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].
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.
library(DiagrammeR)
grViz("
digraph risk_factors {
graph [layout = neato, overlap = false, fontname = Helvetica,
bgcolor = 'transparent', splines = true]
node [shape = circle, style = 'filled, rounded', fillcolor = 'lightblue',
fontname = Helvetica, width = 1.2, height = 1.2, fontcolor = 'black']
edge [color = grey70, penwidth = 2]
# Central node
IBD [label = 'IBD Risk', fillcolor = 'salmon', width = 1.5, height = 1.5,
fontsize = 16, fontcolor = 'white']
# Risk factor nodes with better color contrast
Genetic [label = 'Genetic\nSusceptibility', fillcolor = 'lavender', pos = '0,4!']
Microbiome [label = 'Microbiome\nImbalance', fillcolor = 'lightyellow', pos = '2,4!']
Smoking [label = 'Smoking', fillcolor = 'plum', pos = '4,3!']
Appendectomy [label = 'Appendectomy', fillcolor = 'wheat', pos = '4,1!']
Medications [label = 'Medications', fillcolor = 'lightcyan', pos = '2,-4!']
Hygiene [label = 'Hygiene', fillcolor = 'lightpink', pos = '0,-4!']
Diet [label = 'Dietary\nHabits', fillcolor = 'khaki', pos = '-2,-4!']
Sleep [label = 'Sleep', fillcolor = 'lavender', pos = '-4,-3!']
VitD [label = 'Vit D & UV\nexposure', fillcolor = 'gold', pos = '-4,-1!']
Stress [label = 'Stress', fillcolor = 'tan', pos = '-4,1!']
Activity [label = 'Physical\nactivity', fillcolor = 'skyblue', pos = '-4,3!']
Antibiotics [label = 'Antibiotic\nExposure', fillcolor = 'coral', pos = '-2,4!']
BreastFeeding [label = 'Breast\nFeeding', fillcolor = 'palegreen', pos = '2,-2!']
Geography [label = 'Geographical\nFactors', fillcolor = 'thistle', pos = '0,-2!']
Infections [label = 'Infections', fillcolor = 'lightcoral', pos = '4,-1!'] # Changed from salmon to lightcoral
# Connect all factors to IBD center
Genetic -> IBD
Microbiome -> IBD
Smoking -> IBD
Appendectomy -> IBD
Medications -> IBD
Hygiene -> IBD
Diet -> IBD
Sleep -> IBD
VitD -> IBD
Stress -> IBD
Activity -> IBD
Antibiotics -> IBD
BreastFeeding -> IBD
Geography -> IBD
Infections -> IBD
# Add some cross-connections between related factors
Genetic -> Microbiome [style = dashed, dir = both, constraint = false]
Diet -> Microbiome [style = dashed, dir = both, constraint = false]
Antibiotics -> Microbiome [style = dashed, dir = both, constraint = false]
Geography -> VitD [style = dashed, dir = both, constraint = false]
Stress -> Sleep [style = dashed, dir = both, constraint = false]
Hygiene -> Infections [style = dashed, dir = both, constraint = false]
}
")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]).
library(ggplot2)
library(dplyr)
library(forcats)
library(scales)
# Create the data frame
regional_data <- data.frame(
Region = c("NORTH AMERICA", "EUROPE", "GLOBAL", "EAST ASIA AND PACIFIC",
"SUB-SAHARAN AFRICA", "CENTRAL ASIA", "LATIN AMERICA AND CARIBBEAN",
"SOUTH ASIA", "MIDDLE EAST AND NORTH AFRICA"),
Value = c(79.8, 33.1, 23.2, 21.3, 16.2, 15.2, 14.8, 13.3, 9)
)
# Create a clean, professional bar chart
ggplot(regional_data, aes(x = fct_reorder(Region, Value),
y = Value, fill = Region)) +
geom_col(alpha = 0.8, width = 0.7) +
geom_text(aes(label = Value), hjust = -0.1, size = 3.5, fontface = "bold") +
scale_fill_manual(values = c(
"NORTH AMERICA" = "#E41A1C", # Red for highest value
"EUROPE" = "#377EB8", # Blue
"GLOBAL" = "darkgray", # Gray for global reference
"EAST ASIA AND PACIFIC" = "#4DAF4A", # Green
"SUB-SAHARAN AFRICA" = "#984EA3", # Purple
"CENTRAL ASIA" = "#FF7F00", # Orange
"LATIN AMERICA AND CARIBBEAN" = "#FFFF33", # Yellow
"SOUTH ASIA" = "#A65628", # Brown
"MIDDLE EAST AND NORTH AFRICA" = "#F781BF" # Pink
)) +
labs(
title = "Disease Associated Life Years (DALYs) associated with IBD",
subtitle = "By geographic region per 100,000 population",
x = "",
y = "Rate per 100,000",
caption = "Data represents standardized rates across regions"
) +
coord_flip() + # Flip to make long region names readable
theme_minimal() +
theme(
axis.text.y = element_text(size = 10, face = "bold"),
axis.text.x = element_text(size = 10),
axis.title.x = element_text(size = 12, face = "bold", margin = margin(t = 10)),
plot.title = element_text(size = 16, face = "bold", hjust = 0.5),
plot.subtitle = element_text(size = 12, hjust = 0.5, margin = margin(b = 15)),
legend.position = "none",
panel.grid.major.y = element_blank(),
panel.grid.minor.x = element_blank()
) +
scale_y_continuous(expand = expansion(mult = c(0, 0.1))) # Add space for labels
Figure 4 A. Disease Associated Life Years (DALYs) associated with inflammatory bowel disease by geographic region (adapted from Piovani D. et al.[11]).
library(ggplot2)
library(dplyr)
library(forcats)
library(scales)
# Create the data frame
regional_data <- data.frame(
Region = c("NORTH AMERICA", "EUROPE", "EAST ASIA AND PACIFIC", "GLOBAL",
"LATIN AMERICA AND CARIBBEAN", "CENTRAL ASIA",
"MIDDLE EAST AND NORTH AFRICA", "SOUTH ASIA", "SUB-SAHARAN AFRICA"),
Value = c(63, 18.2, 14.5, 12.6, 5.05, 4.97, 4.52, 2.5, 1.77)
)
# Create a clean, professional bar chart
ggplot(regional_data, aes(x = fct_reorder(Region, Value),
y = Value, fill = Region)) +
geom_col(alpha = 0.8, width = 0.7) +
geom_text(aes(label = Value), hjust = -0.1, size = 3.5, fontface = "bold") +
scale_fill_manual(values = c(
"NORTH AMERICA" = "#E41A1C", # Red for highest value
"EUROPE" = "#377EB8", # Blue
"EAST ASIA AND PACIFIC" = "#4DAF4A", # Green
"GLOBAL" = "darkgray", # Gray for global reference
"LATIN AMERICA AND CARIBBEAN" = "#FF7F00", # Orange
"CENTRAL ASIA" = "#FFFF33", # Yellow
"MIDDLE EAST AND NORTH AFRICA" = "#A65628", # Brown
"SOUTH ASIA" = "#F781BF", # Pink
"SUB-SAHARAN AFRICA" = "#984EA3" # Purple
)) +
labs(
title = "Years lived with a disability from IBD",
subtitle = "By geographic region per 100,000 population",
x = "",
y = "Rate per 100,000",
caption = "Data highlights the significant burden in Western regions compared to developing areas"
) +
coord_flip() + # Flip to make long region names readable
theme_minimal() +
theme(
axis.text.y = element_text(size = 10, face = "bold"),
axis.text.x = element_text(size = 10),
axis.title.x = element_text(size = 12, face = "bold", margin = margin(t = 10)),
plot.title = element_text(size = 16, face = "bold", hjust = 0.5),
plot.subtitle = element_text(size = 12, hjust = 0.5, margin = margin(b = 15)),
legend.position = "none",
panel.grid.major.y = element_blank(),
panel.grid.minor.x = element_blank(),
plot.caption = element_text(size = 9, hjust = 0.5, face = "italic", margin = margin(t = 10))
) +
scale_y_continuous(expand = expansion(mult = c(0, 0.15))) # Add more space for labels
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]).
library(knitr)
library(kableExtra)
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]).
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.
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].
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.
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.
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.
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.
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
Location of disease
Disease behavior
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 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.
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.
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.
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].
UC is classified based on the anatomical extent of colonic involvement, which guides both clinical decision-making and therapeutic strategies
Age at diagnosis
Disease extent
Disease severity
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]).
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.
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).
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 |
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 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.
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
Step 2: Follow-up based on FC levels
A. If FC is normal:
B. If FC is elevated:
Step 3: Imaging findings & ongoing management
A. No evidence of transmural inflammation:
B. Evidence of transmural inflammation or persistently elevated FC:
library(DiagrammeR)
library(htmltools)
# Create the Management Pathway for IDTI flowchart
grViz("
digraph IDTI_Management_Pathway {
# Graph settings
graph [layout = dot, rankdir = TB, nodesep = 0.5, ranksep = 0.8]
node [fontname = 'Helvetica', fontsize = 12]
edge [color = 'black', arrowhead = vee]
# Define nodes
start [label = 'Initial Evaluation\\nReview risk factors, baseline FC',
shape = oval, style = filled, fillcolor = 'lightblue']
decision1 [label = 'FC Result?',
shape = diamond, style = filled, fillcolor = 'lightcoral']
normal_fc [label = 'Normal FC',
shape = box, style = filled, fillcolor = 'palegreen']
elevated_fc [label = 'Elevated FC',
shape = box, style = filled, fillcolor = 'lightpink']
avoid_triggers [label = 'Avoid triggers',
shape = box, style = filled, fillcolor = 'lightyellow']
imaging [label = 'Imaging',
shape = box, style = filled, fillcolor = 'lightyellow']
reassess_3_6 [label = 'Reassess 3-6mo',
shape = box, style = filled, fillcolor = 'lightyellow']
recheck_fc [label = 'Recheck FC 6mo',
shape = box, style = filled, fillcolor = 'lightyellow']
decision2 [label = 'Imaging Result?',
shape = diamond, style = filled, fillcolor = 'lightcoral']
no_inflammation [label = 'No Transmural\\nInflammation',
shape = box, style = filled, fillcolor = 'palegreen']
inflammation [label = 'Transmural\\nInflammation',
shape = box, style = filled, fillcolor = 'lightpink']
monitor_fc [label = 'Monitor FC',
shape = box, style = filled, fillcolor = 'lightyellow']
early_treatment [label = 'Early CD treatment',
shape = box, style = filled, fillcolor = 'lightyellow']
reassess_symptoms [label = 'Reassess if symptoms',
shape = box, style = filled, fillcolor = 'lightyellow']
monitor [label = 'Monitor',
shape = box, style = filled, fillcolor = 'lightyellow']
# Define edges
start -> decision1
decision1 -> normal_fc
decision1 -> elevated_fc
normal_fc -> avoid_triggers
elevated_fc -> imaging
avoid_triggers -> reassess_3_6
imaging -> decision2
decision2 -> no_inflammation
decision2 -> inflammation
no_inflammation -> monitor_fc
inflammation -> early_treatment
monitor_fc -> reassess_symptoms
early_treatment -> monitor
# Additional connections
reassess_3_6 -> recheck_fc [constraint = false]
recheck_fc -> decision1 [constraint = false]
}
")# Add some CSS styling for better appearance
tags$style(HTML("
.node oval {
fill: lightblue;
}
.node box {
fill: lightyellow;
}
.node diamond {
fill: lightcoral;
}
"))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.
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"))| 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 |
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")| 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 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 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 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 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].
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].
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.
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"))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 a following Chapter.
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]
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")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].
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].
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")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 a latter Chapter.
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 in a latter Chapter) [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].
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 |
** Infliximab combination therapy with an IMM is the preferred choice.
*** Preferred with fistulizing disease.
**** Patients over 65, frail, or with severe comorbidities.
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 a latter Chapter.
Management of pouchitis is discussed in a latter Chapter.
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 in a latter Chapter) [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)
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].
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 |
| 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
** 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.
Despite advances in medical therapies, surgery remains crucial for managing complications and refractory Inflammatory bowel disease (IBD). Approximately 30% of UC and 70% of CD patients require surgery during their lifetime [1,2].
Surgery should not be seen as a last resort but as an integral part of IBD management. The interplay between medical and surgical therapies highlights the need for a coordinated approach, where biologics and surgical interventions complement each other. Multidisciplinary care, involving gastroenterologists and surgeons from diagnosis, ensures optimal timing and selection of treatments.
Modern surgical advancements, including minimally invasive techniques and perioperative biologic optimization, have improved outcomes and reduced complications [3,4].
Acute Severe UC (ASUC)
Toxic Megacolon
Dysplasia/Cancer
– 2% at 10 years. – 8% at 20 years. – 18% at 30 years.
Chronic Refractory Disease
Unlike UC, surgery for CD is not curative and focuses on managing complications, symptom relief, and bowel preservation [17]. Despite advancements in medical therapy, approximately two-thirds of CD patients still require surgery during their disease course [9]. A critical concern is the cumulative risk of repeated resections, which may precipitate short bowel syndrome [10].
This requires a conservative surgical approach, emphasizing bowel-sparing techniques and reducing resection length [20,21]. Surgeons should take a long-term view, considering the patient’s lifetime risk of overall bowel loss when planning treatments [11,12].
The main surgical criteria of CD are:
Strictures
Fistulizing disease
Abscesses
Refractory to medical therapy inflammation
Malignancy
Perianal CD (PACD)
PACD affects 30-50% of CD patients, frequently developing early in the disease [16,17]. This causes chronic pain, discharge, and incontinence, significantly impairing quality of life. PACD encompasses diverse lesions including fissures, skin tags, strictures, fistulas (simple or complex), and rarely anal cancer. Optimal management requires accurate diagnosis using clinical assessment combined with pelvic MRI (gold standard) and endoanal ultrasound for complete fistula evaluation [38???????].
Surgical approach depends on disease type (UC vs CD), location, extent, comorbidities, and long-term outcomes [18,19,20].
Mostly in patients with ASUC or toxic megacolon who are not responding to 72 hours maximal medical therapy, or Uncontrolled hemorrhage [19,21,22].
