associated with additional symptoms or persistent inflammation, progression to CD has been observed [2,3].

The clinical significance of IDTI remains to be determined. Although IDTI can occur in the context of other aetiologies such as non-steroidal anti-inflammatory drugs (NSAIDs) use and rheumatological diseases [4,5]

# Install packages if needed
if (!require(ggplot2)) install.packages("ggplot2")
if (!require(ggforce)) install.packages("ggforce")
library(ggplot2)
library(ggforce)

# Sample data for progression outcomes
progression_data <- data.frame(
  Outcome = c("Progressed to CD", "Persistent Lesions", "Resolved"),
  Percentage = c(5, 30, 65)  # Estimated percentages
)

# Create stacked bar chart
ggplot(progression_data, aes(x = "", y = Percentage, fill = Outcome)) +
  geom_bar(stat = "identity", color = "#333333", size = 0.3) +
  coord_polar("y", start = 0) +  # Semi-donut style for attractiveness
  geom_text(aes(label = paste0(Percentage, "%")), position = position_stack(vjust = 0.5), 
            color = "#333333", size = 4.5, fontface = "bold") +
  scale_fill_manual(values = c("#FF6B6B", "#FFA07A", "#76C893")) +  # Red, coral, green
  labs(title = "Long-Term Outcomes of IDTI", fill = "Outcome") +
  theme_void() +
  theme(
    plot.title = element_text(hjust = 0.5, size = 16, face = "bold", color = "#333333"),
    legend.position = "right",
    plot.background = element_rect(fill = "white", color = NA),
    plot.margin = margin(15, 15, 15, 15)
  )

The following is recommended:

• A minority of patients (ranging from none to a few in each study) progressed to CD.

• Some patients had lesions that persisted but did not worsen, while others had complete resolution.

• No specific predictive factors for disease progression were consistently identified.

• Abdominal pain at the time of colonoscopy was associated with a higher risk of progression in studies including both diagnostic and non-diagnostic colonoscopies.

Current Understanding and Management

The lack of clear predictors of progression complicates decision-making. Some cases of IDTI may represent early, pre-clinical CD, while others are due to transient, non-specific inflammation. NSAID use has been implicated in IDTI but was only reported in a minority of patients in the studies reviewed.

Given this uncertainty, a cautious, stepwise approach is recommended.

The proposed clinical pathway for IDTI management lies in steps as the following

Step 1: Initial evaluation

• Review potential risk factors: NSAID use, smoking, recent infection.
• Obtain baseline fecal calprotectin (FC) to assess intestinal inflammation.

Step 2: Follow-up based on FC levels

A. If FC is normal:

• Likely transient ileitis.
• Avoid potential triggers (NSAIDs, infections) and reassess in 3–6 months.
• No further intervention needed unless symptoms develop.

B. If FC is elevated:

• Consider cross-sectional imaging (e.g., MRI enterography or CT enterography) to assess for transmural inflammation.
• Recheck FC in 6 months.

Step 3: Imaging findings & ongoing management

A. No evidence of transmural inflammation:

• Likely reversible etiology.
• Monitor FC periodically and reassess if symptoms arise.

B. Evidence of transmural inflammation or persistently elevated FC:

• Consider early treatment for CD, even in the absence of symptoms.
• Longitudinal monitoring with FC, clinical assessment, and imaging may be necessary.

# Install packages if needed
if (!require(ggplot2)) install.packages("ggplot2")
if (!require(ggforce)) install.packages("ggforce")
library(ggplot2)
library(ggforce)

# Shortened and structured action labels
management_data <- data.frame(
  x = c(5, 3, 7, 2, 8),
  y = c(5, 4, 4, 3, 3),
  label = c(
    "Initial Evaluation\nReview risk factors, baseline FC",
    "Normal FC \nAvoid triggers \nreassess 3-6 mo",
    "Elevated FC \nImaging \nrecheck FC 6 mo",
    "No Transmural Inflammation \nMonitor FC \nreassess if symptoms",
    "Transmural Inflammation \nEarly CD treatment \nmonitor"
  ),
  fill = c("#4ECDC4", "#76C893", "#A3BFFA", "#D4A4EB", "#FF6B6B")
)


ggplot() +
  # Draw rounded rectangles for steps
  geom_rect(
    data = management_data,
    aes(xmin = x - 1.2, xmax = x + 1.2, ymin = y - 0.4, ymax = y + 0.4, fill = fill),
    color = "#222", radius = unit(0.2, "cm")
  ) +
  # Add text labels
  geom_text(
    data = management_data,
    aes(x = x, y = y, label = label),
    color = "#222", size = 4.2, fontface = "bold", lineheight = 1.1
  ) +
  # Draw arrows for flow
  geom_curve(aes(x = 5, y = 4.6, xend = 3, yend = 4.4), arrow = arrow(length = unit(0.25, "cm")), curvature = 0.2, color = "#333", size = 0.8) +
  geom_curve(aes(x = 5, y = 4.6, xend = 7, yend = 4.4), arrow = arrow(length = unit(0.25, "cm")), curvature = -0.2, color = "#333", size = 0.8) +
  geom_curve(aes(x = 3, y = 3.6, xend = 2, yend = 3.4), arrow = arrow(length = unit(0.25, "cm")), curvature = 0.2, color = "#333", size = 0.8) +
  geom_curve(aes(x = 7, y = 3.6, xend = 8, yend = 3.4), arrow = arrow(length = unit(0.25, "cm")), curvature = -0.2, color = "#333", size = 0.8) +
  # Set color scale and theme
  scale_fill_identity() +
  labs(title = "Management Pathway for IDTI") +
  theme_void() +
  theme(
    plot.title = element_text(hjust = 0.5, size = 18, face = "bold", color = "#333"),
    plot.background = element_rect(fill = "#F5F5F5", color = NA)
  ) +
  coord_cartesian(xlim = c(0, 10), ylim = c(2.5, 5.5))

While most cases of IDTI do not progress to CD, careful follow-up is needed to identify those at risk. A systematic approach—including FC monitoring, imaging, and evaluation of risk factors can help differentiate between transient ileitis and early CD, ensuring appropriate management while avoiding unnecessary interventions.

References

1. M. Agrawal et al Journal of Crohn’s and Colitis, 2021, 1455–1463 doi:10.1093/ecco-jcc/jjab030
2. Siddiki H, Lam-Himlin D, Pasha SF, Gurudu SR, Leighton JA. Terminal ileitis of unknown significance: long-term follow-up and outcomes in a single cohort of patients. Am J Gastroenterol 2015;110[Suppl 1]:S768–S9.
3. Wang WF, Wang ZB, Yang YS, Linghu EQ, Lu ZS. Long-term follow-up of nonspecific small bowel ulcers with a benign course and no requirement for surgery: is this a distinct group? BMC Gastroenterol 2011;11:7
4. Long MD, Kappelman MD, Martin CF, Chen W, Anton K, Sandler RS. Role of nonsteroidal anti-inflammatory drugs in exacerbations of inflam matory bowel disease. J Clin Gastroenterol 2016;50:152–6.
5. Rodríguez-Lago I, Merino O, Azagra I, et al. Characteristics and pro gression of preclinical inflammatory bowel disease. Clin Gastroenterol Hepatol 2018;16:1459–66.

Chapter 5: Extra-intestinal manifestations

Extra-intestinal manifestations (EIMs) represent a significant aspect of IBD, extending beyond the gastrointestinal tract and impacting various systems.

EIMs have been defined as“an inflammatory pathology in a patient with IBD that is located outside the gut and for which the pathogenesis is either dependent on extension/translocation of immune responses from the intestine, or is an independent inflammatory event perpetuated by IBD or that shares a common environmental or genetic predisposition with IBD”[1].

These frequently affect the joints, skin, and eyes, but can also involve the liver, lungs, and pancreas [2]. Up to 50% of patients with IBD may develop at least one extra-intestinal condition[3].

EIMs can be categorized into those stemming from inflammatory pathologies at remote anatomical sites (classical, true EIMs), those resulting from systemic inflammation and associated treatments, and those with broader associations with the disease[1]. figure 1.

The occurrence of EIMs can precede, coincide with, or follow the diagnosis of IBD, and their presence can substantially diminish the quality of life for affected individuals [4]. Often, these manifestations necessitate specific therapeutic interventions or at least require careful consideration when formulating treatment strategies for the underlying IBD [2]. The precise origins of EIMs in IBD are complex and not fully elucidated, but are thought to arise from a combination of factors, including immune-mediated mechanisms, genetic predispositions, and environmental influences [2].

library(knitr)
library(kableExtra)

# Create the table
df <- data.frame(
  `Body Region` = c(
    "Eyes", "Oral cavity", "Liver", "Musculoskeletal", "Nervous system", "Cardiovascular", "Lungs", "Skin"
  ),
  `Classical (true) EIMs` = c(
    "Uveitis, Episcleritis, Scleritis",
    "Oral CD, Orofacial granulomatosis, Metastatic CD, Sensorineural hearing loss",
    "Primary sclerosing cholangitis",
    "Spondyloarthritis",
    "", "", "", 
    "Erythema nodosum, Pyoderma gangrenosum, Sweet syndrome"
  ),
  `Complications of IBD and its treatment` = c(
    "Drug-induced cataracts and other drug-induced and nutritional eye disease",
    "", 
    "Portal vein thrombosis, Hepatic amyloidosis, DILI, Autoimmune hepatitis, Autoimmune pancreatitis",
    "Metabolic bone disease (drug or nutritionally induced)",
    "Peripheral neuropathy (drug or nutritionally induced), Venous sinus thrombosis, Stroke",
    "Ischaemic heart disease, Cerebrovascular accident, Mesenteric ischaemia",
    "Drug-induced lung fibrosis, Inflammatory bronchial/parenchymal lung disease (e.g. asthma, bronchiectasis)",
    "Drug-induced skin disease (e.g. anti-TNF psoriasis), Drug-induced skin cancer, Drug hypersensitivity"
  ),
  `Associated conditions` = c(
    "", "", 
    "Granulomatous hepatitis",
    "Non-inflammatory arthralgia, Osteoporosis",
    "Central demyelination",
    "", "", 
    "Vitiligo, Psoriasis, Eczema, Epidermolysis bullosa acquisita, Cutaneous polyarteritis nodosa, Hidradenitis suppurativa"
  )
)

