Ulcerative colitis overview

About UC

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) characterised by chronic inflammation in the gastrointestinal tract (GI)¹, affecting the colon and rectum². Both UC and another type of IBD, Crohn’s disease, are debilitating and chronic relapsing conditions^1,3. In contrast to Crohn’s disease, which involves patchy lesions scattered throughout the GI tract and inflammation across all layers of the bowel wall, the inflammation in UC is usually restricted to the mucosal layer and causes superficial damage to the bowel wall².

With a peak onset between 30 and 40 years of age, UC typically presents with bloody stools and diarrhoea, accompanied by urgency, faecal incontinence and fatigue⁴. Severe disease can present with fever and weight loss⁴.

The burden of gastrointestinal symptoms and faecal incontinence associated with UC can have a substantial impact on many aspects of patient quality of life (QoL)⁴

UC is associated with high morbidity and work disability⁵. Approximately 50% of people with UC will require UC-related hospitalisation during their disease course, and the 5- and 10-year cumulative risk of colectomy is 10–15%⁵.

Characterised by a relapsing and remitting course, UC involves alternating periods of flares and remissions^2,6,7. The factors triggering flares are not fully understood, but may include environmental triggers, stress, diet and alterations in the gut microbiota^2,6,7.

A diagnosis of UC is based on a combination of symptoms, findings from endoscopy and histology, and exclusion of other differential diagnoses and enteric infections⁴. UC is classified at diagnosis according to the extent and severity of disease⁸, which helps to inform subsequent treatment decisions⁹.

Prevalence of UC

Approximately 4.9 million cases of IBD were reported worldwide in 2019³. Although IBD has been closely linked to a Westernised environment and lifestyle⁸, with highest prevalence in the USA and Europe^8,10, IBD prevalence has been increasing in Asian countries, including China and Japan, over recent years^3,11,12.

Worldwide, the incidence of UC is around 9–20 cases per 100,000 persons per year, with a prevalence of 156–291 cases per 100,000 persons per year⁸

In contrast to Crohn’s disease, UC is more prevalent in adults and less prevalent in the paediatric population⁸.

Burden of UC

The symptoms of UC can have an adverse impact on the daily life of patients, and reduce QoL^4,13,14 across physical, sexual, psychological, and social domains⁴. An overview of the burden of UC on patients is shown in Figure 1.

Figure 1. Overview of the burden of ulcerative colitis and impacts on quality of life^4,5,15-18. UC, ulcerative colitis.

Physical burden of UC

The gastrointestinal symptoms, faecal incontinence and complications of UC can have a dramatic impact on QoL⁴. Particular IBD-related complications that can adversely impact patient QoL include chronic changes in bowel function, surgical scars and ostomy⁴.

Several studies have shown that UC has a significant impact on the quality of sexual life in both men and women^4,16. Substantial problems with sexual functioning have been reported in those with active disease^4,14.

The physical and clinical burden of UC can also vary according to disease severity and extent of disease¹³.

Higher morbidity rates, poorer health-related QoL, and difficulties in social and professional activities have been reported for people with moderate-to-severe UC, compared with the general population⁴

Acute UC flares have been associated with prolonged hospitalisation, and readmission of patients previously hospitalised for a UC flare has been associated with increased mortality¹⁹.

Colectomy is considered one of the most important adverse outcomes in people with UC²⁰. Total proctocolectomy is still required in 15% of patients, particularly in those refractory to medications or who develop complications⁴. People with extensive or severe UC at diagnosis, or those with an early need for corticosteroids, are at higher risk of colectomy¹⁸.

Extra-intestinal manifestations and cancer risk add to the burden of UC^15,18.

Psychosocial burden of UC

Patients with UC report limitations to their social interactions, activities and relationships because of the unpredictable nature of the disease^4,14. People with UC can perceive a degree of social stigmatisation in response to their disruptive symptoms, which can lead to a desire for social withdrawal⁴.

Anxiety and depression are common in people with UC⁴. Findings of a cohort study indicate patients’ perception of their functional disability appear to be related to greater symptoms of anxiety and depression⁴. Fatigue, stress and sleep disorders have also been noted in people with UC⁴.

Dissatisfaction with body image is common in people with IBD, is associated with anxiety and depression, and is also linked to lower QoL, self-esteem and sexual satisfaction, leading to substantial psychological challenges⁴.