The entire colon is removed with the rectum left in place. An end-ileostomy is constructed to allow the patient to recover from the acute inflammatory response. The procedure is potentially life-saving in the setting of an emergency with a mortality rate of less than 5% in high-volume centers [10]. Patients can eventually ideally undergo completion proctectomy with an ileal pouch-anal anastomosis (IPAA) for curative treatment [23,24].
Bridge procedure is a strategy for the critically ill; frequently patients proceed to definitive surgery later [23].
Elective procedure of choice for medically managed UC - typically younger patients desiring to avoid a permanent stoma and maintain fecal continence [23], such:
• Colorectal adenocarcinoma or high-grade dysplasia • Chronic refractory UC (failed ≥3 drug classes) • Steroid dependence (>10mg prednisone for >6 months) • Growth retardation in pediatric UC
Technical considerations
Pouch configuration:
J-pouch (most common): 15-20cm ileal loop, double-stapled technique [25,26].
S-pouch: Reserved for patients with short mesentery [27,28].
Kock pouch: Alternative for patients unsuitable for anal anastomosis [29,30]
Robotic Approach (da Vinci Xi)
Key steps include complete mesocolic excision and rectal dissection to pelvic floor using a 8mm camera trocar port at RUQ, three 8mm robotic ports, and two 5mm assistant ports [31–33]. The leak rates are 3.2% robotic vs. 8.1% for open surgery with an operative time 45 minutes longer. It is thought that robotics don’t reduce leaks in experienced hands, but may benefit trainees through tremor reduction [13,32]
Diverting ileostomy
It is recommended for malnourished (albumin <3g/dl), those on high-dose steroids (>20mg prednisone), or incomplete doughnut rings [34–36]. Long-term pouch survival is 93% at 10 years, 82% at 20 years [37,38]. The leading causes of failure is chronic pouchitis (38%), and anastomotic stricture (22%) [39–42].
The median daily bowel movements is 5 (range 3-10) [15, 23,36,37. Nighttime incontinence is 28% at 5 years [43,44]. Sexual dysfunction happens in 15% of males (erectile dysfunction), and 12% of females (dyspareunia) [43–45].
Quality of Life Metrics like the Cleveland Global QoL score is 0.82 (vs 0.91 healthy controls) [46,47].
The general objective of surgery in CD is to maintain intestinal length and quality of life and to reduce the risk of recurrence. This is highlighted by the high rate of recidivism following CD surgery, where “endoscopic recidivism is seen in up to 70% and clinical recidivism of 30% within 5 years” after ICR [48–50]. This basic difference in recurrence pattern constitutes a crucial aspect of CD surgical treatment. It suggests even technically successful CD surgery is frequently a transient surgical solution requiring chronic medical therapy and close monitoring.
Is the most common surgery for CD; it is indicated for localized terminal ileal disease with fibrostenotic (narrowing) or inflammatory disease that is not medically responsive [10,51]. It is removal of a terminal ileal segment and right colon with subsequent ileocolic anastomosis to restore continuity [51–53].
Although it relieves symptoms in most patients, recurrence is a significant problem, up to 70% have endoscopic recurrence and 30% clinical recurrence within 5 years [54–56].
It must be limited to patients with localized disease who have had relatively few previous resections to prevent the development of short bowel syndrome from combined bowel loss [51,56,57].
• Patient Selection Criteria (10,51)
Epidemiology and clinical context: Relapsing Crohn’s disease (CD) affects ~0.3% of populations in Western countries, characterised by recurrent inflammatory flares after remission, risking progressive bowel damage [1]. The STRIDE-II guidelines emphasise corticosteroid-free clinical remission (Crohn’s Disease Activity Index [CDAI] <150), endoscopic healing (Simple Endoscopic Score for CD [SES-CD] <3), and patient-reported outcomes as treatment goals [2]. Early intervention prevents complications like strictures or fistulae, requiring personalised therapy based on disease severity, location, and prior treatment response.
Anti-TNF therapies: Tumour necrosis factor (TNF) inhibitors, infliximab and adalimumab, remain first-line for moderate-to-severe relapsing CD. The ACCENT I trial demonstrated infliximab (5 mg/kg every 8 weeks) achieved remission in 39% at week 54 versus 21% with placebo [3]. The CHARM trial reported adalimumab (40 mg every other week) maintained remission in 36% at week 56 versus 12% with placebo [4]. Therapeutic drug monitoring (TDM) optimises outcomes; a 2023 study showed proactive TDM with infliximab increased remission rates by 20% versus reactive monitoring, reducing secondary loss of response (23-46% of patients) [5]. Immunogenicity is mitigated with combination therapy; the SONIC trial found infliximab plus azathioprine achieved 56.8% steroid-free remission at week 26 versus 44.4% with infliximab alone [6].
IL-12/23 and integrin inhibitors: Ustekinumab, an interleukin (IL)-12/23 inhibitor, is effective for anti-TNF failures. The UNITI trials showed ustekinumab (90 mg subcutaneous every 8 weeks) achieved remission in 38% at week 44 versus 20% with placebo [7]. Vedolizumab, an α4β7 integrin inhibitor, targets gut-specific leukocyte trafficking, with the GEMINI 2 trial reporting 39% remission at week 52 (300 mg every 8 weeks) versus 22% with placebo [8]. The 2024 VISIBLE-2 trial confirmed subcutaneous vedolizumab’s efficacy, achieving 48% remission at week 52, offering a safer profile for elderly patients or those with infection risks [9]. However, vedolizumab’s slower onset limits its use in acute flares.
Small molecule therapies: Upadacitinib, a JAK1-selective inhibitor, was approved in 2023 for moderate-to-severe CD. The U-EXCEL trial demonstrated 49.5% remission at week 12 (45 mg daily) versus 29.1% with placebo, with 45.5% endoscopic response versus 13.1% [10]. Its oral administration enhances compliance, but safety concerns (e.g., herpes zoster risk, 2.11 per 100 patient-years) necessitate careful patient selection, avoiding those ≥65 years or with cardiovascular risks [11]. Etrasimod, a sphingosine 1-phosphate receptor modulator, showed promise in the CULTIVATE trial for refractory CD, reducing inflammation by limiting immune cell trafficking [12].
Treat-to-target and monitoring: The CALM trial established that tight control, adjusting therapy based on biomarkers (C-reactive protein [CRP], faecal calprotectin), reduced major adverse outcomes (e.g., hospitalisation, surgery) by 40% compared to symptom-driven care [13]. Endoscopic remission correlates with reduced complications, with SES-CD <3 as a long-term target [14]. Regular MRE or ultrasound monitors disease activity, while smoking cessation is critical, as it worsens disease and reduces biologic efficacy [15].
Adjunctive and emerging strategies: Thiopurines (azathioprine, 6-mercaptopurine) maintain remission in mild-to-moderate disease or reduce biologic immunogenicity [6]. Emerging therapies, like guselkumab (IL-23 inhibitor), showed 30% remission in refractory CD in the GALAXI trials, offering potential for bio-exposed patients [16]. Faecal microbiota transplantation is under investigation but lacks robust evidence for relapsing CD [17].
Pathophysiology and diagnostic challenges: Stricturing CD, affecting ~50% of patients within 10 years, results from chronic inflammation driving fibrosis, causing bowel narrowing and obstruction [1]. Differentiating inflammatory versus fibrotic strictures is critical, as fibrotic lesions resist medical therapy. Magnetic resonance enterography (MRE) is gold standard, with delayed gadolinium enhancement indicating fibrosis, while ultrasound elastography is emerging for non-invasive assessment [18]. The Lémann score quantifies cumulative bowel damage, guiding therapeutic decisions [19].
Medical therapy for inflammatory strictures: Anti-TNFs target inflammation in mixed inflammatory-fibrotic strictures. A 2023 STRIDE-II post-hoc analysis showed early infliximab (within 2 years of diagnosis) reduced stricture formation by 30% compared to delayed therapy, emphasising early intervention [20]. However, established fibrotic strictures respond poorly, with a 2024 study reporting only 20% symptom relief with infliximab or adalimumab [21]. Ustekinumab and vedolizumab are less effective, with real-world data showing 25% and 20% remission rates, respectively, in stricturing cohorts, limiting their role in advanced disease [22]. Upadacitinib’s role is under investigation, with preliminary U-EXCEL data suggesting endoscopic improvement in inflammatory strictures, but no specific fibrosis data exist [10].
Endoscopic interventions: Endoscopic balloon dilation (EBD) is preferred for short (<5 cm), anastomotic strictures. A 2024 meta-analysis reported 90% technical success and 70% clinical efficacy (symptom relief) at 1 year, though 50% required repeat dilation within 2 years [23]. Perforation risk (3-5%) and inefficacy in long or de novo strictures limit its use. Stent placement is experimental, with high migration rates (30%) precluding routine adoption [24].
Surgical management: Strictureplasty preserves bowel length, ideal for short, non-penetrating jejunal or ileal strictures. A 2023 study reported a 23% recurrence rate at 5 years, with 6% major complications (e.g., anastomotic leak) [25]. Resection is reserved for long, refractory, or fistulizing strictures, with laparoscopic approaches reducing complications by 30% versus open surgery [26]. The decision between strictureplasty and resection depends on disease extent, prior resections, and short bowel syndrome risk.
Emerging anti-fibrotic therapies: No approved anti-fibrotic therapies exist, but the 2025 STENOVA trial is evaluating pirfenidone, an anti-fibrotic used in pulmonary fibrosis, with preclinical models showing reduced collagen deposition in CD [27]. Targeting transforming growth factor-β (TGF-β) or IL-13 pathways is under investigation, with phase 2 trials planned for 2026 [28]. These agents aim to halt fibrosis progression, addressing an unmet need in stricturing CD.
Monitoring and prevention: Regular imaging (MRE, ultrasound) tracks stricture progression, with faecal calprotectin and CRP guiding therapy escalation [19]. Smoking, delayed biologics, and NSAID use increase stricture risk, necessitating lifestyle modification and early aggressive therapy [15]. The treat-to-target approach, validated in CALM, applies to stricturing disease to minimise inflammatory burden [13].
Clinical burden and classification: Fistulizing Crohn’s disease, particularly perianal fistulae, affects 30-50% of patients, causing significant morbidity, including a 59% risk of faecal incontinence and impaired quality of life (Crohn’s Anal Fistula Quality of Life [CAF-QoL] score) [29]. Fistulae are classified as internal (e.g., enteroenteric, enterovesical) or external (e.g., perianal, enterocutaneous), with perianal fistulae being most common [30]. Effective management requires a multidisciplinary approach, integrating medical, surgical, and emerging therapies, guided by pelvic MRI or rectal endoscopic ultrasound for accurate fistula mapping [31].
Anti-TNF therapies: Infliximab remains the cornerstone for perianal fistulae, with the ACCENT II trial showing 36% fistula closure at week 54 versus 19% with placebo [32]. Adalimumab is comparably effective, with a 2023 real-world study reporting 40% closure at 1 year [33]. Combination with azathioprine enhances efficacy, reducing relapse by 50%, as per SONIC [6]. Therapeutic drug monitoring optimises outcomes, with infliximab trough levels >5 µg/mL correlating with fistula healing [5]. However, long-term closure is achieved in only 30-50% of patients [30]. Certolizumab and golimumab lack robust fistula-specific data but can be used in refractory cases [34].
IL-12/23 and IL-23 inhibitors: Ustekinumab achieves fistula response in 24% of patients, per 2024 real-world data, but is less effective than anti-TNFs [35]. Risankizumab, an IL-23 p19 inhibitor, was approved for moderate-to-severe CD in 2022. The SEQUENCE trial (2023) showed risankizumab was superior to ustekinumab for endoscopic remission (week 48) in anti-TNF failures, but fistula-specific data are limited [36]. A phase 2 study reported 30.5% fistula response at week 12, suggesting potential in bio-exposed patients with inflammatory or fistulizing phenotypes, though anti-TNFs remain preferred for severe fistulae due to stronger evidence [37]. Risankizumab’s low immunogenicity and infection risk (comparable to ustekinumab) make it a promising option for patients intolerant to anti-TNFs [36].
JAK inhibitors: Upadacitinib, approved for CD in 2023, shows promise for fistulizing disease. The U-EXCEED and U-EXCEL trials reported 47.7% complete fistula resolution at week 12 (45 mg daily) versus 9.1% with placebo, driven by JAK1-selective inhibition of pro-inflammatory cytokines (e.g., IL-6, IL-23) [10]. Filgotinib, a JAK1 inhibitor, achieved significant fistula response (week 24) in the DIVERGENCE 2 trial for perianal CD, with 200 mg daily outperforming placebo [38]. Safety concerns, including herpes zoster (relative risk 1.57) and potential cardiovascular events, require careful monitoring, especially in patients ≥65 years or with comorbidities [11]. JAK inhibitors’ oral administration and rapid onset are advantageous, but data on long-term fistula closure are pending.
Surgical interventions: Seton placement prevents abscesses in complex fistulae, with 80% maintaining drainage at 1 year, per St. Mark’s consensus [31]. Fistulotomy is reserved for simple fistulae due to sphincter damage risk. The ligation of the intersphincteric fistula tract (LIFT) procedure achieves 60% healing at 1 year in CD, offering a sphincter-sparing option [39]. Surgical decisions are guided by fistula complexity and response to medical therapy, with MRI assessing track resolution [31].
Mesenchymal stem cells (MSCs): Darvadstrocel, allogeneic adipose-derived MSCs, is approved for perianal fistulae. The ADMIRE-CD trial reported 50% fistula closure at week 52 versus 34% with placebo, with sustained efficacy at 2 years [40]. A 2024 meta-analysis confirmed 64% closure rates, though high costs and limited availability restrict use [41]. MSCs are ideal for refractory fistulae after anti-TNF failure, requiring surgical collaboration for local injection.