# Render the table
kable(df, format = "html", escape = FALSE, align = "l", caption = "Extraintestinal Manifestations in IBD") %>%
  kable_styling(full_width = FALSE, bootstrap_options = c("striped", "hover", "condensed"))

Extraintestinal Manifestations in IBD

Body.Region	Classical..true..EIMs	Complications.of.IBD.and.its.treatment	Associated.conditions
Eyes	Uveitis, Episcleritis, Scleritis	Drug-induced cataracts and other drug-induced and nutritional eye disease
Oral cavity	Oral CD, Orofacial granulomatosis, Metastatic CD, Sensorineural hearing loss
Liver	Primary sclerosing cholangitis	Portal vein thrombosis, Hepatic amyloidosis, DILI, Autoimmune hepatitis, Autoimmune pancreatitis	Granulomatous hepatitis
Musculoskeletal	Spondyloarthritis	Metabolic bone disease (drug or nutritionally induced)	Non-inflammatory arthralgia, Osteoporosis
Nervous system		Peripheral neuropathy (drug or nutritionally induced), Venous sinus thrombosis, Stroke	Central demyelination
Cardiovascular		Ischaemic heart disease, Cerebrovascular accident, Mesenteric ischaemia
Lungs		Drug-induced lung fibrosis, Inflammatory bronchial/parenchymal lung disease (e.g. asthma, bronchiectasis)
Skin	Erythema nodosum, Pyoderma gangrenosum, Sweet syndrome	Drug-induced skin disease (e.g. anti-TNF psoriasis), Drug-induced skin cancer, Drug hypersensitivity	Vitiligo, Psoriasis, Eczema, Epidermolysis bullosa acquisita, Cutaneous polyarteritis nodosa, Hidradenitis suppurativa

Musculoskeletal manifestations

Most prevalent impacting as many as 40% of patients [5]. They are classified within the spectrum of spondyloarthritis (SpA), which are a group of chronic, immune-mediated inflammatory joint diseases. These can be broadly categorized based on the predominant manifestations into axial SpA, primarily affecting the spine and sacroiliac joints, and peripheral SpA, involving the joints of the limbs.

The most common SpA conditions associated with IBD are peripheral arthritis (13%), followed by sacroiliitis (10%) and ankylosing spondylitis (3%) [6].

Peripheral SpA are classified as oligoarticular (< 5 joints) or polyarticular (>=5 joints) and is usually non-deforming [2].

Axial SpA is characterized by inflammation of the sacroiliac joints (sacroiliitis) and spine (spondylitis) and further divided into ankylosing spondylitis (radiographic axial SpA) and non-radiographic axial SpA. Patients with axial SpA typically experience chronic lower back pain and stiffness that is worse in the morning or after periods of inactivity and improves with exercise [7]. Ankylosing spondylitis in patients with IBD occurs in 5% to 10% of patients and the strength of the HLA-B27 association in spondylitis complicating IBD is less (approximately 50%–70%) compared to idiopathic spondylitis (>90%).

The pooled prevalence of sacroiliitis on cross-sectional imaging in IBD patients is 21.0% (95% CI 17–26%) [8]. The prevalence of IBD among patients with spondyloarthritis ranges from 4% to 12%, and subclinical gut inflammation has been reported in approximately 40-50% of SpA patients [8].

library(knitr)
library(kableExtra)

# Create the data frame
arthritis_df <- data.frame(
  `Feature` = c(
    "Prevalence",
    "Number of joints",
    "Joint type",
    "Joint distribution",
    "Symmetry",
    "Relation to IBD activity",
    "Duration"
  ),
  `Type 1 (Pauciarticular)` = c(
    "More common in CD than UC",
    "Less than 5 joints",
    "Mainly large joints",
    "Knee > ankle > wrist > elbow > MCP > hip > shoulder",
    "Asymmetric involvement",
    "Parallels intestinal disease activity",
    "Self-limited episodes that last < 10 weeks"
  ),
  `Type 2 (Polyarticular)` = c(
    "",
    "Five or more joints",
    "Mainly small joints",
    "MCP > knees > PIP > wrist > ankle > elbow > shoulder",
    "Symmetric or asymmetric, may be erosive",
    "Clinical course independent of IBD activity",
    "Persistent inflammation for months or even years"
  )
)

# Render the table
kable(arthritis_df, format = "html", escape = FALSE, align = "l", 
      col.names = c("Feature", "Type 1 (Pauciarticular)", "Type 2 (Polyarticular)")) %>%
  kable_styling(full_width = FALSE, bootstrap_options = c("striped", "hover", "condensed"), position = "center")

Feature	Type 1 (Pauciarticular)	Type 2 (Polyarticular)
Prevalence	More common in CD than UC
Number of joints	Less than 5 joints	Five or more joints
Joint type	Mainly large joints	Mainly small joints
Joint distribution	Knee > ankle > wrist > elbow > MCP > hip > shoulder	MCP > knees > PIP > wrist > ankle > elbow > shoulder
Symmetry	Asymmetric involvement	Symmetric or asymmetric, may be erosive
Relation to IBD activity	Parallels intestinal disease activity	Clinical course independent of IBD activity
Duration	Self-limited episodes that last	Persistent inflammation for months or even years

# Load the required package
library(knitr)

# Create the table data
arthritis <- data.frame(
  Feature = c(
    "Prevalence",
    "Number of joints",
    "Joint type",
    "Joint distribution",
    "Symmetry",
    "Relation to IBD activity",
    "Duration"
  ),
  `Type 1 (Pauciarticular)` = c(
    "More common in CD than UC",
    "Less than 5 joints",
    "Mainly large joints",
    "Knee > ankle > wrist > elbow > MCP > hip > shoulder",
    "Asymmetric involvement",
    "Parallels intestinal disease activity",
    "Self-limited episodes that last < 10 weeks"
  ),
  `Type 2 (Polyarticular)` = c(
    "",
    "Five or more joints",
    "Mainly small joints",
    "MCP > knees > PIP > wrist > ankle > elbow > shoulder",
    "Symmetric or asymmetric, may be erosive",
    "Clinical course independent of IBD activity",
    "Persistent inflammation for months or even years"
  )
)

# Display the table
kable(arthritis, caption = "Comparison of Type 1 and Type 2 Arthritis in IBD")

Comparison of Type 1 and Type 2 Arthritis in IBD

Feature	Type.1..Pauciarticular.	Type.2..Polyarticular.
Prevalence	More common in CD than UC
Number of joints	Less than 5 joints	Five or more joints
Joint type	Mainly large joints	Mainly small joints
Joint distribution	Knee > ankle > wrist > elbow > MCP > hip > shoulder	MCP > knees > PIP > wrist > ankle > elbow > shoulder
Symmetry	Asymmetric involvement	Symmetric or asymmetric, may be erosive
Relation to IBD activity	Parallels intestinal disease activity	Clinical course independent of IBD activity
Duration	Self-limited episodes that last < 10 weeks	Persistent inflammation for months or even years

Management of peripheral and axial spondyloarthropathy

Management of bowel inflammation is an important therapeutic target as this can also induce remission or reduction of activity for musculoskeletal manifestations. Use of non steroidal anti inflammatory drugs in IBD is still controversial due to concerns of increasing bowel inflammation. While there is no convincing evidence that NSAIDs exacerbate UC flare, there is potential association with CD flare [9].

Selective cyclooxygenase-2 (COX-2) inhibitors have fewer gastrointestinal side effects than traditional nonsteroidal anti-inflammatory drugs and can be considered for short-term use. For peripheral SpA, treatment options include nonsteroidal anti-inflammatory drugs and COX-2 inhibitors, corticosteroids, sulfasalazine, methotrexate and anti-TNF agents.

Ustekinumab might be useful for managing peripheral arthritis while existing evidence for vedolizumab is conflicting. Both medications are not recommended for axial SpA. For axial SpA, treatment options include physical therapy, nonsteroidal anti-inflammatory drugs and COX-2 inhibitors, anti-TNF agents, and JAK inhibitors 2.

Management of Peripheral and Axial Spondyloarthropathy in IBD (Adapted from [10 and 11]).

Therapy	Peripheral Spondyloarthropathy	Axial Spondyloarthropathy
Sulfasalazine	May be used	Should not be used
Methotrexate	Can be used	Should not be used
TNF-antagonist	Can be used	Can be used
JAK inhibitor	Should not be used	Can be used
Anti-IL-12/23 (Vedolizumab)	Should not be used	Should not be used
Anti-IL-23 p19 (Ustekinumab)	May be used	Should not be used
S1P-R modulator (Ozanimod, Etrasimod)	Should not be used	Should not be used

Skin manifestations

Skin manifestations of IBD are common and occur in up to 15% of patients, often reflecting underlying disease activity and posing diagnostic and therapeutic challenges. Cutaneous EIMs can be categorized into four groups based on their pathophysiological mechanisms and association with underlying intestinal disease. T

Table. Cutaneous EIMs categorization (Adapted from [12])

Category	Characteristics	Examples
Reactive	Share common pathogenic links, but not histopathological features of IBD.	Erythema nodosum, pyoderma gangrenosum, Sweet syndrome, oral lesions.
Specific	Same histopathological features of IBD but occurs outside GI tract.	Metastatic CD
Associated	Do not share histological or pathogenic links but observed frequently with IBD.	Hidradenitis suppurativa, psoriasis, atopic dermatitis, rosacea, vitiligo, alopecia areata, leukocytoclastic vasculitis, systemic lupus erythematosus, polyarthritis nodosa.
Complications	Consequences of IBD or adverse events to IBD treatment	Anti TNF adverse events like paradoxical psoriasis, Eczema-like/psoriasiform eczema, Paradoxical hidradenitis Suppurativa.