Overall, it is important to consider psychological comorbidities and their impact on the course of the disease in people with UC.

Socioeconomic burden of UC

In people with active UC, debilitating symptoms and poor control of bodily functions can impair daily activities, including employment and leisure activities⁴. Negative impacts of UC on work productivity include presenteeism, UC-related sick leave and absenteeism due to medical visits^5,21.

The socioeconomic burden of UC also includes the cost of ongoing treatment and provision of healthcare services^18,22,23.

There is an ongoing upward trajectory in global expenditure associated with the provision of healthcare services for people diagnosed with UC^22,23

The escalating trend in disease-related expenditure can be attributed not only to increased prevalence of UC, but also the chronic nature of the disease, which necessitates long-term and, frequently, costly therapeutic interventions^18,22,23.

A systematic review of 40 studies across the USA and Europe reported a high economic burden in people with moderate-to-severe UC starting treatment with biologics or small-molecule drugs^18,22,23. This high economic burden was driven primarily by the cost of these treatments and outpatient visits associated with drug administration and monitoring^18,22,23. However, biologic initiation was shown to reduce the indirect cost burden to these patients and improve QoL²². Aside from prescription costs increasing the total healthcare costs associated with biologic treatments, hospitalisation-related expenses were the main drivers of medical costs, followed by outpatient visits and emergency services’ costs²².

Most patients experience a mild-to-moderate disease course at diagnosis, involving varied periods of remission or mild activity⁵. Approximately 10–15% of people with ulcerative colitis (UC) experience a more aggressive course of disease, with a cumulative risk of relapse of 70–80% at 10 years⁵.

While the extent of UC, severity of disease and prognosis are all key considerations that can influence treatment selection in UC^9,15,24, disease extent can also inform decisions around the optimal route of drug administration²⁵.

Extent of UC

The extent of disease in UC can be classified anatomically into the following groups, based on the Montreal classification²⁶ (Figure 2).

• Ulcerative proctitis – disease involvement is limited to the rectum
• Left-sided UC (distal UC) – disease involvement is limited to a proportion of the colorectum distal to the splenic flexure
• Extensive UC (pancolitis) – disease involvement extends proximal to the splenic flexure

Figure 2. Disease extent and rates of progression in patients with ulcerative colitis^5,27. (Adapted²⁷ under Creative Commons License CC BY 4.0). IQR, interquartile range; UC, ulcerative colitis. *Proportion of patients with the indicated extent of disease at diagnosis, according to a systematic review of population-based cohort studies in adults with ulcerative colitis (N=15,316). ^†Proportion of patients that progressed to the indicated extent of disease, with median follow-up ranging from 1–20 years.

Although most patients have left-sided colitis at diagnosis⁵, disease extent often changes over time^5,26. Overall rates of progression in people with UC range from 12 to 30%, and the cumulative risk of progression over 5 years is approximately 13%⁵.

Severity of UC

An objective assessment of UC severity is key for guiding clinical management and predicting long-term outcomes in patients⁹

In particular, it is important to identify people with severe UC who need hospital admission, compared with those with mild or moderate activity who can be managed as outpatients²⁸.

Tools to assess UC severity

The European Crohn’s and Colitis Organisation (ECCO) guidelines acknowledge that UC disease severity and activity can be measured according to several different definitions²⁵, using a range of different instruments²⁹.

The Truelove and Witts’ criteria³⁰ are considered the best validated and most widely used index for identifying severe UC^28,9, and modified versions of the original criteria from 1955 still inform management – particularly for identifying outpatients who require hospital admission and intensive treatment^9,29

Modified criteria from Truelove and Witts are summarised in Table 1, according to the 2017 ECCO guidelines²⁹.

Table 1. Disease activity in ulcerative colitis (Adapted²⁹). Based on criteria modified from Truelove and Witts et al. 1995³⁰. bpm, beats per minute; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

However, the Truelove and Witts’ criteria do not provide a quantitative or longitudinal measure of severity, and do not consider nocturnal symptoms, extra-intestinal manifestations or endoscopic severity⁹. Building upon Truelove and Witts’ original criteria, various other quantitative disease activity indices have been developed or proposed to address this gap. These include^8,9:

• The Montreal classification system^8,24,26 – considers systemic illness or toxicity²⁶, and is commonly used to evaluate extent and severity of disease^8,24,29
• The Mayo Clinic score⁹ – considers endoscopic findings and Physician’s Global Assessment score⁹
• The Simple Clinical Colitis Activity Index – considers nocturnal bowel frequency, urgency of defecation, general wellbeing and extracolonic features⁹

The 2017 ECCO guidelines and 2019 consensus guidelines from the British Society of Gastroenterology support use of the Montreal classification system to guide UC severity assessment in UC^29,24 (Table 2).