Multidisciplinary and emerging strategies: The St. Mark’s algorithm integrates seton placement, anti-TNFs, and MRI monitoring, with psychological support addressing mental health burdens [29]. Antibiotics (ciprofloxacin, metronidazole) are first-line for symptom control but lack sustained efficacy [30]. Emerging therapies include guselkumab, with 30% fistula response at week 12 in GALAXI, and hyperbaric oxygen therapy, showing 40% healing in a 2024 pilot study [16, 42]. Faecal microbiota transplantation and regenerative medicine (e.g., platelet-rich plasma) are under investigation but lack phase 3 data [17].
# Load required packages
library(ggplot2)
library(dplyr)
# Create data frame
therapy_data <- data.frame(
Therapy = c("Infliximab", "Adalimumab", "Ustekinumab", "Vedolizumab", "Upadacitinib"),
Remission_Rate = c(39, 36, 38, 39, 49.5),
Week = c("Week 52", "Week 52", "Week 52", "Week 52", "Week 12")
)
# Create the plot
ggplot(therapy_data, aes(x = reorder(Therapy, -Remission_Rate),
y = Remission_Rate,
fill = Therapy)) +
geom_col(width = 0.7) +
geom_text(aes(label = paste0(Remission_Rate, "%")),
vjust = -0.5,
size = 4,
fontface = "bold") +
scale_y_continuous(limits = c(0, 55),
expand = c(0, 0)) +
labs(title = "Remission Rates of Advanced Therapies for Relapsing Crohn's Disease",
subtitle = "Based on ACCENT I, CHARM, UNITI, GEMINI 2, and U-EXCEL trials",
x = NULL,
y = "Remission Rate (%)",
caption = "*Upadacitinib data shown at Week 12 (all others at Week 52)") +
theme_minimal() +
theme(
plot.title = element_text(face = "bold", size = 16, hjust = 0.5),
plot.subtitle = element_text(size = 12, hjust = 0.5),
axis.text.x = element_text(angle = 45, hjust = 1, size = 11),
legend.position = "none",
plot.caption = element_text(face = "italic", hjust = 0)
)
# Load required packages
library(ggplot2)
library(dplyr)
library(tidyr)
# Create data frame
data <- data.frame(
Procedure = c("EBD", "Strictureplasty"),
Efficacy_1yr = c(70, 80),
Recurrence_5yr = c(50, 23)
)
# Reshape data for plotting
data_long <- data %>%
pivot_longer(cols = -Procedure,
names_to = "Outcome",
values_to = "Percentage")
# Clean up outcome names
data_long$Outcome <- ifelse(data_long$Outcome == "Efficacy_1yr",
"1-Year Efficacy",
"5-Year Recurrence")
# Create the plot
ggplot(data_long, aes(x = Outcome, y = Percentage, fill = Procedure)) +
geom_col(position = "dodge", width = 0.7) +
geom_text(aes(label = paste0(Percentage, "%")),
position = position_dodge(width = 0.7),
vjust = -0.5,
size = 5,
fontface = "bold") +
scale_fill_manual(values = c("EBD" = "#4E79A7", "Strictureplasty" = "#F28E2B")) +
scale_y_continuous(limits = c(0, 100),
expand = c(0, 0)) +
labs(title = "Comparison of EBD and Strictureplasty Outcomes",
subtitle = "In stricturing Crohn's Disease",
x = NULL,
y = "Percentage (%)",
caption = "Based on 2023 and 2024 studies") +
theme_minimal() +
theme(
plot.title = element_text(face = "bold", size = 18, hjust = 0.5),
plot.subtitle = element_text(size = 14, hjust = 0.5, margin = margin(b = 20)),
axis.text.x = element_text(size = 12, face = "bold"),
axis.text.y = element_text(size = 11),
axis.title.y = element_text(size = 12, margin = margin(r = 10)),
legend.position = "top",
legend.title = element_text(face = "bold", size = 12),
legend.text = element_text(size = 11),
plot.caption = element_text(face = "italic", hjust = 0.5, margin = margin(t = 15)),
panel.grid.major.x = element_blank()
)
# Load required packages
library(ggplot2)
library(dplyr)
library(forcats) # for factor manipulation
# Create data frame
fistula_data <- data.frame(
Treatment = c("Placebo", "Infliximab", "Adalimumab", "Upadacitinib", "MSCs"),
Closure_Rate = c(26.5, 36, 40, 47.7, 50), # Using midpoint for placebo range
Week = c("Week 52", "Week 52", "Week 52", "Week 12", "Week 52"),
Lower_Bound = c(19, 36, 40, 47.7, 50), # For error bars
Upper_Bound = c(34, 36, 40, 47.7, 50) # For error bars
)
# Reorder treatments by closure rate
fistula_data <- fistula_data %>%
mutate(Treatment = fct_reorder(Treatment, Closure_Rate))
# Create the visualization
ggplot(fistula_data, aes(x = Treatment, y = Closure_Rate, fill = Treatment)) +
geom_col(width = 0.7) +
geom_errorbar(aes(ymin = Lower_Bound, ymax = Upper_Bound),
width = 0.2, color = "darkgray", linewidth = 0.8) +
geom_text(aes(label = ifelse(Treatment == "Placebo",
"19-34%",
paste0(Closure_Rate, "%"))),
vjust = -0.8, size = 4.5, fontface = "bold") +
geom_text(aes(label = ifelse(Week != "Week 52",
paste0("(", Week, ")"),
"")),
vjust = 1.2, size = 3.5, color = "darkred") +
scale_fill_manual(values = c("Placebo" = "#999999",
"Infliximab" = "#4E79A7",
"Adalimumab" = "#F28E2B",
"Upadacitinib" = "#E15759",
"MSCs" = "#59A14F")) +
scale_y_continuous(limits = c(0, 60), expand = c(0, 0)) +
labs(title = "Fistula Closure Rates in Fistulizing Crohn's Disease",
subtitle = "Based on ACCENT II, 2023 cohort, ADMIRE-CD, and U-EXCEL trials",
x = NULL,
y = "Closure Rate (%)",
caption = "Note: Upadacitinib data shown at Week 12 (all others at Week 52)\nPlacebo shows range of 19-34% across studies") +
theme_minimal() +
theme(
plot.title = element_text(face = "bold", size = 18, hjust = 0.5),
plot.subtitle = element_text(size = 14, hjust = 0.5, margin = margin(b = 15)),
axis.text.x = element_text(angle = 45, hjust = 1, size = 12, face = "bold"),
axis.text.y = element_text(size = 11),
axis.title.y = element_text(size = 12, margin = margin(r = 10)),
legend.position = "none",
plot.caption = element_text(face = "italic", size = 10, hjust = 0.5,
margin = margin(t = 15), lineheight = 1.2),
panel.grid.major.x = element_blank()
)
Acute Severe Ulcerative Colitis (ASUC) is a medical emergency, affecting up to 25% of patients with UC with 1% mortality rate [1]. Diagnosis is based on the modified Truelove and Witts criteria [2], which includes:
Complications include: toxic megacolon, bowel perforation, gastrointestinal bleeding, thromboembolism, electrolyte imbalance, and colectomy.
Red Flags: Watch for toxic megacolon, severe anemia, systemic toxicity, or signs of perforation.
Always evaluate for triggering factors like NSAID use or enteric infections.
Admission:
Initial Investigations:
Abdominal X-ray to assess for colonic dilation (>6 cm suggests toxic megacolon).
Abdominal CT if signs of peritonitis or suspected perforation. Immunosuppressive treatment and old age can mask the signs of toxicities so keep a high index of suspicion.
Screen for biological therapy eligibility: viral serologies, latent TB, lipid and magnesium levels (shouldn’t delay treatment).
Endoscopy:
Avoid:
First-Line Therapy:
Monitoring:
If there is no response to IV corticosteroids after 3 days based on the above criteria, initiate rescue therapy [10].
Options include:
Cyclosporine VS Infliximab; * Short term outcomes are comparable between infliximab and cyclosporin as salvage therapies (CONSTRUCT trial) [14]. * Efficacy: ~70% short-term colectomy-free survival for both [14]. * Long-term efficacy and safety results remain similar for both treatments. * Cyclosporin-treated patients had a higher relapse rate than those treated with infliximab. * In case of previous failure to anti-TNF and especially to infliximab, cyclosporin is an alternative to surgery and a bridge to another biological maintenance therapy. * The selection of second-line therapies can be influenced by clinicians' habits, patients' features, safety, or efficacy concerns. * Infliximab is generally preferred due to ease of administration and familiarity. * Cyclosporine may be considered in patients previously exposed to anti-TNF agents.
Contraindications to rescue therapy:
Consider switching salvage agent if first fails.
Combination of ustekinumab with cyclosporine in patients with steroid refractory ASUC and previous exposure to biological therapy (AntiTNF, Vedolizumab, and JAK2) can achieve colectomy-free remission [16].
Tofacitinib: oral JAK inhibitor
Despite the use of salvage therapy like calcineurin inhibitors or infliximab, colectomy rates remain close to 30% for patients presenting with ASUC.
After induction of remission, long-term maintenance therapy is critical to prevent relapse [18].
Options include:
Therapy should be tailored based on patient response, prior medications, and risk factors.
Steroids should not be used for maintenance due to long-term side effects.
Use predictive scores, reassess daily, escalate early.
Pitfalls:
# Load required packages
library(ggplot2)
library(dplyr)
library(stringr)
# Create timeline data with wrapped text
timeline_data <- data.frame(
Day = c("Day 0", "Day 3", "Day 4-7", "Post-acute"),
Description = c(
"Admit, exclude infection,\nstart IV steroids",
"Assess response; if refractory\n→ salvage therapy",
"Evaluate salvage response;\nescalate or surgery",
"Plan long-term management\nor surgery"
),
Position = 1:4
)
# Create the timeline visualization
ggplot(timeline_data, aes(x = Position, y = 0)) +
# Add timeline
geom_segment(aes(x = 0.5, xend = 4.5, y = 0, yend = 0),
color = "black", linewidth = 2, alpha = 0.7) +
# Add larger phase markers (circles)
geom_point(aes(fill = Day), size = 35, shape = 21, color = "black") +
# Add day labels inside circles
geom_text(aes(label = Day), color = "white", fontface = "bold", size = 5) +
# Add description boxes below circles
geom_label(aes(y = -0.25, label = Description),
fill = "lightyellow", color = "black",
size = 4.5, label.padding = unit(0.6, "lines"),
lineheight = 0.8) +
# Customize colors
scale_fill_manual(values = c("Day 0" = "#4E79A7",
"Day 3" = "#F28E2B",
"Day 4-7" = "#E15759",
"Post-acute" = "#59A14F")) +
# Theme adjustments
theme_void() +
theme(
plot.title = element_text(face = "bold", size = 18, hjust = 0.5, margin = margin(b = 15)),
plot.subtitle = element_text(size = 14, hjust = 0.5, margin = margin(b = 25)),
legend.position = "none",
plot.margin = margin(1, 1, 1.5, 1, "cm")
) +
# Set limits to ensure everything is visible
ylim(-0.4, 0.2) +
xlim(0.5, 4.5) +
# Add titles
labs(title = "ASUC Management Timeline",
subtitle = "Clinical Pathway for Acute Severe Ulcerative Colitis")
# Load required packages
library(DiagrammeR)
library(htmltools)
# Create the ASUC management flowchart
grViz("
digraph ASUC_Management_Flowchart {
# Graph settings
graph [layout = dot, rankdir = TB, nodesep = 0.5, ranksep = 0.8]
node [fontname = 'Helvetica', fontsize = 12]
edge [color = 'black', arrowhead = vee]
# Define nodes with different shapes for different types of steps
start [label = 'Hospital admission\nSuspect ASUC',
shape = oval, style = filled, fillcolor = 'lightblue']
initial_workup [label = 'Initial work up:\n- CBC, CRP/ESR, Albumin\n- Stool studies (C.Diff)\n- Flex sigmoidoscopy (Mayo score)\n- Abdominal X ray',
shape = box, style = filled, fillcolor = 'lightyellow']
start_steroids [label = 'Start IV steroids\n0.8mg/kg',
shape = box, style = filled, fillcolor = 'lightyellow']
assess_day3 [label = 'Assess response day 3\nOxford score',
shape = diamond, style = filled, fillcolor = 'lightcoral']
responder [label = 'Responder to steroid',
shape = box, style = filled, fillcolor = 'palegreen']
non_responder [label = 'Non-responder to steroid',
shape = box, style = filled, fillcolor = 'lightpink']
transition [label = 'Transition to oral steroid\nGradual tapering of steroid\nMaintenance therapy: biological or\nsmall molecules',
shape = box, style = filled, fillcolor = 'lightyellow']
salvage [label = 'Start salvage therapy:\nInfliximab or Cyclosporine',
shape = box, style = filled, fillcolor = 'lightyellow']
reassess [label = 'Reassess day 4-7',
shape = diamond, style = filled, fillcolor = 'lightcoral']
salvage_responder [label = 'Responder',
shape = box, style = filled, fillcolor = 'palegreen']
salvage_non_responder [label = 'Non-responder',
shape = box, style = filled, fillcolor = 'lightpink']
maintenance [label = 'Plan maintenance therapy:\nbiological or small molecules',
shape = box, style = filled, fillcolor = 'lightyellow']
surgery [label = 'Urgent surgical referral',
shape = box, style = filled, fillcolor = 'lightyellow']
# Define edges
start -> initial_workup
initial_workup -> start_steroids
start_steroids -> assess_day3
assess_day3 -> responder
assess_day3 -> non_responder
responder -> transition
non_responder -> salvage
salvage -> reassess
reassess -> salvage_responder
reassess -> salvage_non_responder
salvage_responder -> maintenance
salvage_non_responder -> surgery
}
")# Add some CSS styling for better appearance
tags$style(HTML("
.node oval {
fill: lightblue;
}
.node box {
fill: lightyellow;
}
.node diamond {
fill: lightcoral;
}
.node note {
fill: lightgrey;
}
"))Ileal pouch anal anastomosis (IPAA) is the most common operation done for ulcerative colitis. There are two techniques to perform the IPAA:
Hand-Sewn IPAA with Mucosectomy: In this method, a mucosectomy is first performed by removing the rectal mucosa from the distal rectum to the dentate line, leaving a short muscular cuff. The ileal pouch is then anastomosed to the anal transitional zone using a hand-sewn technique, approximating the full thickness of the pouch wall to the internal sphincter and the remaining anal mucosa.