Show in sidebar

Table. Most common cutaneous manifestations in IBD. (Adapted from [11])

Manifestation	Features	Management
Erythema nodosum	○ Symmetrical, raised, tender, erythematous, or violaceous subcutaneous nodules [1–5 cm] ○ Extensor surface of lower limbs > head, neck, trunk and arms ○ In 2–15% IBD ○ CD > UC ○ F > M	Treat underlying IBD — Supportive: bed rest, elevation, anal- gesia, compression hosiery — Skin directed: topical corticosteroids — Systemic: corticosteroids [if severe], potassium iodide, dapsone, TNFα ant- agonists, hydroxychloroquine
Pyoderma gangrenosum	○ Single or multiple erythematous papules/pustules ○ Rapid necrosis with irregular violaceous margins and purulent discharge ○ Often occurs after trauma [pathergy] ○ Secondary infection may occur ○ Shins and peristomal areas most common ○ High recurrence rate [>25%] ○ Severe and debilitating ○ In 0.4–5% of IBD ○ IBD in 30–50% of PG ○ UC > CD ○ F > M	Supportive: wound care, analgesia, avoidance of trauma — Topical corticosteroids, topical tacrolimus — Systemic corticosteroids, TNFα antagonists, dapsone, tetracyclines, metronidazole — Severe: IV cyclosporin, TNFα antagonists, ustekinumab, JAKi
Sweet syndrome [acute febrile neutrophilic dermatosis]	○ Acute onset of tender erythematous papules and nodules on limbs, trunk, head, and neck, varying sizes, associated with fever and neutrophilia. ○ Rare ○ CD > UC ○ F > M	Treatment of underlying IBD — Topical corticosteroids — Systemic corticosteroids
Oral lesions	○ 5–50% ○ CD > UC	1. Aphthous ulcers: painful avoid or round ulcers, labial or buccal mucosa, and pseudomembranous base and erythematous margin 2. Periodontitis: swelling, redness, bleeding of gingiva, loose teeth associated with perianal disease and smoking 3. Peristomal vegetans: pustules, haemorrhagic erosions, ulcers 4. Orofacial granulomatosis: Recurrent and persistent buccal swelling and oral ulcers, facial palsy, cervical lymphadenopathy
Metastatic CD	○ Rare, CD only	○ Extraintestinal sites: legs, intertriginous areas > facial, genital ○ Abscesses, fistulae, ulcers, nodules.
Hidradenitis Suppurativa	○ IBD in 3.3% HS ○ CD > UC ○ 0.4–15% in CD ○ 0.1–6.1% in UC ○ F > M ○ Obesity and smoking are risk factors	Recurrent, painful inflamed skin lesions, developing abscesses and interconnected sinus tracts in flexural sites [axillae, inguinal, perianal]
Anti TNF adverse events		1. Paradoxical psoriasis: body, scalp, face; flexures > extensors [in contrast to typical psoriasis] 2. Palmoplantar pustulosis, 3. Paradoxical hidradenitis suppurativa:

Hepatobiliary manifestations

Hepatobiliary manifestations of IBD are common, affecting up to 50% of patients. They encompass a range of conditions affecting the liver, gallbladder, and biliary ducts, with primary sclerosing cholangitis (PSC) being the most well-recognized and extensively studied association [11]. Although, other hepatobiliary disorders, such as fatty liver disease, granulomatous hepatitis, autoimmune liver and pancreas disease, gallstone formation, can also occur in association with IBD [2].

Primary sclerosing cholangitis

Is a chronic, progressive cholestatic liver disease characterized by inflammation and fibrosis affecting both the intrahepatic and extrahepatic bile ducts with a substantial risk of developing end-stage liver disease, malignancies, and increased mortality [2]. PSC has a well-established association with IBD, particularly UC, with approximately 60%–80% of PSC patients also having underlying IBD [2]. Approximately 4% of UC patients and 0.6% of CD patients have PSC [13].

PSC may precede the development of IBD, and in some instances several years after undergoing proctocolectomy for UC.

Male sex, extensive ulcerative colitis, non-smoking status, and a history of appendectomy were found to be significantly associated with primary sclerosing cholangitis [13].

The diagnosis involves a combination of clinical, biochemical, and imaging findings. Elevated liver enzymes, particularly alkaline phosphatase, are often the first indication of PSC. Magnetic resonance cholangiopancreatography (MRCP) is the imaging modality of choice and characteristic features include multifocal strictures, beading, and dilation of the bile ducts.

IBD patients with asymptomatic PSC have a worse prognosis compared to IBD patients without PSC [14]. PSC greatly increases the risk of hepatobiliary (cholangiocarcinoma and gallbladder malignancy) and colorectal cancer, and surveillance using ultrasound and/or MRCP for hepatobiliary cancer and annual colonoscopy for colorectal cancer is recommended [15].

Several drugs have been evaluated for the treatment of PSC, none have shown a benefit in slowing progression, or preventing complications. Liver transplantation (LT) remains the only proven life-extending intervention.

Ursodeoxycholic acid [UDCA] [15–20 mg/kg/day] improves liver biochemistry but does not improve fatigue, pruritus, risk of cholangiocarcinoma, or mortality [11]. The role of UDCA on the risk of CRC development remains controversial and cannot be recommended solely for reducing colorectal cancer risk in IBD due to conflicting evidence [11].

Ocular manifestations

Ocular EIMs manifest in 2%–7% of IBD patients and include anterior uveitis, episcleritis, and scleritis, .There are a number of other less common ocular manifestations that have been reported in the literature including conjunctivitis, keratitis, retinal vasculitis, optic neuritis, central retinal vein occlusion and orbital myositis [16].

Ocular EIM	Clinical features	Association with IBD activity	Risk of Vision Loss	Management
Anterior Uveitis (iritis)	Discomfort or pain, may be bilateral, red eye, blurred vision, headache, photophobia.	May or may not be associated	Yes	Urgent ophthalmology referral if suspected First line: topical steroids Second line: systemic steroids, steroid-sparing agents, or biologic therapy [TNFα antagonists]
Scleritis	Severe pain that wakes patients from sleep, unilateral or bilateral, with or without red eye.	Yes	Yes	Urgent ophthalmology referral if suspected First line: oral NSAIDs or oral steroids Second line: steroid-sparing immunomodulators, biologics [TNFα antagonists]
Episcleritis	Painless or mild discomfort, unilateral or bilateral, hyperaemia.	Yes	No	Treatment of underlying disease, topical lubricants, and cool compresses Topical NSAIDs

Venous thromboembolism

Is a prevalent and potentially life-threatening complication for patients with IBD. CD and UC are independent risk factors for the development of venous thromboembolism (VTE) with an estimated risk to be approximately two-fold or higher compared to the general population. This heightened risk is particularly pronounced during periods of active disease, hospitalization, and surgical interventions. The thrombotic risk appears similar between men and women, and between patients with UC and CD.

All individuals with IBD who require hospitalization, regardless of the underlying cause, including disease exacerbation or surgical intervention, should receive pharmacological prophylaxis against VTE [11]. Prophylactic low-molecular-weight heparin is recommended over unfractionated heparin to prevent VTE in acutely and critically ill patients with IBD [17].

Extended thromboprophylaxis (3-6 weeks) following discharge from the hospital is recommended for patients with IBD who have undergone major surgery [11]. Extended pharmacological thromboprophylaxis after discharge in non-surgical hospitalized patients and outpatients with active IBD is currently not recommended. However, outpatients with severe IBD flares and a high risk of VTE, whether related to the disease or not, may benefit from pharmacological thromboprophylaxis until the flare resolves [11].

Direct oral anticoagulants (DOACs) at therapeutic doses is recommended as first line in patients with IBD presenting with an acute VTE [11]. Risk factors for VTEs should be investigated to guide duration of anticoagulation.

IBD flare, recent surgical procedure, and hospitalization are considered risk factors for VTE and VTE is considered provoked and 3 months of anticoagulation is recommended, while unprovoked VTE should be treated indefinitely [11].