Stapled IPAA: In the stapled approach, the ileal pouch is anastomosed to the distal rectal mucosa just above the anal transitional zone, preserving a short rectal cuff. The remaining rectal mucosa requires regular follow-up due to the potential risk of developing dysplasia or cancer.
The surgery for a pouch almost always involves two or three steps.
The Pouchitis Disease Activity Index (PDAI) has been developed to standardize diagnostic criteria and assess the severity of pouchitis [9].
### Type of Inflammatory Pouch Disorders
library(knitr)
library(kableExtra)
# Create the data frame
pouch_types <- data.frame(
Term = c("Intermittent Pouchitis", "Chronic Antibiotic-Dependent Pouchitis", "Chronic Antibiotic-Refractory Pouchitis", "Crohn’s-like Disease of the Pouch"),
Definition = c("Isolated, infrequent episodes that resolve with therapy or spontaneously, followed by extended periods (> months) of normal function.",
"Recurrent episodes that respond to antibiotics but relapse shortly after stopping (days/weeks). Requires recurrent/continuous therapy.",
"Relapsing or continuous symptoms with inadequate response to standard antibiotic therapy, requiring escalation to other therapies.",
"Defined by features like fistulae (>12mo post-op), strictures, or pre-pouch ileitis. Often coexists with pouchitis.")
)
# Generate the formatted table
kable(pouch_types, format = "html", col.names = c("Term", "Definition"), align = c('l', 'l'), caption = "Table 1: Types of Inflammatory Pouch Disorders") %>%
kable_styling(bootstrap_options = c("striped", "hover", "condensed"), full_width = F) %>%
column_spec(1, bold = TRUE, width = "5cm") %>%
column_spec(2, width = "15cm")| Term | Definition |
|---|---|
| Intermittent Pouchitis | Isolated, infrequent episodes that resolve with therapy or spontaneously, followed by extended periods (> months) of normal function. |
| Chronic Antibiotic-Dependent Pouchitis | Recurrent episodes that respond to antibiotics but relapse shortly after stopping (days/weeks). Requires recurrent/continuous therapy. |
| Chronic Antibiotic-Refractory Pouchitis | Relapsing or continuous symptoms with inadequate response to standard antibiotic therapy, requiring escalation to other therapies. |
| Crohn’s-like Disease of the Pouch | Defined by features like fistulae (>12mo post-op), strictures, or pre-pouch ileitis. Often coexists with pouchitis. |
library(ggplot2)
library(dplyr)
# Create data
complication_data <- data.frame(
Complication = c("Pouchitis (by 2 yrs)", "Pouchitis (lifetime)", "Chronic Pouchitis", "Crohn's-like Disease", "Colectomy (5-yr risk)", "Colectomy (10-yr risk)"),
Percentage = c(48, 80, 17, 10, 7.0, 9.6),
Group = c("Pouchitis", "Pouchitis", "Pouchitis", "Pouchitis", "Colectomy", "Colectomy")
)
# Order the factors for the plot
complication_data$Complication <- factor(complication_data$Complication,
levels = complication_data$Complication[order(complication_data$Percentage)])
# Create the plot
ggplot(complication_data, aes(x = Complication, y = Percentage, fill = Group)) +
geom_col(width = 0.7) +
geom_text(aes(label = paste0(Percentage, "%")), hjust = -0.1, size = 3.5, fontface = "bold") +
coord_flip() + # Makes horizontal bars for easier reading
scale_fill_manual(values = c("Colectomy" = "steelblue", "Pouchitis" = "salmon")) +
labs(title = "Prevalence and Risk of Complications after IPAA",
subtitle = "Based on referenced clinical data [3]",
x = "",
y = "Percentage of Patients (%)",
fill = "Complication Type") +
theme_minimal() +
theme(legend.position = "top") +
expand_limits(y = c(0, 85)) # Adjust to make room for labels
library(DiagrammeR)
# Define the graph using DOT language
grViz("
digraph pouchitis_algorithm {
# Global graph settings
graph [layout = dot, rankdir = TB, fontname = Helvetica, nodesep = 0.5]
node [shape = box, style = 'rounded, filled', fillcolor = 'lightgrey', fontname = Helvetica, width = 3.5, height = 0.8]
edge [fontname = Helvetica, fontsize = 10]
# Nodes (Decision and Action points)
start [label = 'Patient presents with\nsymptoms of pouchitis', shape = oval, fillcolor = 'lightblue']
a1 [label = 'Evaluate for alternative causes:\nC. diff, stricture, cuffitis, CD']
d1 [label = 'Symptoms resolve?', shape = diamond, fillcolor = 'lightyellow']
a2 [label = 'Diagnose Pouchitis\n(PDAI, symptoms, endoscopy)']
d2 [label = 'Episode Type?', shape = diamond, fillcolor = 'lightyellow']
t1 [label = 'Infrequent Episode\n→ 2-4 wk antibiotics\n(Cipro/Metro)']
t2 [label = 'Chronic Antibiotic-DEPENDENT\n→ Chronic/cyclical abx\n→ Consider advanced therapy']
t3 [label = 'Chronic Antibiotic-REFRACTORY\n→ Advanced therapy\n(Vedolizumab has EMA approval)']
t4 [label = 'Crohn\\'s-like Disease\n→ Advanced therapy\n→ Short-term budesonide']
end [label = 'Symptom Control', shape = oval, fillcolor = 'lightblue']
# Edges (The flow)
start -> a1
a1 -> d1
d1 -> a2 [label = 'No']
d1 -> end [label = 'Yes (e.g., C. diff cured)']
a2 -> d2
d2 -> t1 [label = 'Infrequent']
d2 -> t2 [label = 'Dependent']
d2 -> t3 [label = 'Refractory']
d2 -> t4 [label = 'Crohn\\'s-like']
t1 -> end
t2 -> end
t3 -> end
t4 -> end
# Force a straight line from d1 to end
{rank = same; d1; end}
}
")By: Heba Al Farhan
Effective preoperative management in inflammatory bowel disease (IBD) is central to improving surgical outcomes, minimizing complications, and enhancing recovery. Research indicates that patients undergoing surgery for IBD, such as Crohn’s disease (CD) and ulcerative colitis (UC), benefit from a comprehensive, multidisciplinary approach to optimization. This detailed review explores strategies with supporting evidence, including nutritional, pharmacological, and psychological interventions, alongside relevant statistics and data.
Surgical intervention is required in approximately 20-30% of UC patients and up to 70-80% of CD patients during their lifetime. Preoperative management plays a critical role in reducing risks like infections, anastomotic failure, and prolonged recovery periods. Studies consistently demonstrate that addressing modifiable factors preoperatively can lower complication rates significantly. For instance, Molina Arriero et al. (2023) reported a 35% reduction in surgical complications among patients who underwent structured preoperative programs compared to those receiving standard care (3).
Malnutrition is prevalent in IBD patients undergoing surgery, with rates as high as 50-60% in Crohn's disease cases and 20-40% in ulcerative colitis. Malnourished patients are 2.5 times more likely to experience postoperative infections and complications (6). Tools like the Malnutrition Universal Screening Tool (MUST) and serum albumin measurements (threshold <3.0 g/dL) are recommended for nutritional evaluation (7).
Research highlights EEN as an effective strategy to reduce surgical complications. Vanderstappen et al. (2024) found that EEN reduced postoperative infection rates by up to 40%, improved albumin levels by 20-30%, and shortened hospital stays by 25% relative to patients receiving standard oral nutrition (6,8).
PN is especially beneficial for patients with severe obstruction or inflammation. According to Efron et al. (2007), preoperative PN in malnourished patients reduced the incidence of anastomotic leaks to 8% from 15% in non-optimized individuals (7). However, PN was associated with an 8-12% increased risk of catheter-related infections (5).
Correcting deficiencies in vitamin D, iron, and zinc is essential for recovery. Forbes et al. (2017) emphasized that addressing anemia, prevalent in 30-40% of IBD patients, is critical, as untreated anemia doubles postoperative complication risks (10). Table 1:
| Deficiency Type | Prevalence | Cut-off Values | Impact | Treatment |
|---|---|---|---|---|
| Anemia | 30-40% of IBD patients (Forbes et al., 2017) | - Men: Hb <13 g/dL. - Non pregnant women: Hb <12 g/dL. - Pregnant women: Hb <11 g/dL. | - Untreated anemia doubles the risk of postoperative complications, including infections and delayed wound healing. - Contributes to fatigue and poor quality of life. | - Iron Deficiency Anemia (IDA): Intravenous iron (e.g., ferric carboxymaltose) for active disease or severe deficiency. - ACD: Erythropoiesis-stimulating agents in severe cases. - Vitamin B12/Folate Deficiency: Parenteral vitamin B12 (1000 mcg IM monthly) and oral/IV folate. |
| Vitamin D Deficiency | Up to 70% of IBD patients | - Deficiency: 25(OH)D <20 ng/mL - Insufficiency: 20-30 ng/mL | - Low bone density - Worsened inflammation - Potentially detrimental immunomodulatory effects. | - High-dose supplementation (50,000 IU weekly) until levels normalize >30 ng/mL. - Maintenance dose of 1,000-2,000 IU daily. - Regularly monitor levels. |
| Zinc Deficiency | Common, especially in those with chronic diarrhea or high-output fistulas | Serum zinc <70 mcg/dL | - Impaired wound healing - Increased risk of infections - Worsened diarrhea | - Mild Deficiency: Oral zinc sulfate (220 mg daily for 2-3 weeks). - Severe Deficiency: IV zinc for cases with severe malabsorption or prolonged PN. |
| Magnesium Deficiency | Seen in chronic diarrhea, ileostomies, or high-output fistulas | Varies (monitor levels closely) | Worsened diarrhea, muscle weakness, and potential cardiac arrhythmias. | - Use oral magnesium chloride or sulfate. - Severe cases may require IV magnesium sulfate. |
| Calcium Deficiency | Common in patients on corticosteroids or with low bone density | Varies (typically assessed with serum calcium) | - Weak bones and increased risk of fractures in long term. | - 1,000-1,500 mg calcium daily along with vitamin D supplementation to improve absorption. |
| Selenium Deficiency | Rare, seen in severe malnutrition or prolonged PN | Varies (often assessed indirectly) | - Poor antioxidant defense and immune function. | Selenium supplementation via oral or IV routes based on severity. |
Balancing immunosuppression to maintain disease control while minimizing postoperative complications is a complex challenge. (Table 2)
Studies indicate that the risk of postoperative infections in patients using biologics does not exceed 15% if the timing of the last dose aligns with the mid-treatment interval (4,8). Vanderstappen et al. (2024) recommend administering the last dose at least four weeks before surgery to avoid adverse outcomes (6).
Chronic steroid use (>20 mg/day of prednisone or equivalent) is strongly linked to complications, including a 20-30% increased risk of wound infections and a 15% higher chance of anastomotic leaks. Tapering corticosteroids to below 10 mg/day preoperatively has been shown to halve these risks (7, 2).
| Medication | Timing of Last Dose/Preoperative Adjustments | Risk of Postoperative Complications | Recommendations for Continuation/Tapering | Notes on Special Considerations |
|---|---|---|---|---|
| Infliximab | Plan surgery mid-dose interval; monitor closely in high-risk or malnourished patients. | Low if timed appropriately (≤15%) | Continue if last dose is 4–8 weeks before surgery | |
| Adalimumab | Administer last dose 2 weeks pre-surgery to minimize infection risk while maintaining disease control. | Low if timed appropriately (≤10–15%) | Continue; adjust dose timing | |
| Vedolizumab | 4–6 weeks before surgery | Minimal (<5%) | Continue; no significant impact on wound healing | Focuses primarily on gut-specific immunity; generally safe for perioperative use. |
| Ustekinumab | 8–12 weeks before surgery | Minimal if preoperative interval is respected (<5%) | Continue; administer last dose 8-12 weeks before surgery | Adjust timing carefully due to long dosing interval; assess disease stability. |
| IL-23 Inhibitors (Skyrizi, Tremfya) | 8–12 weeks before surgery | Minimal if timed appropriately (<5%) | Continue; schedule based on individual patient response. | Long dosing intervals may require adjustment and ensure disease stability. Monitor infection risk. |
| JAK Inhibitors (Tofacitinib, Upadacitinib) | 7 days before surgery | Moderate to high (10–25% risk of infections, VTE risk higher with tofacitinib) | Temporarily discontinue 1 week before surgery | Increased infection risk, particularly with tofacitinib. Strong risk-benefit evaluation required; monitor for VTE in high-risk patients. |
| Corticosteroids | Reduce to ≤10 mg/day prednisone equivalent; ideally discontinue before surgery | High (20–30% risk of wound infections, 15% chance of anastomotic leaks) | Taper to lowest effective dose; avoid abrupt discontinuation to prevent adrenal insufficiency | Chronic use increases infection risk; patients on prolonged corticosteroid therapy may require perioperative stress dosing. |
IBD patients face a threefold increased risk of VTE compared to the general population. Fiorindi et al. (2021) demonstrated that extended prophylaxis with low-molecular-weight heparin (LMWH) reduced VTE events from 10% to under 3%, underscoring its importance in perioperative protocols (9).
| Prophylaxis Type | Dose | Recommended Guidelines/Recommendations | Notes on Efficacy and Safety |
|---|---|---|---|
| Low Molecular Weight Heparin (LMWH) | - Enoxaparin: 40 mg subcutaneously once daily - Dalteparin: 5,000 IU subcutaneously once daily | - Recommended by gastroenterological societies (e.g., ACG) for all hospitalized IBD patients, including preoperative cases - Focus on high-risk or hospitalized individuals | - Significant reduction in VTE events (OR 0.27, NNT = 35) - Slight increase in major bleeding risk (OR 2.02, NNH = 114) |
| Extended LMWH | LMWH continued up to 28 days post-surgery | - Suggested for patients undergoing major abdominal surgeries or those with additional risk factors such as immobilization or disease severity | - Effective in preventing post-discharge VTE - Requires patient-specific risk-benefit analysis due to bleeding concerns |
| Unfractionated Heparin (UFH) | Dosage dependent on patient-specific factors as per medical protocols | - Considered in patients where LMWH is contraindicated or unavailable | - Potentially less effective than LMWH - Associated with higher rates of heparin-induced thrombocytopenia compared to LMWH |
| Direct Oral Anticoagulants (DOACs) | Dose varies depending on the type (e.g., apixaban, rivaroxaban) | - Not universally recommended for routine use in preoperative IBD due to limited evidence specifically in this population | - Evidence around safety and efficacy in IBD remains limited - May be considered in selected cases under careful monitoring |
| Mechanical Prophylaxis | Use of compression stockings or pneumatic devices | - Often used as an adjunct, especially in patients at risk of bleeding or contraindications to pharmacologic prophylaxis | - No direct effect on reducing VTE mortality - Beneficial as part of a multifactorial approach to reducing clot formation during hospitalization |
Cohen et al. (2024) stressed the importance of preoperative bowel preparation and antibiotic prophylaxis, which reduced surgical site infections by 20-30% in patients undergoing colorectal surgery. However, routine mechanical bowel preparation alone did not significantly improve outcomes and is now selectively used for fecal load reduction in obstructive cases (4).