References

1. Hedin C, Vavricka S, Stagg AJ, et al. The Pathogenesis of Extraintestinal Manifestations: Implications for IBD Research, Diagnosis, and Therapy. Journal of Crohn s and Colitis 2018;13:541. Available at: https://doi.org/10.1093/ecco-jcc/jjy191 [Accessed March 2025].
2. Rogler G, Singh AG, Kavanaugh A, et al. Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. Gastroenterology 2021;161:1118. Available at: https://doi.org/10.1053/j.gastro.2021.07.042 [Accessed March 2025].
3. Vavricka SR, Schoepfer A, Scharl M, et al. Extraintestinal Manifestations of Inflammatory Bowel Disease. Inflammatory Bowel Diseases 2015;21:1982. Available at: https://doi.org/10.1097/mib.0000000000000392 [Accessed March 2025].
4. Vavricka SR, Rogler G, Gantenbein C, et al. Chronological Order of Appearance of Extraintestinal Manifestations Relative to the Time of IBD Diagnosis in the Swiss Inflammatory Bowel Disease Cohort. Inflammatory Bowel Diseases 2015;21:1794. Available at: https://doi.org/10.1097/mib.0000000000000429 [Accessed April 2025].
5. Vavricka SR, Brun L, Ballabeni P, et al. Frequency and Risk Factors for Extraintestinal Manifestations in the Swiss Inflammatory Bowel Disease Cohort. The American Journal of Gastroenterology 2010;106:110. Available at: https://doi.org/10.1038/ajg.2010.343 [Accessed April 2025].
6. Karreman MC, Luime JJ, Hazes JMW, et al. The Prevalence and Incidence of Axial and Peripheral Spondyloarthritis in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Journal of Crohn s and Colitis 2016. Available at: https://doi.org/10.1093/ecco-jcc/jjw199 [Accessed April 2025].
7. Jansen FM, Vavricka SR, Broeder AA den, et al. Clinical management of the most common extra‐intestinal manifestations in patients with inflammatory bowel disease focused on the joints, skin and eyes. United European Gastroenterology Journal 2020;8:1031. Available at: https://doi.org/10.1177/2050640620958902 [Accessed February 2025].
8. Evans J, Sapsford M, McDonald SD, et al. Prevalence of axial spondyloarthritis in patients with inflammatory bowel disease using cross-sectional imaging: a systematic literature review. Therapeutic Advances in Musculoskeletal Disease 2021;13. Available at: https://doi.org/10.1177/1759720x21996973 [Accessed March 2025].
9. Moninuola O, Milligan W, Lochhead P, et al. Systematic review with meta‐analysis: association between acetaminophen and nonsteroidal anti‐inflammatory drugs (NSAIDs) and risk of Crohn’s disease and ulcerative colitis exacerbation. Alimentary Pharmacology & Therapeutics 2018;47:1428. Available at: https://doi.org/10.1111/apt.14606 [Accessed March 2025].
10. Greuter T, Rieder F, Kucharzik T, et al. Emerging treatment options for extraintestinal manifestations in IBD. Gut 2020;70:796. Available at: https://doi.org/10.1136/gutjnl-2020-322129 [Accessed April 2025].
11. Gordon H, Burisch J, Ellul P, et al. ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. Journal of Crohn s and Colitis 2023;18:1. Available at: https://doi.org/10.1093/ecco-jcc/jjad108 [Accessed March 2025].
12. Greuter T, Navarini AA, Vavricka SR. Skin Manifestations of Inflammatory Bowel Disease. Clinical Reviews in Allergy & Immunology 2017;53:413. Available at: https://doi.org/10.1007/s12016-017-8617-4 [Accessed March 2025].
13. Fraga M, Fournier N, Safroneeva E, et al. Primary sclerosing cholangitis in the Swiss Inflammatory Bowel Disease Cohort Study: prevalence, risk factors, and long-term follow-up. European Journal of Gastroenterology & Hepatology 2016;29:91. Available at: https://doi.org/10.1097/meg.0000000000000747 [Accessed March 2025].
14. Trivedi P, Crothers H, Mytton J, et al. Effects of Primary Sclerosing Cholangitis on Risks of Cancer and Death in People With Inflammatory Bowel Disease, Based on Sex, Race, and Age. Gastroenterology 2020;159:915. Available at: https://doi.org/10.1053/j.gastro.2020.05.049 [Accessed April 2025].
15. Gordon H, Biancone L, Fiorino G, et al. ECCO Guidelines on Inflammatory Bowel Disease and Malignancies. Journal of Crohn s and Colitis 2022;17:827. Available at: https://doi.org/10.1093/ecco-jcc/jjac187 [Accessed March 2025].
16. Taleban S, Li D, Targan SR, et al. Ocular Manifestations in Inflammatory Bowel Disease Are Associated with Other Extra-intestinal Manifestations, Gender, and Genes Implicated in Other Immune-related Traits. Journal of Crohn s and Colitis 2015;10:43. Available at: https://doi.org/10.1093/ecco-jcc/jjv178 [Accessed March 2025].
17. Schünemann HJ, Cushman M, Burnett A, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Advances 2018;2:3198. Available at: https://doi.org/10.1182/bloodadvances.2018022954 [Accessed March 2025].

Chapter 6: Investigating a patient suspected of having IBD

Diagnosing IBD can be challenging due to the complexity and wide variation of its clinical features. The diagnosis of IBD doesn’t rely on a single diagnostic test but instead on a constellation of clinical features, laboratory abnormalities, radiological changes, endoscopic observations, and histologic criteria [1]. The first challenge is differentiating between IBD and acute gastrointestinal illnesses [2, 3].

Even though IBD typically presents chronically over months and sometimes years, it is seldom that the presentation is subacute over weeks. Therefore, it is essential to rule out infections that mimic IBD (Table 1) by performing proper stool testing [4]. Patients with UC are frequently diagnosed with recurrent dysentery (amoeba) and are unnecessarily given repetitive courses of antibiotics. Another challenge is to differentiate between IBD, mainly CD, and irritable bowel disease (IBS), as a large proportion of patients with CD are initially misdiagnosed as IBS for an extended period, which leads to delays in diagnosis and treatment. These warrants paying careful attention to “red flags” during history taking.

Table 1. Pathologic features of infections that can mimic inflammatory bowel disease.

Pathogen	Key IBD like features	Ancillary studies
Salmonella enterica typhi & paratyphi serovars Shigella spp.	Lymphoid hyperplasia, ulcers, crypt architectural distortion Continuous distribution proximally from the rectum, chronic active colitis with marked architectural distortion	Stool culture and PCR
Entamoeba histolytica	Cryptitis, ulcers, pyloric metaplasia, Paneth cell hyperplasia, architectural distortion	Trophozoites are positive with trichrome and PAS stains
Sexually transmitted proctitis (Treponema pallidum, Chlamydia trachomatis)	Dense lymphohistiocytic infiltrate with prominent plasma cells, lymphoid aggregates, mild actively cryptitis, poorly formed granulomas	Treponema pallidum: Immunohistochemistry, serologic studies Chlamydia trachomatis: Nucleic acid amplification test or PCR on rectal swab specimens
Mycobacterium tuberculosis	Hyperplastic Peyer patches, fissures, architectural distortion, transmural lymphoid aggregates, mural fibrosis, inflamed submucosal blood vessels, granulomata	Acid-fast stains, RT-PCR on paraffin-embedded tissue or stool, serologic gold test QuantiFERON
Yersinia spp.	Architectural distortion, mural lymphoid hyperplasia and fibrosis, transmural lymphoid aggregates, and epithelioid granulomata	Stool culture and RT-PCR on paraffin-embedded tissue
Actinomyces spp.	Mucosal lymphoid hyperplasia, transmural lymphoid aggregates and epithelioid granulomata, perianal fibrosing	Organisms are gram positive and stain with GMS
Basidiobolus ranarum	Increased lamina propria inflammation including plasma cells, neutrophils, eosinophils, ulcers, granulomata, thickening of pericolic fat	GMS, PAS-D

The red flag score is a partially validated tool that can be used accurately to detect patients with a high probability of CD (Table 2) [5,6]. Delays in diagnosing IBD can lead to the development of disease complications and treatment resistance [7]. In certain parts of the world where intestinal tuberculosis (ITB) is endemic, patients with CD can be misdiagnosed with ITB and treated with anti-tuberculous medications for periods that extend to 2 years before the diagnosis is challenged. Predictive models incorporating clinical, biochemical, and endoscopic findings have been introduced to help distinguish both conditions and mitigate this obstacle [8].

Table 2. The Red Flag Index (RFI)

Item	Score
Non-healing or complex perianal fistula or abscess or perianal lesions (apart from hemorrhoids)	5
First-degree relative with confirmed inflammatory bowel disease	4
Weight loss (5% of usual body weight) in the last 3 months	3
Chronic abdominal pain (>3 months)	3
Nocturnal diarrhoea	3
Mild fever in the last 3 months	2
No abdominal pain 30-45 min after meals, predominantly after vegetables	2
No rectal urgency	2

A minimum Red Flags index value of 8 highly predicted CD diagnoses with sensitivity and specificity bootstrap estimates of 0.94 (95% confidence interval 0.88-0.99) and 0.94 (0.90-0.97), respectively. Positive and negative likelihood ratios were 15.1 (9.3-33.6) and 0.066 (0.013-0.125). The association between CD diagnosis and a Red Flags index value of ≥8 corresponds to an OR of 290 (p < 0.0001).

Patients with IBD can have both local and systemic manifestations with very high variability. This symptom heterogeneity can be attributed mainly to disease location, extent, severity, and phenotype. The most common gastrointestinal symptoms are diarrhea, abdominal pain, tenesmus, and malnutrition. Presenting with dominant systemic symptoms such as fever, weakness, fatigue, and extra intestinal manifestations of IBD is not uncommon, especially in younger patients.

Symptoms of UC include bloody diarrhea, rectal bleeding, urgency, tenesmus, and abdominal cramps. In a small percentage of patients, the first presentation of UC can be explosive and require urgent hospitalization due to the higher risk of perforation or exsanguination, which is labeled acute severe ulcerative colitis (ASUC). These patients typically present with very severe symptoms and systemic toxicity. Acute infections should be carefully excluded in patients before initiating rescue therapies, such as intravenous corticosteroids, infliximab, or cyclosporin.

It is prudent to be able to distinguish between the two major types of IBD, UC and CD, as this has significant implications for the patient’s future disease course. This is, however, quite difficult sometimes, which is why around 10% percent of patients with IBD are initially labeled as IBD unclassified (IBDU) [9].

Patients’ CD typically presents with abdominal pain, diarrhea, vomiting, weight loss, and fever. About a quarter of patients with CD present with perianal manifestations such anal fissures, perianal fistulae and abscesses, and skin tags, which can be very implicative of the diagnosis [10]. Upper GI involvement of CD is commonly seen in young patients and less so in adults [2,3].

How to investigate a patient who might have IBD?

Laboratory investigations

Baseline laboratory investigations

Baseline laboratory testing of patients presenting with symptoms suspicious of IBD includes essential blood and stool testing.

Complete blood count (CBC) is beneficial in detecting anemia, which could be caused by chronic inflammation, malabsorption, or bleeding; leukocytosis, which could reflect active inflammation of superimposed infection; and thrombocytosis, which reflects ongoing inflammation.

Additional blood tests include liver profile, electrolytes, renal profile, thyroid function test, and c-reactive protein (CRP). CRP is a non-specific inflammatory marker that supports the diagnosis of IBD when elevated but with limited sensitivity, as 15-20% of patients do not produce CRP.

Stool tests

These include stool analysis, stool culture, polymerase chain reaction (PCR) assay for clostridium difficile toxin, and fecal calprotectin (FC). FC is a protein released from neutrophils during inflammation and detected in the stool. The level of FC correlates with the degree of intestinal inflammation and disease location. FC is more likely to be elevated in the presence of colonic involvement and less likely if the disease is limited to the small bowel. Nevertheless, a normal FC decreases the likelihood of IBD, and an elevated FC should prompt further investigations such as ileocolonoscopy, cross-sectional imaging, or video capsule endoscopy (VCE) to confirm or rule out IBD. FC is widely used to screen for IBD with a sensitivity of 85.8% (95% CI: 78.3–91) and a specificity of 91.7% (95% CI: 84.5–95.7) to distinguish between IBD and IBS. Issues that require careful attention when interpreting FC levels include sample acquisition, sample processing, cut-off points, and the pre-test probability of IBD [11].