Psychological factors, including heightened anxiety and depression, affect up to 40-50% of IBD patients preoperatively. This psychological distress is linked to poor compliance with preoperative optimization measures and slower recovery. Hazel et al. (2025) reported that inclusion of psychologists in multidisciplinary teams (MDTs) reduced anxiety scores by 30% and postoperative recovery times by two to three days (2). Peer-support programs like those offered by the Crohn’s & Colitis Foundation provide an additional layer of emotional support and education (5).
Effective preoperative care necessitates an MDT approach, incorporating gastroenterologists, colorectal surgeons, dietitians, psychologists, and even physiotherapists in some cases. Molina Arriero et al. (2023) found that multidisciplinary care resulted in a 50% reduction in postoperative readmission rates and a significant decrease in average hospital stay duration (3).
Prehabilitation, which combines physical, nutritional, and psychological optimization, is increasingly recognized as a critical component of preoperative care. Fiorindi et al. (2021) revealed that patients enrolled in structured prehabilitation programs experienced 20% fewer complications, 15% shorter hospital stays, and 40% fewer ICU admissions compared to non-participants (9,1).
Recent studies and guidelines provide clear recommendations on the timing of resuming biologic agents after surgery for inflammatory bowel disease. These recommendations focus on ensuring patient safety while minimizing the risk of disease recurrence. Here's a summary of the current evidence and expert guidance:
| Biologic Agent | Timing | Key Findings | Notes |
|---|---|---|---|
| Anti-TNF Agents | Within 2 to 4 weeks post-surgery (18, 19, 20) | - Strongly recommended for preventing postoperative recurrence. - Safe to use perioperatively; detectable drug levels are not associated with increased infections. - Earlier initiation is encouraged for high-risk patients. | - Timing remains debatable, especially in patients with complications. |
| Vedolizumab | Within 2 to 4 weeks post-surgery (17, 20, 21) | - Effective in reducing recurrence rates. - Recommended for high-risk patients. - Supported by recent trials like REPREVIO. | - Limited data on long-term outcomes compared to anti-TNF agents. - Tailored approach required for patients with prior biologic failures. |
| JAK Inhibitors | As early as 3 to 5 days post-surgery (if no complications) (17) | - Limited data available. - May provide rapid disease control without increasing complication rates. | - Lack of robust evidence makes their use controversial. - Not widely recommended in current guidelines. |
| General Considerations | Timing depends on patient recovery and absence of complications/infections (17, 20) | - Risk of infection must be ruled out before resuming biologics. - Monitoring tools like fecal calprotectin and endoscopy are essential. - Emerging tools like intestinal ultrasound are promising for non-invasive monitoring. | - A tailored approach is critical for better outcomes. - Newer biologics and small molecules (e.g., IL-12/23 inhibitors, S1P modulators) are not yet fully studied in postoperative settings. |
Vanderstappen et al. (2024) highlighted gaps in global standardization of preoperative optimization protocols, especially regarding nutritional strategies and biologics management (6). While current interventions show strong efficacy, future research should focus on refining and individualizing prehabilitation models, particularly for high-risk patients with severe inflammation or comorbid conditions like diabetes and cardiovascular diseases.
Optimizing preoperative care for IBD patients is a nuanced, multifactorial process involving nutritional supplementation, judicious pharmacological management, and psychological support. Evidence suggests that addressing malnutrition, managing biologics with precision, and employing extended VTE prophylaxis can reduce complications by up to 50%. Emerging MDT-driven models and structured prehabilitation programs have the potential to revolutionize preoperative care further. Standardizing and tailoring these approaches will significantly improve patient outcomes for those navigating the complexities of IBD-related surgery.
Essential tips for management success
By: Heba Al Farhan
Inflammatory Bowel Disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic and progressive condition characterized by intestinal inflammation that may lead to significant complications, such as strictures, fistulas, perforations, and colorectal cancer. Effective management hinges on timely therapeutic interventions and meticulous disease monitoring to tailor treatment adjustments, achieve sustained remission, and prevent progression (1,14).
The development of the STRIDE II framework has revolutionized IBD care, emphasizing a treat-to-target approach that prioritizes long-term therapeutic goals like clinical remission, mucosal healing, and biomarker normalization over symptom management (1). Recommendations from the European Crohn’s and Colitis Organisation (ECCO) and the American College of Gastroenterology (ACG) provide complementary guidance, underscoring the necessity of personalized, evidence-based monitoring strategies that combine clinical assessments, biomarkers, imaging, and endoscopic evaluations (2,3).
This chapter provides a comprehensive overview of IBD monitoring, integrating evidence from STRIDE II, ECCO, and ACG, alongside insights into the latest advances shaping the future of personalized care.
Optimal disease monitoring involves a multimodal, integrated approach to evaluate IBD comprehensively. This ensures accurate detection of active inflammation, guides therapeutic decisions, and assesses treatment response.
A selection of monitoring solutions is available:
Symptom-based assessments rely on indices like the Crohn’s Disease Activity Index (CDAI) for Crohn’s disease and the Mayo Clinic Score (MCS) for ulcerative colitis. These tools focus on patient-reported outcomes such as stool frequency, rectal bleeding, abdominal pain, and health status to give preliminary disease activity estimates (3).
While commonly used, symptom-based measurements often lack correlation with objective inflammation markers. Studies reveal that over 30% of IBD patients classified as being in clinical remission through these indices still exhibit mucosal inflammation detectable via endoscopy (3). This highlights the need for additional monitoring modalities to verify disease activity accurately.
Under STRIDE II, clinical remission is defined as the absence of symptoms, achieved without corticosteroids, and confirmed through additional parameters such as biomarkers or imaging. Combining subjective and objective indicators ensures greater reliability in activity assessments (1).
Endoscopy is considered the
Several dietary regimens have shown benefit for patients with IBD, targeting either induction, maintenance of remission, or both. Examples are outlined in table-1 below:
| Aim | Diet (induction or maintenance therapy) |
|---|---|
| Both | Crohn’s Disease Exclusion Diet (CDED)1 |
| Both | Specific Carbohydrate Diet (SCD)2 |
| Both | Mediterranean diet3 |
| Both | Plant-based diet4 |
| Both | Paleo Auto-Immune Protocol (AIP)2 |
| Induction | CD-TREAT5 |
| Both | Low-emulsifier or carrageenan diets6 |
| Both | Low sulfur diet7 |
| Maintenance | Low-fat diet8 |
| Maintenance | Low-meat diet (FACES)9 |
| Both | Food exclusion based on IgG antibodies10 |
| Both | Novel ulcerative colitis exclusion diet (UCED)11 |
The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines note that no universal “IBD diet” can be recommended to induce or maintain the remission. (12) However, the American Gastroenterological Association (AGA) advises that, barring contraindications, patients with IBD should adopt a Mediterranean diet. This diet is characterized by a high intake of fresh fruits, vegetables, monounsaturated fats, complex carbohydrates, and lean proteins, while minimizing ultra-processed foods, added sugars, and salt. This approach supports overall health and well-being. (13)
Malnutrition in IBD can exacerbate disease, increase postoperative complications, and prolonged hospital stays. It is associated with higher risks of venous thromboembolism, infections, and mortality. All patients should be screened for malnutrition at diagnosis and regularly thereafter. Reliance solely on serum albumin or BMI is discouraged; these markers lack specificity and sensitivity for nutritional status. Instead, a multidisciplinary approach involving dietitian counselling is recommended to identify and manage nutrition-related disorders promptly. (12,13.14,15,16)
Patients with IBD are at risk for micronutrient deficiencies due to diarrhoea, malabsorption, intestinal failure, and reduced dietary intake. Since most of the micronutrients are acute-phase reactants, screening should be performed at least annually and ideally during clinical remission. (12) Screening tests should include:
Anaemia is a common extraintestinal manifestation of IBD, affecting 6–74% of IBD patients, and it is more common in Crohn’s disease than ulcerative colitis. It often results from a combination of iron deficiency anaemia (IDA) and chronic disease (ACD). For patients in remission or mild disease, screening should be obtained every 6-12 months, while patients with active disease such measurements should be obtained at least every 3 months. (17)
| Type of Anemia | Diagnosis |
|---|---|
| Iron deficient anemia (IDA) | Inactive disease: serum Ferritin <30 µg/L Active disease: serum Ferritin up to 100 µg/L |
| Anemia of chronic disease (ACD) | serum ferritin >100 µg/L and transferrin saturation <20% in case of active disease |
| Combined deficiencies | ferritin levels fall between 30 and 100 µg/L. |
Oral iron supplementation is the preferred option in patients with mild anaemia and inactive disease. Intravenous iron is reserved for those with active disease, severe anaemia (haemoglobin <100 g/L), intolerance to oral iron, and in patients who need erythropoiesis-stimulating agents. (12)
Patients with active IBD or those on steroids should have serum calcium and vitamin D monitored every 3–6 months. In remission, monitoring can be extended to every 6–12 months. Supplementation helps prevent low bone mineral density, osteopenia, and osteoporosis. Osteopenia and osteoporosis should be managed according to current osteoporosis guidelines. (12)
Vitamin B12 deficiency is prevalent in Crohn’s disease, particularly after resection of >30 cm of the distal ileum. (18) Diagnosis involves low serum cobalamin levels (<148 pM) and elevated biomarkers like homocysteine (>15 mM) or methylmalonic acid (>270 mM). The diagnosis of clinical B12 deficiency further requires macrocytosis and/or neurological symptoms. (19,12)
Patients with clinical deficiency should receive 1000 mg of vitamin B12 by intramuscular injection every other day for a week and then every month for life (20). Patients with more than 20 cm of ileum resected, should receive 1000 mg of vitamin B12 prophylactically also every month and indefinitely. Oral therapy as a less explored alternative (21) For now, patients must be advised for parenteral formulas.
Probiotics such as Escherichia coli Nissle 1917 and VSL#3 can induce remission in mild to moderate ulcerative colitis and maintain remission in pouchitis. However, their role in Crohn’s disease is limited and not recommended for maintenance therapy. (12)
Oral Nutrition Supplements (ONS) is the First-line support when dietary intake is insufficient, but it is a supportive measure used in addition to normal food. (12)
Enteral Nutrition (Tube Feeding): Preferred over parenteral nutrition (PN) unless contraindicated (e.g., bowel obstruction, high-output fistula). (12)
Parenteral Nutrition (PN): Reserved for patients who’s oral and or tube feeding are proved to be insufficient to meet their requirement, and for patients with severe gastrointestinal dysfunction or complications. Bowel obstruction where there is no possibility to place a feeding tube beyond the obstruction, short bowel syndrome, and presence of anastomotic leak or high out-put fistula are some of the common indications for PN in patients with IBD. (12)
EEN is effective for inducing remission in Crohn’s disease, particularly in children. It also serves as a steroid-sparing bridge therapy and optimizes nutritional status pre-surgery. (12)
Strategies such as thorough chewing, cooking, and processing these foods into a softer consistency can enhance dietary variety and fiber intake. (13)
Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gastrointestinal tract. The pathogenesis of IBD involves a complex interplay of genetic predisposition, immune dysregulation, environmental factors, and alterations in the gut microbiota (1). Patients with IBD are at an increased risk of infections due to the underlying immune dysregulation, the use of immunosuppressive therapies, and the potential for disruption of the gut barrier (2,3).
Infections are a significant cause of morbidity and mortality in patients with IBD. Studies have shown that patients with IBD are at a higher risk of both opportunistic and community-acquired infections compared to the general population (4). The risk of infection is further amplified using immunosuppressive medications, such as corticosteroids, thiopurines, methotrexate, and biologic therapies (2).
A large population-based study found that patients with IBD had a 1.5 to 2-fold increased risk of serious infections compared to the general population (4). The most common infections in IBD patients include respiratory infections, urinary tract infections, and gastrointestinal infections. Opportunistic infections, such as tuberculosis (TB), cytomegalovirus (CMV), and herpes zoster, are also more prevalent in this population (5).
Several factors contribute to the increased risk of infections in patients with IBD:
| Drug Class | Degree of Immunosuppression | Comments |
|---|---|---|
| Aminosalicylates | None | No systemic effects |
| Topical Steroids | Low | Systemic effects with oral budesonide >6 mg/day |
| Systemic Steroids | Moderate-Severe | Doses ≥20 mg for >2 weeks, associated with increased risk of bacterial and fungal infections |
| Vedolizumab | Selective | Gut-selective; increased risk for intestinal infections |
| Methotrexate | Moderate-Severe | Doses >20 mg/week, lower dose is considered low immunosuppression |
| Thiopurines | Moderate-Severe | Doses >3 mg/kg/day (azathioprine) or >1.5 mg/kg/day (6-MP), lower dose is considered low immunosuppression, increase risk of viral infections |
| Anti-TNF Agents | Moderate-Severe | Higher risk of mycobacterial, bacterial and fungal infections, risk further increase with combination therapy |
| Calcineurin inhibitors (Cyclosporine, tacrolimus) | Moderate-Severe | Rarely used because of increased risk of serious infections among other adverse effect |
| JAK Inhibitors | Moderate-Severe | Increased risk of viral infections, including herpes zoster |
| IL 23 inhibitors | Moderate -Severe | Data suggest lower risk of serios infections with IL-23 and JAK inhibitors compared with anti-TNF |
The following table2 summarizes key risk factors associated with the development of colorectal cancer (CRC) in patients with inflammatory bowel disease.11,12,13,14,15
Visible dysplasia is any lesion seen on endoscopy, either polypoid or non-polypoid, and includes:
A. Endoscopically Resectable Lesions
B. Non-resectable or Poorly Demarcated Lesions
Invisible dysplasia refers to dysplasia found on random biopsies with no corresponding visible lesion on endoscopy.