Antibody tests

Several antibodies to microbial antigens that can predict the diagnosis of IBD have been identified and studied. Anti-saccharomyces antibodies (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) are seldom used to help differentiate between CD and UC, respectively. For example, positive ASCA and negative pANCA tests can predict CD with a sensitivity of 54.6% and a specificity of 92.8% (receiver operating characteristic (ROC) curve (AUC)= 0.85, likelihood ratio positive (LR+) = 6.5, likelihood ratio negative (LR-) = 0.5). On the other hand, the sensitivity and specificity of a positive pANCA test alone for UC were 55.3% and 88.5%, respectively (AUC = 0.82; LR+ = 4.5, LR- = 0.5). Other markers, namely anti-outer-membrane protein C (anti-OmpC), anti-pseudomonas fluorescence-associated sequence I2 (anti-I2), and anti-bacterial flagellin (anti-CBir1), can be used to predict the risk of complications and surgery in CD patients but with limited accuracy [12, 13].

Radiological investigations

Intestinal ultrasound

Intestinal ultrasound (IUS) is a non-invasive, radiation-free imaging modality that has become increasingly useful in diagnosing IBD. It detects bowel wall thickness and intramural vascularization and can help detect strictures, abscesses, or fistulae. IUS has the advantage of being point-of-care but is limited by being highly operator-dependent and less accurate in obese patients [14, 15].

Computed tomography enterography (CTE)

Contrast (oral and IV contrasts) enhanced computed tomography (CT) scans focused on the bowel are frequently used to assess the small bowel for areas of inflammation, e.g., wall thickness, mesenteric engorgement, and stenosis or fistulization due to complicated CD [16]. Although they require a short duration to perform and provide comprehensive details of the bowel and surrounding organs, their main disadvantage is radiation exposure.

Magnetic resonance enterography (MRE)

MRE is a radiation-free, cross-sectional modality that provides a high-quality, detailed description of the bowel and the surrounding tissue. MRE’s primary role is to detect inflamed or damaged bowel areas. For this purpose, oral and IV contrasts are needed. MRE is more accurate than CTE in differentiating between active inflammation and fibrosis in areas with luminal narrowing. Susceptibility to motion artifacts and prolonged examination duration are among its main disadvantages [17].

Table 3: Imaging modalities used to investigate for inflammatory bowel disease.

Feature	CT Enterography	MRI Enterography	Intestinal Ultrasound
Radiation Exposure	Higher	No radiation	No radiation
Resolution	High (excellent for bowel wall assessment)	High (excellent for soft tissue and bowel layers)	Moderate (depends on operator and patient factors)
Complications that can be detected	Fistulas, abscesses, perforation, strictures	Fistulas, abscesses, strictures, perianal disease	Abscesses, fistulas, thickening, strictures
Procedure Duration	Fast (5-15 minutes)	Longer (30-45 minutes)	Fast (10-20 minutes)
Cost	Moderate to high	High	Low
Availability	Widely available	Limited availability in some centers	available. Operator dependent

Endoscopy

Ileocolonoscopy

Documenting mucosal inflammation through endoscopy is considered the cornerstone of diagnosing IBD. During the index evaluation, documentation of the site and the extent, pattern, and severity of inflammation is essential. Furthermore, identifying potential disease complications is an integral part of risk stratification [18].

Esophagogastroduodenoscopy (EGD)

In adults, examination of the upper GI tract is usually reserved for patients suspected of having upper GI CD, such as those with symptoms of dyspepsia, nausea, vomiting, dysphagia, or epigastric pain. In contrast, EGD is routinely done at baseline in children being worked up for CD due to the higher prevalence of upper GI CD in this patient population [19].

Video capsule endoscopy (VCE)

VCE is typically used when there is a high suspicion of isolated small bowel CD, especially in the presence of a normal ileocolonoscopy and a high index of suspicion. It is more accurate than cross-sectional modalities (CTE or MRE) for detecting proximal small bowel aphthous ulcers. However, due to the risk of capsule retention, it must be done after ruling out small bowel strictures using cross-sectional imaging [20.

Device-assisted enteroscopy (DAE)

DAE, such as push enteroscopy, anterograde, or retrograde balloon enteroscopy, is used to reach small bowel lesions suspected of CD. This is typically undertaken when tissue biopsy is needed following the detection of inflamed areas by cross-sectional imaging or VCE [21].

Histopathology

Histopathology plays an essential role in confirming the diagnosis of IBD. Features of chronicity and activity must be present to confirm the diagnosis. Features of chronic inflammation include crypt architecture distortion and inflammatory expansion of the lamina propria with basal lymphoplasmacytosis and paneth cell metaplasia or hyperplasia. In CD, other features include pyloric gland metaplasia of the small bowel and right colon, and non-caseating granulomas, which are pathognomonic for CD. Still, they are only seen in up to 25% of cases. Features of activity include neutrophil infiltration in lamina propria, cryptitis, crypt abscesses, and ulcerations [22].

Figure 1: Suggested diagnostic Algorithm for Crohn’s disease.

library(ggplot2)
library(ggforce)
library(dplyr)

# Define node positions
nodes <- data.frame(
  id = 1:15,
  x = c(5, 5, 3, 7, 3, 7, 5, 6, 8, 8, 8, 6, 5, 3, 7),
  y = c(14, 12.5, 11, 11, 9.5, 9.5, 7, 8.5, 8.5, 6.5, 5.5, 5.5, 4, 4, 4),
  label = c(
    "Clinical suspicion of\nCrohn's disease",
    "Ileocolonoscopy and Biopsy",
    "+ve for Crohn's",
    "-ve for Crohn's",
    "Treat Crohn's",
    "CTE / MRE",
    "Deep Enteroscopy\n& Biopsy",
    "+ve finding",
    "-ve finding",
    "Video Capsule\nEndoscopy",
    "-ve",
    "+ve",
    "-ve for Crohn's\nTreat alternative cause",
    "+ve for Crohn's\nRisk stratify and treat",
    "-ve for Crohn's\nTreat alternative cause"  # Second outcome node
  ),
  type = c(
    "start", "test", "result", "result", "treatment", 
    "test", "test", "result", "result", "test", 
    "result", "result", "outcome", "outcome", "outcome"
  )
)

# Define consistent color scheme
node_colors <- c(
  start = "#FFDDC1",         # Light orange
  test = "#C1E1FF",          # Light blue
  result = "#FDFD96",        # Light yellow
  treatment = "#C4F0C5",     # Light green
  outcome = "#FFB3B3"        # Light red
)

nodes$fill <- node_colors[nodes$type]

# Define connections with proper offsets
connections <- tribble(
  ~from, ~to, ~curvature,
  1, 2, 0,
  2, 3, -0.2,
  2, 4, 0.2,
  3, 5, 0,
  4, 6, 0,
  6, 8, -0.1,
  6, 9, 0.1,
  9, 10, 0,
  10, 11, 0.2,
  10, 12, -0.2,
  12, 7, -0.3,
  8, 7, 0.3,
  7, 13, -0.2,
  7, 14, 0.2,
  11, 15, 0
)

# Generate edge coordinates with proper offsets
edges <- connections %>%
  left_join(nodes, by = c("from" = "id")) %>%
  left_join(nodes, by = c("to" = "id"), suffix = c("_start", "_end")) %>%
  mutate(
    # Apply vertical offset to avoid overlapping
    y_start = y_start - 0.4,
    y_end = y_end + 0.4
  )

# Create plot with minimal aesthetic
ggplot() +
  # Nodes with rounded rectangles
  geom_rect(
    data = nodes,
    aes(xmin = x - 1.8, xmax = x + 1.8, ymin = y - 0.4, ymax = y + 0.4, fill = fill),
    color = "black", alpha = 0.9, size = 0.6, radius = unit(0.3, "cm")
  ) +
  
  # Node text
  geom_text(
    data = nodes,
    aes(x = x, y = y, label = label),
    size = 3.3, lineheight = 0.85, fontface = "bold", color = "black"
  ) +
  
  # Arrows with fixed endpoints
  geom_curve(
    data = edges,
    aes(x = x_start, y = y_start, xend = x_end, yend = y_end, curvature = curvature),
    arrow = arrow(length = unit(0.25, "cm"), type = "closed"),
    color = "gray30", size = 0.7
  ) +
  
  # Styling
  scale_fill_identity() +
  coord_fixed(ratio = 0.8, xlim = c(1, 9), ylim = c(3, 15)) +
  theme_void() +
  ggtitle("Crohn's Disease Diagnostic Pathway") +
  theme(
    plot.title = element_text(hjust = 0.5, size = 18, face = "bold", margin = margin(b = 15)),
    plot.margin = margin(20, 20, 30, 20),
    plot.background = element_rect(fill = "white", color = NA)
  )