A. Low-Grade Dysplasia (LGD)
B. High-Grade Dysplasia (HGD)
Figures 2 and 3(adopted from AGA Clinical Practice Update on Endoscopic Surveillance and Management of Colorectal Dysplasia in Inflammatory Bowel Diseases: Expert Review)21 provide classification and detection of dysplasia in IBD and a structured management approach of dysplasia in inflammatory bowel disease (IBD) based on visibility, grade, resectability, and associated risk factors.
| Risk Category | Criteria | Surveillance Interval |
|---|---|---|
| High Risk | PSC, severe inflammation, dense psudoinflammation, CRC in FDR <50, <5 year history of invisible dysplasia or high risk visible dysplasia | Every 1 year |
| Intermediate Risk | Mild inflammation, family CRC but no 1st-degree relative <50 years, <5 year history of invisible dysplasia or high-risk visible dysplasia, <5year history of low risk visible dysplasia | Every 2- 3 year |
| Low Risk | Maintaining disease remission with mucosal healing pulse either of 2 consecutive examinations without dysplasia, Minimal colitis (UC proctitis or<1/3 of the colon in CD) | Every 5 years |
Table 1: Surveillance strategies recommended for patients with IBD based on risk stratification. CD: Crohn’s disease; UC: Ulcerative Colitis; CRC: colorectal cancer; FDR: first-degree relative; PSC: primary sclerosing
| Risk Factor | Explanation |
|---|---|
| Duration of Disease | CRC risk increases significantly after 8–10 years of IBD onset. Longer duration = higher cumulative inflammation and mutation burden. |
| Extent of Colitis | Risk is highest in pancolitis, intermediate in left-sided colitis, and negligible in proctitis. |
| Primary Sclerosing Cholangitis (PSC) | Strongest independent risk factor. PSC + IBD increases CRC risk 4–10× even with mild colitis. |
| Severity of Inflammation | Ongoing or recurrent inflammation promotes DNA damage and dysplasia. Histologic inflammation is strongly correlated with cancer risk. |
| Family History of CRC | Especially if CRC occurs in a first-degree relative <50 years old. Suggests genetic susceptibility. |
| History of Dysplasia | Prior diagnosis of low-grade or high-grade dysplasia increases progression risk to CRC. |
| Strictures | May harbor or mask underlying dysplasia or carcinoma. Require biopsy or resection if suspicious. |
| Post-inflammatory Polyps (Pseudopolyps) | Marker of previous severe inflammation; associated with increased CRC risk indirectly. |
| Younger Age at IBD Diagnosis | More prolonged exposure to inflammation increases cumulative cancer risk. |
| Male Sex | Some studies suggest a slightly higher CRC risk in men with IBD. |
| Immunosuppressive Therapy | Conflicting evidence; some concern with long-term use of thiopurines (not directly a proven CRC risk factor). |
Table 3 illustrates the recommended guidelines intervals following the initial colonoscopy, tailored to the individual’s CRC risk21.21
| US Society (Methodology) | Initiation after Symptom Onset (years) | Intervals (years) | Risk Factors that Determine Interval |
|---|---|---|---|
| ACG [2019] (GRADE) | 8–10 | 1–2 | PSC, other risk factors for CRC, previous histology |
| ASGE [2015] (GRADE) | 8 | 1–3 | PSC, inflammation, FDR with CRC |
| AGA 2021: Clinical Practice Update | 8–10 | 1–5 | PSC and other risk factors, prior histology, inflammatory burden, consecutive examinations without dysplasia |
ACG: American College of Gastroenterology ,ASGE: American Society of Gastrointestinal Endoscopy ,AGA: American Gastroenterological Association,PSC: Primary sclerosing cholangitis, CRC: Colorectal cancer ,FDR: First-degree relative.
Note: Individuals with ulcerative proctitis or proctosigmoiditis and CD limited to the ileum should undergo age specific screening as per general guidelines.
| Guideline (Year of Publication) | Type of Endoscopic Surveillance | Random or Targeted Biopsies |
|---|---|---|
| SCENIC Consensus (2015) | HD recommended If SD, dye-CE recommended If HD, dye-CE suggested | No consensus |
| SCENIC Commentary (2022) | HD-WLE, dye-CE, or VCE | Random limited to highest-risk groups only (PSC, prior dysplasia, atrophic scarred colon, ongoing active inflammation) |
| ECCO Guideline (2017) | HD recommended | Random if WL Targeted only if dye-CE |
| ECCO Guideline (2023) | HD-WLE, dye-CE, or VCE | Random in high-risk (PSC or history of dysplasia) |
| ACG Clinical Guideline (2019) | If SD, dye-CE recommended If HD, dye-CE or VCE recommended | No recommendation |
| AGA Clinical Practice Update (2021) | HD recommended Dye-CE should be considered VCE acceptable alternative if HD | Random if WL only and all patients with high risk (PSC or history of dysplasia) Targeted if dye-CE or VCE |
| BSG Guideline (2019) | HD recommended If SD, dye-CE recommended If HD, dye-CE suggested NBI not suggested | Targeted recommended |
Table 4:Overview of recommendations from international organizations for dysplasia surveillance in patients with IBD. ACG, American College of Gastroenterology; AGA, American Gastroenterological Association; BSG, British Society of Gastroenterology; CE, chromoendoscopy; ECCO, European Crohn’s and Colitis Organization; HD, high definition; SD, standard definition; WLE, white-light endoscopy; NBI, narrow band imaging; PSC, primary sclerosing cholangitis; VCE, virtual chromoendoscopy.
| Modality | Technology | Advantages | Limitations | Guideline Recommendation |
|---|---|---|---|---|
| SD-WLE | Standard-definition white-light endoscopy | Widely available | Low detection rate; misses flat lesions | Not recommended |
| HD-WLE | High-definition white-light endoscopy | Better mucosal detail; allows targeted biopsies | Less sensitive than CE for not available | Acceptable if CE |
| Dye-Based Chromoendoscopy (CE) | Dye application (indigo carmine/methylene blue) | Highest sensitivity; detects flat dysplasia | Time-consuming; needs expertise | Gold standard (SCENIC, ECCO, AGA) |
| Narrow-Band Imaging (NBI) | Optical filter-enhanced blue/green light | No dye needed; highlights vascular patterns | Lower sensitivity than dye-CE; operator dependent | Acceptable alternative (ECCO 2023) |
| Virtual Chromoendoscopy (VCE) | Digital contrast (iSCAN, FICE, OE) | No dye; faster setup | Evolving evidence; possibly less sensitive | Acceptable alternative if HD used |
| Risk Factor | Details |
|---|---|
| Immunosuppressive therapy | Thiopurines (AZA/6-MP): Increased risk of non-Hodgkin lymphoma |
| Immunosuppressive therapy | Anti-TNF agents: Slightly increased risk |
| Immunosuppressive therapy | Combination therapy: Highest risk, especially for hepatosplenic T-cell lymphoma |
| Duration and severity of IBD | Chronic inflammation may contribute, though data are mixed |
| Male sex | Particularly increased risk for hepatosplenic T-cell lymphoma |
| Age | Older patients have higher baseline lymphoma risk |
| EBV status (seronegative) | Thiopurine use in EBV-negative patients linked to EBV-related lymphoma |
| Lymphoma Type | Association with IBD | Details | Key References |
|---|---|---|---|
| Non-Hodgkin Lymphoma (NHL) | Most common | Especially B-cell lymphomas (e.g., diffuse large B-cell lymphoma). Associated mainly with thiopurine use. | Kandiel et al., JAMA, 2005; 293(19):2462–70 |
| Hepatosplenic T-cell Lymphoma (HSTCL) | Rare but serious | Aggressive T-cell lymphoma. Seen mostly in young males on combination therapy (thiopurines + anti-TNF). | Kotlyar et al., Clin Gastroenterol Hepatol, 2015; 13(4):847–58 |
| EBV-positive Lymphoproliferative Disorders | Linked to EBV seronegative patients | Seen in those starting thiopurines while EBV-naïve. Includes B-cell lymphomas, sometimes fatal. | Beaugerie et al., Lancet, 2009; 374(9701):1617–25 |
| Peripheral T-cell Lymphoma (PTCL) | Rare | Reported in IBD patients, usually after prolonged |
Transition is the process of migrating a patient with chronic disease from pediatric to adult care (1). It is characterized by uninterrupted, coordinated, comprehensive care with attention to the clinical, psychosocial and educational/vocational needs of adolescent and young adult (AYA) patients (2,3). Failed transition and transfer is associated with increased emergency department visit, hospitalization, medication escalation, surgery and overall poor patient adherence and attitude (1,4–5)
A successful transition program should include the following elements:
A multidisciplinary approach is essential for addressing the medical, nutritional, psychological, and social needs of transitioning patients.(8) The team may include:
Patient Name: Dateof Birth: / / Today’s Date / / (MRN# )
Directions to Youth and Young Adults : Please check the box that best describes your skill leve l in the following areas that are
| No, I do not know how to do this | No, but I want to learn | No, but I am learning to do this | Yes, I have started doing this | Yes, I always do this | |
|---|---|---|---|---|---|
| Managing Medications | |||||
| 1. Do you fill a prescription if you need to? | |||||
| 2. Do you know what to do if you are having a bad reaction to your medications? | |||||
| 3. Do you reorder medications before they run out? | |||||
| 4. Do you explain any medications (name and dose) you are taking to healthcare providers? | |||||
| 5. Do you speak with the pharmacist about drug interaction s or other concerns related to your medications? | |||||
| Appointment Keeping | |||||
| 6. Do you call the doctor’s office to make an appointment? | |||||
| 7. Do you follow-upon referrals for tests or check-ups or labs? | |||||
| 8. Do you arrange for your ride to medical appointments? | |||||
| 9. Do you call the doctor about unusual changes in your health (for example: allergic reactions)? | |||||
| Tracking Health Issues | |||||
| 10. Do you fill out the medical history form, including a list of your allergies? | |||||
| 11. Do you keep a calendar or list of medical and other appointments? | |||||
| 12. Do you tell the doctor or nurse what you are feeling? | |||||
| 13. Do you contact the doctor when you have a health concern? | |||||
| 14. Do you make or help make medical decisions pertaining to your health? | |||||
| 15. Do you attend your medical appointment or part of your appointment by yourself? | |||||
| Talking with Providers | |||||
| 16. Do you ask questions of your nurse or doctor about your health or health care? | |||||
| 17. Do you answer questions that are asked by the doctor, nurse, or clinic staff? | |||||
| 18. Do you ask your doctor or nurse to explain things more clearly if you do not understand their instructions to you? | |||||
| 19. Do you tell the doctor or nurse whether you followed their advice or recommendations? | |||||
| 20. Do you explain your health history to your healthcare providers (including past surgeries, allergies, and medications)? |
Please circle how you feel about the following statements
| Not at all important | Not too important | Somewhat important | Important | Very important | |
|---|---|---|---|---|---|
| How important is it to you to manage your own healthcare? | 1 | 2 | 3 | 4 | |
| How confident do you feel about your ability to manage your own health care? | 1 | 2 | 3 | 4 |
important for transition to adult healthcare. There is no right or wrong answer and your answers will remain confidential and private.
Directions to Caregivers / Parents : If your youth or young adult is unable to complete the tasks below on their own, please check the box that best describes your skill level. Check here if you area parent/caregiver completing this form.
By: Ahmed Al-Darmaki
With the latest advancements in immunosuppressants and biologics part of a prolonged therapeutic approach in treating patients with inflammatory bowel disease (IBD), patients are susceptible to hepatitis B virus (HBV) reactivation—even those who are not previously known to be infected. The range of morbidity and mortality associated with HBV reactivation among IBD patients spans from mild reactivation to hepatic decompensation with even non-hepatitis related deaths, which necessitates improved protocols to manage the situation. This anecdotal review aims to advocate for HBV screening and vaccination efforts, as well as concurrent oral antiviral treatments to reduce the risk of reactivation when managing IBD patients on an immunosuppressive course, as well as to reduce the risk of infection/reactivation during non-treatment periods.
IBD, encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is increasingly prevalent in older populations. While historically considered a disease of young adults, up to 30% of IBD patients are now over 60 years old, and approximately 10–15% of new diagnoses occur after age 60 (1, 2)
In this population, it is important to distinguish between two clinical groups:
| Feature | Elderly-Onset IBD | Younger-Onset IBD |
|---|---|---|
| Common Location (CD) | Colonic | Ileal/Ileocolonic |
| UC Extent | Left-sided/Distal | Pancolitis more common |
| Disease Behavior (CD) | Inflammatory | Complicated (stricturing/penetrating) |
| Extraintestinal Manifestations | Less common | More common |
| Immunosuppressive use | Less frequent | More frequent |
| Surgery | Lower cumulative risk | Higher cumulative risk |
| Cancer surveillance | More relevant | Age-dependent |
| Polypharmacy risk | High | Moderate |
| Diagnostic delay | More likely | Less likely |
Elderly patients often have atypical presentations, a higher burden of comorbidities, and are commonly prescribed multiple medications. These factors increase the risk of both disease- and treatment-related complications, making diagnosis, therapeutic planning, and long-term care more complex. Careful, individualized strategies are essential to improve outcomes in this population.(3, 5).
As the population ages, the incidence and prevalence of IBD globally in the older population is on the rise (1). In the next ten years, more than 1 in 3 IBD patients will be over the age of 60 (5, 6). From 1995-2016 the prevalence of UC in patients aged >65 years increased by more than three-fold. The median age of patients diagnosed with IBD has increased by more than 7 years in the last twenty years (1). Research out of France and Denmark find that 1 in 8 patients with a new diagnosis of UC and 1 in 20 with a new diagnosis of CD are diagnosed after the age of 60(1, 3, 5) A recent large nationwide cohort study from Denmark(7) showed similar trends and further classified patients aged ≥70 years as having very late-onset IBD. These patients had comparable risks of IBD-related hospitalizations and corticosteroid use as those diagnosed at 60–69 years but were significantly less likely to receive immunosuppressive therapy or undergo surgery.
The differential diagnosis in older adults is broad and includes(2):
Endoscopic and histologic confirmation is critical. Delays in diagnosis can worsen outcomes. Newer non-invasive markers like fecal calprotectin are helpful but may be elevated in other conditions common in older adults (e.g., diverticulitis).
The interplay of frailty, comorbidities, and diminished functional reserve plays a central role in shaping outcomes for elderly patients with IBD(8, 9). Older individuals are more likely to experience adverse outcomes not only due to the disease itself but due to impaired physiological reserves.
Frailty—reduced strength, endurance, and function— is a stronger predictor of poor clinical outcome than chronological age; 40% of elderly-onset IBD cohort are frail. It correlates with increased hospitalizations, postoperative complications, disability, and mortality(9). Therefore, fraitiliy needs to be screened in all elderly with IBD. Clincial Box 1 list clinical evaluation tools.
Polypharmacy is another hallmark of this population, driven by coexisting cardiovascular, metabolic, musculoskeletal, and neurocognitive conditions. . This increases the chances for drug interactions, side effects, nonadherence to therapy considering there are concurrent medications in addition to corticosteroids, thiopurines or JAK inhibitors (9)
| Frailty Assessment Tool | Key Features |
|---|---|
| Clinical Frailty Scale (CFS) | 9-point visual scale based on clinician judgment. Assesses activity level, dependence, and overall fitness. Practical and widely used at bedside. |
| Fried Frailty Phenotype | Requires 5 criteria: unintentional weight loss, self-reported exhaustion, weakness (grip strength), slowness, and low activity. Frailty = ≥3 criteria. |
| G8 Questionnaire | 8-item screening tool from oncology adapted to IBD. Covers nutrition, mobility, cognition, polypharmacy, and self-rated health. Rapid and practical in clinics. |
| Key Question | Assessment Indicator | Action Suggestion |
|---|---|---|
| Is the patient frail? | CFS ≥ 5, gait speed <0.8 m/s | Avoid or delay immunosuppressants; consider gut-selective agents (e.g., vedolizumab) |
| Any serious comorbidities? | Charlson Index ≥ 5 or active cardiac/pulmonary disease | Prioritize safety and avoid aggressive immunosuppression |
| Polypharmacy risk? | ≥5 concurrent medications, risk of interactions | Simplify regimens, use non-systemic therapies |
| Recent infection history? | ≥2 serious infections in past 12 months | Reassess benefit-risk ratio for biologics |
| Therapy | Use in Elderly | Comments |
|---|---|---|
| Anti-TNF agents | Effective but higher risk of infection, malignancy | Discontinuation common; avoid combination therapy in frail or high-risk patients (2, 8, 11) |
| Vedolizumab | Preferred first-line in many centers; safer profile | Lower systemic risk; favorable infection profile; suitable in multimorbid, frail patients(11, 12) |
| Ustekinumab/IL23 | Safe and well-tolerated in older patients | No increase in adverse events compared with placebo in meta-analysis of all RCTs (IBD and non-IBD). Limited data yet re: age-specific risk, suitable in patients ≥70 years. (11) |
| JAK inhibitors | Use with caution; restricted to select cases only if no other option. | Elevated risk of VTE, CV events, and herpes zoster; requires risk-benefit analysis, give Monitor for bradycardia, liver enzyme |
| S1P modulators (e.g., ozanimod) | Limited data; caution in elderly | elevations; avoid in CV disease or polypharmacy |
| Corticosteroids | Short-term only; avoid chronic use | Associated with delirium, infection, fractures; taper early and transition to maintenance. Use enteral coated sterids wherever possible. (11) |
| 5-ASA | Safe in mild UC; not for Crohn’s | Monitor renal function; watch pill burden in cognitively impaired patients |
| Thiopurines | Limited use due to toxicity, acvoid after age of 60 years. | Risk of lymphoma, skin cancer; avoid unless no alternative; requires age-specific caution |
| Methotrexate | Poorly tolerated; limited role | Hepatotoxicity and cytopenia risks high in elderly; often not preferred |
| Surgery | Consider frailty; elective preferred | Outcomes better with elective surgery; pre-op frailty and nutrition optimization essential |
Managing IBD patients with hepatitis B virus (HBV) exposure requires balancing therapeutic efficacy with hepatic safety. Immunosuppressive medications can precipitate HBV reactivation, potentially causing fulminant hepatitis and liver failure. This necessitates systematic screening, monitoring, and prophylaxis protocols that have become integral to modern IBD care. (13, 14)
HBV prevalence among IBD patients varies significantly by region. Giri et al.'s meta-analysis found global HBsAg positivity of 3.3% in IBD patients, but with marked regional differences: 5.8% in Asia versus 1.4% in Europe. (15) Prior HBV exposure (anti-HBc positivity) shows even greater disparity: 30.3% in Asian versus 8.3% in European populations. These patterns underscore the importance of universal screening regardless of geographic location.
HBV reactivation is defined as reappearance of HBsAg or significant HBV DNA increase in previously inactive infection. Risk depends on baseline serologic status and immunosuppressive regimen:
A. Screening and prevention
All patients with IBD should undergo HBV screening before initiating immunosuppressive therapy. Vaccinate those who are seronegative when feasible, and evaluate the need for antiviral prophylaxis in HBsAg-positive individuals. Recommended screening tests include:
B. Choose Safer Treatments When Possible
When HBV exposure is known, prioritize lower-risk agents such as vedolizumab or ustekinumab whenever clinically appropriate. If higher-risk treatments—such as anti-TNF agents, JAK inhibitors, or prolonged courses of corticosteroids—are required, they should be accompanied by antiviral prophylaxis and close virologic monitoring to reduce the risk of HBV reactivation. See Table 1
C. Monitor During and After Therapy
For patients with confirmed HBV exposure, ongoing care includes regular monitoring of ALT and HBV DNA throughout immunosuppressive treatment and after its completion. In urgent clinical situations, antivirals and IBD therapy may be started at the same time if a two-week lead-in is not feasible. Management depends on HBV serologic status, as outlined below.
D. Management by Serologic Status(13)
| Risk Level | HBsAg+ or HBsAg-/anti-HBc+/HBV DNA- | Action |
|---|---|---|
| High (>10%) | • Anti-TNF agents • Corticosteroids (>40 mg/day) • Corticosteroids (>4 weeks, >20 mg/day) • JAK inhibitors • S1P receptor modulators | Antiviral prophylaxis mandatory |
| Moderate (1-10%) | • Ustekinumab (anti-IL-12/23) • Other anti-IL23 agents | • Anti-TNF agents • JAK inhibitors • Ustekinumab (anti-IL-12/23) & anti-IL23 agents |
| Low (<1%) | • Azathioprine • Methotrexate • Mycophenolate mofetil • Corticosteroids (low-dose <10 mg/day) for ≤1 week) • Vedolizumab | • Azathioprine • Methotrexate • Mycophenolate mofetil • Corticosteroids (<40 mg/day for ≤1 week) • Vedolizumab |
**S1P receptor modulators (ozanimod, etrasimod): Risk category based on mechanism of lymphocyte sequestration rather than broad immunosuppression. Limited HBV reactivation data available; close monitoring recommended until more safety data emerge. Note: Vedolizumab not specifically listed in EASL table but considered low-risk based on gut-selective mechanism
The coexistence of sickle cell disease (SCD) and autoimmune diseases like IBD is rare but clinically important as it appears to be associated with both a severe phenotype of autoimmune disease and worsening of SCD(17). Historically, limited reports have made it difficult to define the true overlap, though both diseases share key immunoinflammatory pathways such as TNF-α, IL-6, and neutrophil extracellular traps (NETs) that may contribute to organ injury in both conditions(18, 19) . The baseline hyperinflammatory state in SCD can exacerbate IBD activity, while intestinal microvascular occlusion may mimic IBD-related ischemic changes. Clinically, overlapping features such as chronic abdominal pain and anemia complicate diagnosis, often leading to delays in identifying IBD in SCD patients.
Geographic differences may explain the under-recognition of SCD-IBD overlap, with SCD common in Africa and the Middle East, and IBD more prevalent in Western countries. A recent French study—the largest to date—found colonic involvement in 95.8% of SCD-IBD cases and PSC in 33.3%, far higher than typical IBD cohorts. Histology confirmed classical IBD features, not ischemic colitis, ruling out sickle-related vascular injury as the cause.(20)
Outcomes depend on early diagnosis, minimizing corticosteroid exposure, and selecting therapies with low infection and hematologic risk. Severe infections remain a major cause of morbidity and mortality, particularly in patients on systemic immunosuppression(21).
Multidisciplinary care is essential: hematologists and gastroenterologists must collaborate to tailor safe and effective regimens.
Psychological Impact of IBD
Common emotional challenges: anxiety, depression, stress, and reduced quality of life (QoL).
Stigma, embarrassment, and social isolation due to symptoms (e.g., urgency, incontinence).
Impact on work, relationships, and daily functioning.(1)
Key Counseling Strategies for IBD Patients
A. Building a Therapeutic Alliance
Active listening, empathy, and validating patient concerns.
Encouraging open communication about symptoms and emotional distress.(2)
B. Psychoeducation
Educating patients about IBD, treatment options, and self-management.
Addressing misconceptions (e.g., diet, stress as a cause vs. trigger).
C. Cognitive Behavioral Therapy (CBT) and Mindfulness
CBT for managing anxiety, depression, and maladaptive coping.
Mindfulness-based stress reduction (MBSR) for symptom relief.(3)
Coping Mechanisms for Patients
A. Lifestyle Modifications
Diet adjustments (low-residue, FODMAP, hydration).
Regular exercise to reduce stress and improve well-being.
B. Social Support and Peer Groups
Importance of family, friends, and IBD support groups (e.g., Crohn’s & Colitis Foundation).(4-5)
C. Stress Management Techniques
Relaxation training (deep breathing, progressive muscle relaxation).(4)
Journaling and expressive writing for emotional processing.
Addressing Specific Challenges
Flare-ups: Preparing emergency plans (bathroom access, medication).(6)
Sexual Health & Body Image: Counseling on intimacy concerns.(7)
Transitional Care: Pediatric to adult IBD care counseling.
The Role of Multidisciplinary Care
Collaboration between gastroenterologists, psychologists, dietitians, and social workers.
Integrated care models for holistic IBD management.(8)
Colonoscopy at 6 months (active care) or no colonoscopy (standard care)
Study Design: Randomized, double-blind
Result:
Conclusion: Active management of post-operative Crohn’s disease patients with surveillance colonoscopy at 6 months and drug escalation as necessary leads to lower rates of endoscopic recurrence at 18 months compared to standard treatment.
Comment : In active group, If the colonoscopy showed endoscopic recurrence , medical therapy was escalated as follows:
Original study: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61908-5/abstract
Infliximab vs Cyclosporine in Acute Severe Ulcerative Colitis
Study Design: Randomized, open-label, multicenter trial
Result:
Conclusion: Infliximab and cyclosporine showed similar efficacy in preventing colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids.
Original study: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61747-0/abstract
Infliximab for Moderate to Severe Ulcerative Colitis
Study Design: Randomized, double-blind, placebo-controlled trials
Result:
Conclusion: Infliximab is effective for inducing and maintaining clinical response and remission, and promoting mucosal healing in patients with moderate to severe ulcerative colitis.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa053426
Vedolizumab for Ulcerative Colitis and Crohn’s Disease
Study Design: Randomized, double-blind, placebo-controlled trials
Result:
Conclusion: Vedolizumab is an effective and safe treatment option for patients with moderate to severe ulcerative colitis and Crohn’s disease.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa1307924
Ustekinumab for Crohn’s Disease
Study Design: Randomized, double-blind, placebo-controlled trials
Result:
Conclusion: Ustekinumab is an effective and safe treatment option for patients with moderate to severe Crohn’s disease, regardless of prior anti-TNF exposure.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa1604670
Upadacitinib for Ulcerative Colitis
Study Design: Randomized, double-blind, placebo-controlled trials
Result:
Conclusion: Upadacitinib is an effective oral treatment option for patients with moderate to severe ulcerative colitis.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa2008019
Upadacitinib for Crohn’s Disease
Study Design: Randomized, double-blind, placebo-controlled trials
Result:
Conclusion: Upadacitinib is an effective oral treatment option for patients with moderate to severe Crohn’s disease.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa2202720
Ozanimod for Ulcerative Colitis
Study Design: Randomized, double-blind, placebo-controlled trial
Result:
Conclusion: Ozanimod is an effective oral treatment option for patients with moderate to severe ulcerative colitis.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa1902219
Ozanimod for Ulcerative Colitis
Study Design: Randomized, double-blind, placebo-controlled trial (similar to CELEST, but larger and pivotal)
Result:
Conclusion: Ozanimod is an effective and well-tolerated oral treatment option for patients with moderate to severe ulcerative colitis.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa2022311
Colonoscopy at 6 months (active care) or no colonoscopy (standard care)
Study Design: Randomized, double-blind
Result:
Conclusion: Active management of post-operative Crohn’s disease patients with surveillance colonoscopy at 6 months and drug escalation as necessary leads to lower rates of endoscopic recurrence at 18 months compared to standard treatment.
Comment : In active group, If the colonoscopy showed endoscopic recurrence , medical therapy was escalated as follows:
Original study: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61908-5/abstract
Infliximab vs Cyclosporine in Acute Severe Ulcerative Colitis
Study Design: Randomized, open-label, multicenter trial
Result:
Conclusion: Infliximab and cyclosporine showed similar efficacy in preventing colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids.