References

1. Maaser C, Sturm A, Vavricka SR, Kucharzik T, Fiorino G, Annese V, Calabrese E, Baumgart DC, Bettenworth D, Borralho Nunes P, Burisch J, Castiglione F, Eliakim R, Ellul P, Gonzalez-Lama Y, Gordon H, Halligan S, Katsanos K, Kopylov U, Kotze PG, Krustins E, Laghi A, Limdi JK, Rieder F, Rimola J, Taylor SA, Tolan D, van Rheenen P, Verstockt B, Stoker J, European Cs, Colitis O, the European Society of G, Abdominal R. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. J Crohns Colitis. 2019;13(2):144-64.
2. Gomollon F, Dignass A, Annese V, Tilg H, Van Assche G, Lindsay JO, Peyrin-Biroulet L, Cullen GJ, Daperno M, Kucharzik T, Rieder F, Almer S, Armuzzi A, Harbord M, Langhorst J, Sans M, Chowers Y, Fiorino G, Juillerat P, Mantzaris GJ, Rizzello F, Vavricka S, Gionchetti P, Ecco. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management. J Crohns Colitis. 2017;11(1):3-25.
3. Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, Burisch J, Gecse KB, Hart AL, Hindryckx P, Langner C, Limdi JK, Pellino G, Zagorowicz E, Raine T, Harbord M, Rieder F, European Cs, Colitis O. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders. J Crohns Colitis. 2017;11(6):649-70.
4. Panarelli NC. Infectious Mimics of Inflammatory Bowel Disease. Mod Pathol. 2023;36(7):100210.
5. Danese S, Fiorino G, Mary JY, Lakatos PL, D’Haens G, Moja L, D’Hoore A, Panes J, Reinisch W, Sandborn WJ, Travis SP, Vermeire S, Peyrin-Biroulet L, Colombel JF. Development of Red Flags Index for Early Referral of Adults with Symptoms and Signs Suggestive of Crohn’s Disease: An IOIBD Initiative. J Crohns Colitis. 2015;9(8):601-6.
6. Fiorino G, Bonovas S, Gilardi D, Di Sabatino A, Allocca M, Furfaro F, Roda G, Lenti MV, Aronico N, Mengoli C, Angeli E, Gaffuri N, Peyrin-Biroulet L, Danese S. Validation of the Red Flags Index for Early Diagnosis of Crohn’s Disease: A Prospective Observational IG-IBD Study Among General Practitioners. J Crohns Colitis. 2020;14(12):1777-9.
7. Jayasooriya N, Baillie S, Blackwell J, Bottle A, Petersen I, Creese H, Saxena S, Pollok RC, group P-Is. Systematic review with meta-analysis: Time to diagnosis and the impact of delayed diagnosis on clinical outcomes in inflammatory bowel disease. Aliment Pharmacol Ther. 2023;57(6):635-52.
8. Choudhury A, Dhillon J, Sekar A, Gupta P, Singh H, Sharma V. Differentiating gastrointestinal tuberculosis and Crohn’s disease- a comprehensive review. BMC Gastroenterol. 2023;23(1):246.
9. Prenzel F, Uhlig HH. Frequency of indeterminate colitis in children and adults with IBD - a metaanalysis. J Crohns Colitis. 2009;3(4):277-81.
10. Munster LJ, Monnink GLE, van Dieren S, Mundt MW, D’Haens G, Bemelman WA, Buskens CJ, van der Bilt JDW. Fistulizing Perianal Disease as a First Manifestation of Crohn’s Disease: A Systematic Review and Meta-Analysis. J Clin Med. 2024;13(16).
11. Dajti E, Frazzoni L, Iascone V, Secco M, Vestito A, Fuccio L, Eusebi LH, Fusaroli P, Rizzello F, Calabrese C, Gionchetti P, Bazzoli F, Zagari RM. Systematic review with meta-analysis: Diagnostic performance of faecal calprotectin in distinguishing inflammatory bowel disease from irritable bowel syndrome in adults. Aliment Pharmacol Ther. 2023;58(11-12):1120-31.
12. Reese GE, Constantinides VA, Simillis C, Darzi AW, Orchard TR, Fazio VW, Tekkis PP. Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Am J Gastroenterol. 2006;101(10):2410-22.
13. Xiong Y, Wang GZ, Zhou JQ, Xia BQ, Wang XY, Jiang B. Serum antibodies to microbial antigens for Crohn’s disease progression: a meta-analysis. Eur J Gastroenterol Hepatol. 2014;26(7):733-42.
14. Dal Buono A, Faita F, Armuzzi A, Jairath V, Peyrin-Biroulet L, Danese S, Allocca M. Assessment of activity and severity of inflammatory bowel disease in cross-sectional imaging techniques: a systematic review. J Crohns Colitis. 2025;19(2).
15. Malik S, Venugopalan S, Tenorio BG, Khan SR, Loganathan P, Navaneethan U, Mohan BP. Diagnostic accuracy of bowel ultrasonography in patients with inflammatory bowel disease: a systematic review and meta-analysis. Ann Gastroenterol. 2024;37(1):54-63.
16. Qiu Y, Mao R, Chen BL, Li XH, He Y, Zeng ZR, Li ZP, Chen MH. Systematic review with meta-analysis: magnetic resonance enterography vs. computed tomography enterography for evaluating disease activity in small bowel Crohn’s disease. Aliment Pharmacol Ther. 2014;40(2):134-46.
17. Yoon HM, Suh CH, Kim JR, Lee JS, Jung AY, Kim KM, Cho YA. Diagnostic Performance of Magnetic Resonance Enterography for Detection of Active Inflammation in Children and Adolescents With Inflammatory Bowel Disease: A Systematic Review and Diagnostic Meta-analysis. JAMA Pediatr. 2017;171(12):1208-16.
18. Spiceland CM, Lodhia N. Endoscopy in inflammatory bowel disease: Role in diagnosis, management, and treatment. World J Gastroenterol. 2018;24(35):4014-20.
19. Annunziata ML, Caviglia R, Papparella LG, Cicala M. Upper gastrointestinal involvement of Crohn’s disease: a prospective study on the role of upper endoscopy in the diagnostic work-up. Dig Dis Sci. 2012;57(6):1618-23.
20. Kopylov U, Yung DE, Engel T, Vijayan S, Har-Noy O, Katz L, Oliva S, Avni T, Battat R, Eliakim R, Ben-Horin S, Koulaouzidis A. Diagnostic yield of capsule endoscopy versus magnetic resonance enterography and small bowel contrast ultrasound in the evaluation of small bowel Crohn’s disease: Systematic review and meta-analysis. Dig Liver Dis. 2017;49(8):854-63.
21. Neuhaus H, Beyna T. Device-Assisted Enteroscopy in Inflammatory Bowel Disease: From Balloon Enteroscopy to Motorized Spiral Enteroscopy. Gastrointest Endosc Clin N Am. 2025;35(1):59-72.
22. Magro F, Langner C, Driessen A, Ensari A, Geboes K, Mantzaris GJ, Villanacci V, Becheanu G, Borralho Nunes P, Cathomas G, Fries W, Jouret-Mourin A, Mescoli C, de Petris G, Rubio CA, Shepherd NA, Vieth M, Eliakim R, European Society of P, European Cs, Colitis O. European consensus on the histopathology of inflammatory bowel disease. J Crohns Colitis. 2013;7(10):827-51.
23. Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55(6):749-53.

Chapter 7:

References

Chapter 8: Treatment Endpoints and Medical Therapies

This chapter will summarize the principles of the treat-to-target approach in IBD and provide an overview of available medical therapies, including insights into treatment efficacy based on specific disease phenotypes and severity.

Drug dosing, route of administration, key therapy considerations, side effects, and monitoring protocols are explained in Chapter 13.

Treat-to-target in moderate-to-sever IBD

• Focusing solely on symptom resolution fails to alter the disease course [1].

• Achieving targets beyond symptom control, such as biomarker normalization (C- reactive protein (CRP) and fecal calprotectin (FCP)) and endoscopic healing, improves patient long-term outcomes and can modify the disease course [2].

• The STRIDE 2 consensus provided a timeline-based treatment target approach focusing on symptoms, biomarkers, and endoscopic outcomes (Figure 1) [3].

Figure 1. Selecting therapeutic targets in IBD consensus (STRIDE-II) [3]

if (!require(DiagrammeR)) install.packages("DiagrammeR")
library(DiagrammeR)

grViz("
digraph {
  graph [layout = dot, rankdir = TB]

  # Nodes
  node [shape = box, style = filled, fillcolor = lightblue]
  A [label = 'Active IBD\\nTreatment is chosen based on risk assessment']
  B [label = 'Short term targets\\nSymptomatic response\\nCD: ≥50% decrease in abdominal pain and stool frequency)\\nUC: ≥50% decrease in rectal bleeding and stool frequency)']
  C [label = 'Intermediate targets\\nClinical remission\\nnormalized CRP and reduced FCP\\nCD: PRO2 (abdominal pain ≤1, stool frequency ≤3) or HBI <5\\nUC: PRO2 (rectal bleeding = 0, stool frequency = 0) or partial Mayo <3 (no score >1)\\nNormalization of CRP (below upper normal limit) and decrease FCP (100–250 mg/g)']
  D [label = 'Long term targets\\nEndoscopic healing\\nnormalized QoL\\nand absence of disability\\nCD: SES-CD <3 or no ulcerations\\nUC: Mayo endoscopic subscore = 0 or UCEIS ≤1']
  E [label = 'To consider but not formal targets\\nCD : Transmural healing (assessed by MRE, CTE or IUS)\\nUC : Histological healing']

  # Edges
  A -> B -> C -> D -> E

 # Modification nodes
  B -> M1 [color = red, fontcolor = red]
  C -> M1 [color = red, fontcolor = red]
  D -> M1 [color = red, fontcolor = red]
  M1 [label = 'Modify the treatment if the target is not achieved', shape = box, style = filled, fillcolor = lightblue]

  # Styling
  A [fillcolor = lightblue]
}
")

Treatment targets in IBD. IBD: inflammatory bowel disease; CD: Crohn’s disease; UC: ulcerative colitis; PRO: patient-reported outcome; CRP: C-reactive protein; FCP : Fecal calprotectin; QoL: quality of life; SES-CD: Simple Endoscopic Score for Crohn’s disease; UCEIS: Ulcerative Colitis Endoscopic Index of Severity; MRE: magnetic resonance enterography; CTE: computed tomography enterography; IUS: Intestinal ultrasound

• Therapy should be adjusted or modified if treatment targets are not met, with close monitoring being a critical component throughout the course of management [3].

• The time required to achieve each target varies depending on the disease (UC or CD) and the selected therapy [3].

• Transmural healing in CD and histologic remission in UC improve outcomes (e.g., fewer hospitalizations, lower relapse rates) but are not yet formal targets [3,4].

• Less stringent, individualized targets may be appropriate for frail patients, those with comorbidities, or refractory disease after multiple therapy failures [5].

Therapeutic Options for Crohn’s Disease

• Medical therapy of CD is tailored based on disease phenotype, severity, and the burden of inflammation [6].

• Early treatment with effective therapy (top-down approach) in patient at risk of complications has demonstrated greater efficacy and improved outcomes compared to the step-up approach (Figure 2) [7].

library(DiagrammeR)
grViz("
digraph {
  graph [layout = dot, rankdir = BT, nodesep = 0.0, ranksep = 0.0]

  # Nodes
  node [shape = box, style = filled]
  A [label = '5 ASA (UC), Sulfasalazine', fillcolor = '#006600', width = 6.0, height = 0.8]
  B [label = 'Corticosteroids', fillcolor = '#1B4F72', width = 5.0, height = 0.8]
  C [label = 'IMM (AZA, MTX)', fillcolor = '#2E7D9A', width = 4.0, height = 0.8]
  D [label = 'Biologics and small molecules', fillcolor = '#47A8B8', width = 3.0, height = 0.8]
  E [label = 'Surgery', fillcolor = '#60C4D9', width = 2.0, height = 0.8]

  # Edges to form pyramid structure
  A -> B -> C -> D -> E [style = invis]

  # Styling
  A [fontcolor = 'white']
  B [fontcolor = 'white']
  C [fontcolor = 'white']
  D [fontcolor = 'white']
  E [fontcolor = 'white']
  
}
")

Top-down vs. step-up approach in CD . The top-down approach demonstrates greater efficacy and fewer disease complications compared to the step-up approach in Crohn’s disease. Surgery can be considered at any time in the treatment algorithm. 5-ASA: 5-aminosalicylic acid ;AZA: Azathioprine ;MTX: Methotrexate

• A proposed treatment positioning and sequencing for Crohn’s disease is outlined in Figure 4. Approved therapies for IBD patients, including their efficacy in different scenarios, are detailed in Figure 6.

• Management of stricturing and penetrating Crohn’s disease, beyond medical therapy, is covered in Chapter 10.

5-Aminosalicylates (5-ASA)

• 5-ASAs have no role in the management of CD, either for induction or maintenance therapy [8].

• Sulfasalazine may be considered for patients with mild colonic CD [8]].

Corticosteroids

• Enteric-release budesonide is effective for inducing clinical remission in mild to moderate CD limited to the ileum and/or ascending colon [9].

• Systemic corticosteroids (intravenous or oral) can be used to induce remission in CD, but it is essential to ensure the patient has no abscess or pelvic sepsis [10].

• Steroids, in any form, should not be used for maintenance therapy or to induce remission in perianal disease [11].

Immunomodulators

• Thiopurines monotherapy are not used for induction but may be effective for maintaining remission in CD. Their use should balance the risk of side effects with the availability of safer therapies [11].

• Thiopurines are best used in combination with anti-TNF agents in CD to enhance efficacy and reduce immunogenicity of anti-TNF therapy (see chapter 13) [12].

• Unlike thiopurines, methotrexate can be used for both induction and maintenance therapy in CD when administered via the parenteral route [11].

• Given the safety of newer therapies, methotrexate monotherapy is rarely used and is best combined with anti-TNF agents [11].

• Immunomodulators, when used in combination with anti-TNF therapy, can be safely withdrawn after achieving long-term remission, with caution for patients with prior anti-TNF immunogenicity [11].

TNFα antagonists

• Infliximab, adalimumab, and certolizumab pegol can be used for both induction and maintenance therapy in moderate to severe CD [9].

• Infliximab has shown greater efficacy and durability in CD when combined with immunomodulators [13].

• Anti-TNF agents, specifically infliximab, have shown efficacy in patients with penetrating or perianal CD and should be considered first-line therapy for these cases. Certolizumab not recommended as first line therapy for perianal disease [11,14]

• Anti-TNF agents have shown effectiveness in treating most extraintestinal manifestations, such as peripheral and axial arthropathy and pyoderma gangrenosum [15].

• Secondary loss of response to anti-TNF therapy is common, often due to antibody formation, with only one-third maintaining remission after three years. Key risk factors are low drug levels at the end of induction and lack of immunomodulator use [16].

• Infliximab is effective as maintenance therapy in intravenous (IV) and subcutaneous (SC) forms. Switching from IV to SC is safe, with SC dosing based on prior IV dose and subsequent drug level after transition (see Figure 3) [17]

• Patients in clinical remission and with fecal calprotectin levels <250 at the time of switching have a low risk of relapse after transitioning to SC form [17].

IFX maintenance dose	Switching to 120 mg eow	Switching to 240 mg eow	IFX levels do not increase after 8 weeks
5mg/kg/8weeks	✔
10mg/kg/8weeks	✔		Escalate to 240 mg eow
10mg/kg/6weeks	✔
10mg/kg/4weeks		✔

Guidance for switching from IV maintenance Infliximab to SC form based on the Remiswitch study [17]. eow: every other week; IFX: Infliximab.

IL-12/IL-23 inhibitor (Anti IL12/23 )

• Ustekinumab, an anti-p40 subunit agent, inhibits IL-12 and IL-23 and is effective for both induction and maintenance therapy in moderate to severe CD [11].

• In head-to-head trial (SEAVUE), both ustekinumab and adalimumab have been shown to be equally effective in biologic-naive moderate-to-sever CD patients [18].

• Adding immunomodulators to ustekinumab does not provide additional benefit and can compromise the favorable safety profile of the drug [19].

IL23 inhibitors (Anti IL23)

• Risankizumab, guselkumab and mirikizumab, anti-p19 agents that selectively inhibit IL-23, are approved for moderate to severe CD [20-22].

• In a head-to-head trial (SEQUENCE), risankizumab was noninferior to ustekinumab for clinical remission and superior for endoscopic remission in moderate-to-sever CD patients with prior anti-TNF exposure [20].

• In the GALAXI trial, guselkumab outperformed ustekinumab in clinical and endoscopic remission in bio-naïve and bio-exposed moderate-to-severe CD [21].

• In the VIVID trial, mirikizumab was non-inferior to ustekinumab for clinical remission but did not show superiority in endoscopic response in moderate-to-severe CD [22].

Anti-integrin therapy

• Vedolizumab, an anti-integrin agent that inhibits α4β7 integrin, is effective for both induction and maintenance of remission in CD [11].

• Vedolizumab is available in IV form for induction and in both IV and SC forms for maintenance therapy [11].

Janus kinase (JAK) inhibitors

• Upadacitinib, a JAK-1 selective oral inhibitor, is the only JAK inhibitor recommended for induction and maintenance in Crohn’s disease [11].

• It functions with relatively higher selectivity for JAK-1 inhibition [11].

• JAK inhibitors should be used with caution in patients with a history of or at risk for venous thromboembolism (VTE), major adverse cardiovascular events (MACE), and malignancy.

• Additionally, inactivated herpes zoster vaccine (Shingrix®) should be administered prior to starting therapy [23].

Therapeutic positioning and sequencing in moderate to severe Crohn’s disease

Early initiation of highly effective therapy is crucial in moderate to severe Crohn’s disease. The choice of therapy depends on factors such as disease phenotype, the presence or absence of extraintestinal manifestations (EIMs), prior treatment exposure, and comorbidities. The following figure showing a proposed potential therapeutic positioning and sequencing of medications.

A proposed approach for the positioning and sequencing of therapy in Crohn’s disease. Note: This is primarily based on the authors’ opinions, supported by available evidence and clinical experience, and treatment decisions should be made on a case-by-case basis

Clinical Scenario	Anti TNF*	Anti IL12/23	Anti IL23	Anti-integrin	Jak Inhibitor
Bio-naïve and inflammatory phenotype	Preferred second line	Preferred as first line	Preferred as first line	Preferred as first line	Preferred second line
Fistulizing/perianal disease	Preferred as first line **	No efficacy/insufficient data	No efficacy/insufficient data	No efficacy/insufficient data	Preferred second line
Anti-TNF failure		Preferred second line	Preferred as first line	Preferred second line	Preferred as first line***
Anti-IL12/23 failure	Preferred as first line		Preferred as first line	Preferred as first line	Preferred as first line
Safety concerns****	Preferred second line	Preferred as first line	Preferred as first line	Preferred as first line	Preferred second line

• Anti-TNF therapy is most effective when combined with immunomodulators.

** Infliximab combination therapy with an IMM is the preferred choice.

***preferred with fistulizing disease.

**** Patients over 65, frail, or with severe comorbidities.

Therapeutic Options for Ulcerative Colitis

• Management of UC depends on disease severity, extent of colonic involvement, and the presence of complications [24].

• Acute severe ulcerative colitis (ASUC) is considered an emergency and should be managed promptly in an inpatient setting in collaboration with colorectal surgery. Management of ASUC is detailed in Chapter 11.

• Management of pouchitis is discussed in Chapter 12.

• A proposed treatment positioning and sequencing for UC is outlined in Figure 5. Approved therapies for IBD patients, including their efficacy in different scenarios, are detailed in Figure 6.

5-Aminosalicylates (5-ASA)

• For mild to moderate UC, 5-ASA (in oral or topical form) is effective for both induction and maintenance therapy [24].

• A starting dose of at least 2 g/day is recommended for mild disease, while up to 4.8 g/day may be used for moderate disease, with no efficacy difference between divided and once-daily 5-ASA dosing. Better adherence is achieved with once daily dosing and is recommended [24].

• Topical 5-ASA alone is effective for induction and maintenance in mild to moderate distal UC. For proctosigmoiditis and beyond, combined oral and topical 5-ASA is preferred over monotherapy for induction [25].

• 5-ASA can may be stopped when treatment escalation to advanced therapy is needed, offering no added benefit [26].

• 5-ASA is very safe, but creatinine should be checked biannually to monitor for potential interstitial nephritis [27].

Corticosteroids

• Topical steroids can be used for induction of remission in patients with active distal UC, although some studies suggest the superiority of topical 5-ASA [28].

• Colonic-release corticosteroid (Budesonide MMX®) is effective for inducing remission in mild to moderate UC [24].

• Systemic steroids (oral for outpatient and IV for inpatient) are used to induce remission in patients with moderate to severe UC [24].

• Steroids, in any form, should not be used for maintenance therapy [11].

Immunomodulators

• Thiopurine monotherapy is not used for induction but may be effective for maintaining remission in UC. Its use should balance the risk of side effects with the availability of safer therapies [24].

• Thiopurines are best used in combination with anti-TNF agents (specifically infliximab) in UC [29].

• Unlike in CD, methotrexate is ineffective for induction or maintenance in UC. Its use is limited to combination with anti-TNF agents to reduce immunogenicity or as concomitant therapy for coexisting immune-mediated diseases [24].