Original study: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61747-0/abstract
Infliximab for Moderate to Severe Ulcerative Colitis
Study Design: Randomized, double-blind, placebo-controlled trials
Result:
Conclusion: Infliximab is effective for inducing and maintaining clinical response and remission, and promoting mucosal healing in patients with moderate to severe ulcerative colitis.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa053426
Vedolizumab for Ulcerative Colitis and Crohn’s Disease
Study Design: Randomized, double-blind, placebo-controlled trials
Result:
Conclusion: Vedolizumab is an effective and safe treatment option for patients with moderate to severe ulcerative colitis and Crohn’s Disease.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa1307924
Ustekinumab for Crohn’s Disease
Study Design: Randomized, double-blind, placebo-controlled trials
Result:
Conclusion: Ustekinumab is an effective and safe treatment option for patients with moderate to severe Crohn’s disease, regardless of prior anti-TNF exposure.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa1604670
Upadacitinib for Ulcerative Colitis
Study Design: Randomized, double-blind, placebo-controlled trials
Result:
Conclusion: Upadacitinib is an effective oral treatment option for patients with moderate to severe ulcerative colitis.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa2008019
Upadacitinib for Crohn’s Disease
Study Design: Randomized, double-blind, placebo-controlled trials
Result:
Conclusion: Upadacitinib is an effective oral treatment option for patients with moderate to severe Crohn’s disease.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa2202720
Ozanimod for Ulcerative Colitis
Study Design: Randomized, double-blind, placebo-controlled trial
Result:
Conclusion: Ozanimod is an effective oral treatment option for patients with moderate to severe ulcerative colitis.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa1902219
Ozanimod for Ulcerative Colitis
Study Design: Randomized, double-blind, placebo-controlled trial (similar to CELEST, but larger and pivotal)
Result:
Conclusion: Ozanimod is an effective and well-tolerated oral treatment option for patients with moderate to severe ulcerative colitis.
Original study: https://www.nejm.org/doi/full/10.1056/NEJMoa2022311
Anemia is one of the most frequent complications or extraintestinal manifestations (EIMs) of Inflammatory Bowel Disease (IBD), which includes Crohn’s disease and ulcerative colitis. This condition can significantly impact quality of life, contributing to fatigue, reduced physical endurance, and even impaired cognitive function. For healthcare providers caring for IBD patients, recognizing and addressing anemia is essential to holistic disease management¹.
Anemia is common among IBD patients. The World Health Organization (WHO) provides the following age- and gender-specific cut-offs for haemoglobin (Hb) concentration in anemia: <130 g/L for adult men, <120 g/L for adult, non-pregnant women, and <110 g/L for children aged 6–59 months and increasing with age. Studies showed an overall anemia prevalence of 27% in patients with CD and 21% in those with UC², with the prevalence in children as high as 90% at diagnosis³. Higher rates are typically observed during disease flares and in hospitalized patients, and anemia may be present at diagnosis or develop as the disease progresses. Iron deficiency, in particular, is highly prevalent, affecting over half of IBD patients at some point⁴.
Anemia in IBD arises from multiple causes. Iron deficiency anemia (IDA) is the most common type, usually due to chronic blood loss from intestinal inflammation, reduced dietary intake, and malabsorption. Anemia of chronic disease (ACD), or anemia of inflammation, also plays a significant role. Inflammatory cytokines elevate hepcidin levels, which restrict iron availability and impair red blood cell production⁵. Many patients experience a combination of IDA and ACD, and some may have additional contributors like vitamin B12 or folate deficiencies, especially if they have undergone bowel resection⁵,⁶.
Table 1: Comparison of Anemia Types in IBD
| Type of Anemia | Cause | Lab Findings | Treatment Approach |
|---|---|---|---|
| Iron Deficiency Anemia (IDA) | Chronic blood loss, reduced intake, malabsorption | Low hemoglobin, low serum ferritin (<30 μg/L), low transferrin saturation (<16%) | Oral or IV iron supplementation, address bleeding sources |
| Anemia of Chronic Disease (ACD) | Inflammation-mediated iron sequestration | Low/normal hemoglobin, normal/high serum ferritin (>100 ug/L) and transferrin saturation <20%, elevated CRP | Treat underlying inflammation, consider IV iron, possible ESA (erythropoiesis-stimulating agent) |
| Mixed Anemia | Combination of IDA and ACD factors | Features of both IDA and ACD | Combined approach: iron supplementation and anti-inflammatory therapy¹ |
Evaluation should begin with a complete blood count (CBC) to confirm anemia. Next steps include:
Table 2: Structured Evaluation to Differentiate Causes
| Test | Purpose | Interpretation in IBD Context | |
|---|---|---|---|
| Complete Blood Count (CBC) | Confirms anemia, assesses MCV and severity | Microcytic = IDA; Normocytic = ACD or mixed | |
| Serum Ferritin | Marker of iron stores | <30 µg/L = IDA; 30–100 µg/L with inflammation = possible deficiency | |
| Transferrin Saturation (TSAT) | Reflects available circulating iron | <16% suggests iron-restricted erythropoiesis⁸ | |
| CRP or ESR | Inflammatory markers | Elevated in active IBD, supports ACD diagnosis | |
| Vitamin B12/Folate | Rule out additional deficiencies | Check in ileal CD or strict vegetarian diets | |
| Reticulocyte Count | Evaluates bone marrow response | Low in IDA/ACD; high in hemolysis or recovery ⁸ |
The cornerstone of treating anemia in IBD is identifying the underlying cause(s) and tailoring treatment accordingly. Iron replacement is the most common and crucial intervention⁹.
Table 3: Treatment Comparison
| Strategy | Indications | Pros | Cons/Limitations |
|---|---|---|---|
| Oral Iron | Mild anemia, inactive disease | Low cost, convenient | Poor absorption, GI side effects, may worsen inflammation |
| IV Iron (e.g., ferric carboxymaltose) | Recommended as first-line treatment in patients with clinically active IBD, with previous intolerance to oral iron and in patients who need erythropoietin stimulating agents¹ | Rapid response and bypasses gut absorption | Requires infusion, risk of hypersensitivity |
| Erythropoiesis-Stimulating Agents (ESAs) | ACD refractory to iron therapy | Stimulates erythropoiesis | Requires co-admin of IV iron, costly |
| B12/Folate Supplementation | Documented deficiency usually <200 pg/mL [148 pmol/L]¹ | Corrects macrocytic anemia | May be overlooked; needs periodic monitoring |
| Treat Underlying Inflammation | All types of anemia in active IBD | Resolves root cause of ACD/IDA | Requires escalation of IBD therapy |
Intravenous (IV) iron therapy is strongly recommended in patients with moderate-to-severe anemia (hemoglobin <10 g/dL), clinically active IBD, or intolerance or non-responsiveness to oral iron⁹. In these scenarios, inflammation impairs intestinal iron absorption and elevates hepcidin levels, making oral iron ineffective⁸. IV iron bypasses the gastrointestinal tract, delivering iron directly to the bloodstream for efficient use in erythropoiesis.
Commonly used IV formulations include ferric carboxymaltose, iron sucrose, and iron isomaltoside, all of which have been shown to safely and rapidly restore iron stores and improve hemoglobin levels⁹. Recent studies suggest ferric carboxymaltose may offer superior efficacy in fewer infusions, with a lower risk of adverse effects compared to older formulations⁹.
Guidelines such as those from the European Crohn’s and Colitis Organisation (ECCO) recommend IV iron as first-line therapy in IBD patients who are anemic and have active disease, significant iron deficits, or prior oral iron intolerance⁷. Total iron needs are calculated based on weight and hemoglobin level, and follow-up is essential to confirm treatment success and prevent recurrence⁹.
Oral iron remains an option in patients with mild anemia and inactive disease, but gastrointestinal side effects and limited absorption often reduce its utility⁸. In patients who do not respond to iron supplementation or have severe disease, erythropoiesis-stimulating agents (ESAs) can be considered, usually alongside IV iron. Additionally, controlling the underlying IBD inflammation is critical to reducing ongoing iron losses and cytokine-mediated suppression of erythropoiesis⁸. Nutritional deficiencies should also be corrected to support optimal red blood cell production⁶.
Anemia in IBD is a common and impactful complication that requires careful evaluation and a targeted treatment strategy. Identifying whether the anemia is due to iron deficiency, inflammation, or a combination is key to choosing the right therapy. IV iron is often the preferred treatment in active or severe disease, and addressing the underlying inflammation is essential for long-term management. Regular monitoring and a proactive approach can significantly improve outcomes and quality of life for patients living with IBD¹,⁵.
Inflammatory Bowel Disease (IBD), encompassing Crohn’s Disease (CD) and Ulcerative Colitis (UC), often manifests during prime reproductive years. Managing IBD in the context of fertility and pregnancy is crucial, given its implications on reproductive health, maternal outcomes, and fetal well-being. This chapter provides an evidence-based overview that highlights current evidence, patient management strategies, and clinical recommendations.
Patients with quiescent IBD have fertility rates comparable to the general population. However, active disease, nutritional deficiencies, and psychosocial factors can reduce conception rates.¹
Table 1: Factors Influencing Fertility in IBD
| Factor | Effect on Fertility | Notes |
|---|---|---|
| Active inflammation | Decreased | Disrupts ovulation, alters hormone levels |
| Pelvic surgery (e.g., IPAA) | Decreased (up to 3-fold) | Causes adhesions, tubal dysfunction |
| Sulfasalazine in men | Reversible decrease | Affects sperm count and motility² |
| Nutritional deficiencies | Decreased | Especially iron, folate, vitamin B12 |
| Psychological stress | Decreased | Impacts libido and sexual function² |
Goal: Achieve deep clinical and endoscopic remission for at least 3–6 months prior to conception. Multidisciplinary counseling should address nutrition, smoking cessation, and vaccinations.⁵,⁶ Education is crucial to reassure patients about the safety of most therapies.
Table 2: Medication Safety in Preconception and Pregnancy
| Medication | Preconception | During Pregnancy | Breastfeeding | Notes |
|---|---|---|---|---|
| 5-ASA (mesalamine) | Safe | Safe | Safe | First-line for mild UC |
| Azathioprine/6-MP | Continue if already in use | Safe | Safe | |
| Methotrexate | ❌ Contraindicated | ❌ Contraindicated | ❌ Contraindicated | Teratogenic; discontinue 3–6 months prior ³ |
| Corticosteroids | Use with caution | Safe (short-term) | Safe (low dose) | Risk of gestational diabetes, cleft palate ⁷ |
Women with active IBD at conception are at increased risk of:
Maintaining remission is critical for optimizing maternal and neonatal outcomes.
Table 3: Mode of Delivery Recommendations
| Condition | Preferred Delivery Mode | Notes |
|---|---|---|
| Quiescent IBD | Vaginal | Safe and preferred |
| Active perianal CD | Cesarean section | To prevent perineal trauma |
| History of IPAA | Cesarean section | Avoid stress on pelvic floor³ |
Table 4: Breastfeeding Safety of Common IBD Medications⁶,⁸
| Drug | Breastfeeding Status | Notes |
|---|---|---|
| Mesalamine | Safe | Minimal transfer into breast milk |
| Azathioprine | Safe | Metabolites present in low concentrations |
| Corticosteroids | Safe (low dose) | Prefer feeding 4h after dose |
| Methotrexate | ❌ Contraindicated | Excreted in milk; avoid |
Biologic therapies and small molecule drugs are increasingly used for moderate-to-severe IBD and are often continued during pregnancy to maintain remission. Their safety profiles have been a major focus of recent studies.
Recommendation: Continue throughout pregnancy; some clinicians stop at 24–28 weeks to reduce fetal exposure⁶.
Recommendation: May be used throughout pregnancy if clinically indicated.
Recommendation: Use with caution; reserve for essential disease control⁶.
Recommendation: Avoid during pregnancy and lactation⁷.
Table 5: Safety of IBD Medications in Pregnancy and Lactation (Biologics & Small Molecules)
| Drug Class | Example(s) | Pregnancy Use | Lactation Safety | Notes |
|---|---|---|---|---|
| Anti-TNF | Infliximab, Adalimumab | Safe (stop at 24–28 wks optional) | Likely safe | Avoid live vaccines in infants ≤6 months |
| Certolizumab pegol | Safe throughout pregnancy | Safe | Preferred in late pregnancy | |
| Anti-integrin | Vedolizumab | Safe (limited data) | Limited data | Registry data reassuring |
| Anti-IL-12/23 | Ustekinumab | Use if needed | Unknown | Limited human data⁶,⁷ |
| JAK Inhibitors | Tofacitinib, Upadacitinib | ❌ Contraindicated | ❌ Contraindicated | Teratogenic ⁷ |
| S1P modulators | Ozanimod | ❌ Contraindicated | Unknown | Not approved in pregnancy |
Due to transplacental transfer of IgG1 biologics, avoid live vaccines in infants until at least 6 months of age⁶,⁸.
Emerging agents like risankizumab, mirikizumab, and brazikumab are promising but lack extensive pregnancy safety data.
Table 6: Safety of New and Emerging Biologic Therapies in Pregnancy and Breastfeeding
| Drug Class | Agent Name | Pregnancy Safety | Breastfeeding Safety | Notes |
|---|---|---|---|---|
| Anti-IL-23 | Risankizumab | Limited human data; animal studies reassuring | Unknown | Avoid unless essential¹ |
| Mirikizumab | Limited data; caution advised | Unknown | Approved for UC | |
| IL-13/IL-23 | Brazikumab | No human data | Unknown | Trial phase |
| IL-23 (p19) | Guselkumab | Limited data; avoid if possible | Unknown | Crosses placenta in animals |
| S1P Modulator | Etrasimod | ❌ Contraindicated | Unknown | Teratogenic in animals⁷,⁸ |
| JAK Inhibitor | Filgotinib | ❌ Contraindicated | Unknown | Testicular toxicity in preclinical studies but no measurable impact on semen parameters or sex hormones in men⁹ |