• Immunomodulators, when used in combination with anti-TNF therapy, can be withdrawn after achieving long-term remission, with caution for patients with prior anti-TNF immunogenicity [11].

TNFα antagonists

• Infliximab, adalimumab, and golimumab are effective for both induction and maintenance of remission in moderate to severe UC [24].

• Infliximab is approved for use as rescue therapy in ASUC, as is cyclosporine (see Chapter 11) [30].

• Anti-TNF agents have shown effectiveness in treating most extraintestinal manifestations, such as peripheral and axial arthropathy and pyoderma gangrenosum [15].

• Secondary loss of response to anti-TNF therapy is common in UC. Patients with low drug levels after induction, high inflammatory burden, low albumin levels, and lack of immunomodulator use are at higher risk of immunogenicity [31].

• Both IV and SC forms of infliximab are effective for maintenance therapy following IV induction in UC. Transitioning from IV to SC during maintenance is also safe (see ‘Anti-TNF in Treatment of Crohn’s Disease’ and Figure 3) [17].

IL-12/IL-23 inhibitor (Anti IL12/23)

• Ustekinumab, an anti-p40 subunit agent, inhibits IL-12 and IL-23 and is effective for both induction and maintenance therapy in moderate to severe UC [24].

• Adding immunomodulators to ustekinumab does not provide significant additional benefit [19].

IL23 inhibitors (Anti IL23)

• Risankizumab, mirikizumab, and guselkumab, anti-p19 agents that selectively inhibit IL-23, are approved for moderate to severe UC [32-34].

Anti-integrin therapy

• Vedolizumab, an anti-integrin agent targeting α4β7 integrin, is effective for both induction and maintenance of remission in UC, available in both IV and SC forms [35].

• Vedolizumab demonstrated superiority over adalimumab in a head-to-head trial and is preferred for use over adalimumab (VARSITY) [36].

Janus kinase (JAK) inhibitors

• Tofacitinib (non-selective JAKi), upadacitinib (high selectivity for JAK1 inhibition), and filgotinib are approved for moderate to severe UC [37-39].

• JAK inhibitors should be used with caution in patients with a history of or at risk for venous thromboembolism (VTE), major adverse cardiovascular events (MACE), and malignancy. Additionally, inactivated herpes zoster vaccine (Shingrix®) should be administered prior to starting therapy [23].

• Multiple studies have shown that tofacitinib and upadacitinib are effective in patients with ASUC, particularly in cases of prior infliximab exposure, although they are not formally approved for this indication [40,41].

Sphingosine-1-phosphate (S1P) receptor modulators

• S1P receptor modulators, ozanimod and etrasimod, are approved for moderate-to-severe UC [26].

• Ozanimod selectively binds to S1P receptors 1 and 5, whereas etrasimod targets S1P receptors 1, 4, and 5 [26].

• Proper evaluation is required before initiating S1P receptor modulators in patients with heart block, arrhythmia, or macular edema; baseline electrocardiogram (ECG) and ophthalmologic assessments are recommended [42].

Therapeutic positioning and sequencing in UC

Choosing therapy for UC depends on disease severity, extent of colonic involvement, presence of EIMs, prior treatment exposure, and comorbidities. The following figure outlines a proposed therapeutic positioning and sequencing of available therapies.

A proposed approach for the positioning and sequencing of therapy in UC. Note: This is primarily based on the authors’ opinions, supported by available evidence and clinical experience, and treatment decisions should be made on a case-by-case basis

Clinical Scenario	5-ASA*	Anti TNF**	Anti IL12/23	Anti IL23	Anti-integrin	Jak Inhibitor	S1PR Modulator
Mild to moderate disease	Preferred as first line	Preferred second line	Preferred second line	Preferred second line	Preferred second line	Preferred second line	Preferred second line
Moderate to severe disease	Preferred as first line	Preferred as first line	Preferred as first line	Preferred as first line	Preferred as first line	Preferred as first line	Preferred as first line
ASUC	No efficacy/insufficient data	Preferred as first line***	No efficacy/insufficient data	No efficacy/insufficient data	No efficacy/insufficient data	Preferred second line****	No efficacy/insufficient data
Anti-TNF failure	No efficacy/insufficient data		Preferred as first line	Preferred as first line	Preferred second line	Preferred as first line	Preferred second line
Anti-IL12/23 failure	No efficacy/insufficient data	Preferred as first line		Preferred as first line	No efficacy/insufficient data	Preferred as first line	No efficacy/insufficient data
Safety concerns*****	Preferred as first line	Preferred second line	Preferred as first line	Preferred as first line	Preferred as first line	Preferred second line	Preferred second line

• Oral and topical forms ** Adalimumab has low efficacy in UC and is not preferred *** Infliximab is the only anti-TNF agent used in ASUC **** Can be used if prior exposure to infliximab ***** Patients over 65, frail, or with severe comorbidities.

Therapy	Induction	Maintenance	CD	UC	Peripheral Spondylo-arthropathy*	Axial Spondylo-arthropathy	Pregnancy
Oral mesalamine	✓	✓	✗	✓	✗	✗	✓
Topical mesalamine	✓	◯	✗	✓	✗	✗	✓
Systemic corticosteroids	✓	✗	✓**	✓	◯**	◯**	◯**
Colonic-release corticosteroids	✓	✗	✗	✓	✗	✗	✓
Ileal release corticosteroids	✓	✗	✓	✗	✗	✗	✓
Thiopurines monotherapy	✗	✓	✓	✓	✗	✗	✓***
Methotrexate monotherapy	✓	✓	✓	✗	✓	✗	✗
Infliximab	✓	✓	✓	✓	✓	✓	✓
Adalimumab	✓	✓	✓	✓	✓	✓	✓
Certolizumab	✓	✓	✓	✗	✓	✓	✓
Golimumab	✓	✓	✗	✓	✓	✓	✓
Vedolizumab	✓	✓	✓	✓	✗	✗	✓
Ustekinumab	✓	✓	✓	✓	◯	✗	✓
Risankizumab	✓	✓	✓	✓	◯	✗	?
Guselkumab	✓	✓	✓	✓	◯	✗	?
Mirikizumab	✓	✓	✓	✓	◯	✗	?
Tofacitinib	✓	✓	✗	✓	✓	✓	✗
Filgotinib****	✓	✓	✗	✓	✓	?	✗
Upadacitinib	✓	✓	✓	✓	✓	✓	✗
Ozanimod	✓	✓	✗	✓	✗	✗	✗
Etrasimod	✓	✓	✗	✓	✗	✗	✗

Legend: ✓ : Can be used ✗ : Avoid ◯ : Can be considered ? : Insufficient data

Medical therapy in the management of IBD . This figure serves as guidance and does not replace clinical decision-making

• Spondyloarthropathy indications

** Avoid long-term use in all scenarios

***Thiopurines can be continued in pregnancy but not started as monotherapy or for induction.

**** Approved by the EMA but not by the FDA.

References

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12. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-95.
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27. van Staa TP, Travis S, Leufkens HG, Logan RF. 5-aminosalicylic acids and the risk of renal disease: a large British epidemiologic study. Gastroenterology. 2004;126(7):17339.
28. Cohen RD, Woseth DM, Thisted RA, Hanauer SB. A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol. 2000;95(5):1263-76.
29. Panaccione R, Ghosh S, Middleton S, Márquez JR, Scott BB, Flint L, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146(2):392400.
30. Laharie D, Bourreille A, Branche J, Allez M, Bouhnik Y, Filippi J, et al. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet. 2012;380(9857):1909-15.
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32. Feagan BG, Sandborn WJ, Danese S, Wolf DC, Liu WJ, Hua SY, et al. Risankizumab in patients with moderate to severe ulcerative colitis: results from the INSPIRE trial. Gastroenterology. 2023;164(5):S-001.
33. D’Haens G, Dubinsky M, Kobayashi T, Watanabe K, Saito K, Hibi T, et al. Mirikizumab as induction and maintenance therapy for ulcerative colitis: results from the phase 3 LUCENT trials. Gastroenterology. 2023;164(5):S-003.
34. Sandborn WJ, Ferrante M, Bhandari BR, Berliba E, Feagan BG, Hibi T, et al. Guselkumab for the treatment of ulcerative colitis: results from the phase 2b QUASAR study. Gastroenterology. 2022;162(5):S-002.
35. Peyrin-Biroulet L, Loftus EV, Colombel JF, Danese S, Sandborn WJ, Sands BE, et al. Long-term efficacy and safety of vedolizumab subcutaneous in patients with ulcerative colitis: results from the VISIBLE 2 trial. Gastroenterology. 2020;158(5):S-001.
36. Sands BE, Peyrin-Biroulet L, Loftus EV, Danese S, Colombel JF, Törüner M, et al. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381(13):1215-26.
37. Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723-36.
38. Danese S, Ferrante M, Feagan BG, Panés J, Sandborn WJ, Reinisch W, et al. Upadacitinib as induction and maintenance therapy for moderate to severe ulcerative colitis: results from the U-ACHIEVE and U-ACCOMPLISH trials. Gastroenterology. 2023;164(5):S-004.
39. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis: results from the SELECTION trial. Gastroenterology. 2021;160(5):S-005.
40. Berinstein JA, Sheehan JL, Dias R, Baffy N, Osman M, Grinspan AM, et al. Tofacitinib for biologic-experienced hospitalized patients with acute severe ulcerative colitis: a retrospective case-control study. Clin Gastroenterol Hepatol. 2021;19(10):2112-20.
41. Honap S, Pavlidis P, Ray S, Sharma E, Hayee B, Powell N. Upadacitinib as rescue therapy for acute severe ulcerative colitis: a case series. J Crohns Colitis. 2023;17(3):S-012.
42. Sandborn WJ, Feagan BG, D’Haens G, Wolf DC, Jovanovic I, Hanauer SB, et al. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. New England Journal of Medicine. 2021;385(14):1280-91

Chapter 9:

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Chapter 10:

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Chapter 11:

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Chapter 12:

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Chapter 13:

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Chapter 14:

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Chapter 15:

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Chapter 16:

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Chapter 17:

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Chapter 18:

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