Table 2. Montreal classification of disease severity in ulcerative colitis²⁹ (Adapted^26,31). bpm, beats per minute; ESR, erythrocyte sedimentation rate. *The additional category of remission (SO) is defined as asymptomatic. ^†Minimal variation from normal, or no signs of systemic toxicity.

In addition, the updated 2019 American College of Gastroenterology guidelines proposed a UC activity index that incorporates both patient-reported outcomes and laboratory and endoscopy-based values⁹. It also includes an additional severity category for a type of rapid-onset progressive colitis known as fulminant⁹.

However, the 2020 guidelines from the American Gastroenterological Association use UC severity definitions based on Truelove and Witts’ criteria and the Mayo Clinic Score¹⁵.

Selecting the appropriate tool to assess UC severity

In practice, selection of the most appropriate disease severity scoring system for UC can be informed by the most recent version of local UC management guidelines in your region.

To improve care for people with UC, the ECCO guidelines note it is desirable to incorporate simple clinical and/or endoscopic scoring systems into assessments of disease severity and activity²⁹.

Unmet needs and challenges in diagnosis and management of ulcerative colitis (UC) can impact provision of optimal care for people with UC. Join Dr Tim Raine, a gastroenterologist from Cambridge University Hospitals in the UK, for an overview.  

Key unmet needs and challenges in ulcerative colitis management and their impact

How can major unmet needs in UC impact treatment for people with moderate-to-severe UC? Professor Stephen Hanauer, a gastroenterologist from Northwestern University’s Feinberg School of Medicine, USA, provides an answer.

Key unmet needs and challenges in ulcerative colitis

Overall, these major unmet needs in UC management encompass challenges in diagnosis, risk stratification, treatment and communication between healthcare professionals and patients (Figure 3).

Figure 3. Major unmet needs in the management of ulcerative colitis^14,28,32-36. UC, ulcerative colitis.

Addressing unmet needs in UC management

Earlier diagnosis and improved severity assessments

A reduced time to diagnosis and access to timely, effective treatments may help to improve outcomes for people with UC³³. Indeed, extensive and/or severe disease activity at diagnosis has been associated with poor prognosis³³.

Definitions of mild, moderate or severe UC have not been formally validated, and current severity scoring systems are based on historical definitions that are useful in distinguishing patients into disease categories likely to respond to various treatments³⁶. An overall severity scoring system may help to move UC management from a reactive, disease-activity driven approach towards a more proactive approach³⁶. Such an overall severity score could have implications for access to care and may connect point-in-time disease activity scoring systems with the identification of long-term high-risk disease characteristics³⁶.

Limiting corticosteroid use in UC

Corticosteroid use in UC remains persistently high, despite the availability of biologic therapies³⁵. Although corticosteroids can be effective for inducing remission, they are not effective at maintaining remission²⁸.

Corticosteroids are not considered appropriate for long-term use, given the increased risk of adverse effects such as infections, osteoporosis, cataracts and myopathy^28,37, which can outweigh their clinical benefits³³

Improved treatment options to achieve and maintain remission

Although advances in UC treatment have led to an expanded range of therapeutic options for patients, remission and symptom reduction are still not achieved in a considerable proportion of patients^1,38,39. There also remains a high incidence of primary and secondary response failure rate with currently available treatments⁴⁰.

Despite biologic treatments being available for UC, more than 50% of people with moderate-to-severe UC do not achieve sustained remission⁴⁰, and one in three patients with severe disease may still require life-changing colectomy⁴

Therefore, there is a need for more effective and targeted treatment options capable of inducing and maintaining remission in a larger proportion of patients^1,33,38,39, including those with moderate-to-severe and refractory UC^33,41. There is also a need for treatments that can modify the disease course and limit or prevent disease progression in people with UC³². Therapeutic options with a rapid onset of clinical effect would be particularly valued in moderate-to-severe UC³³.

A lack of adherence to UC treatment has been reported in up to 72% of patients across various studies^28,33,35,37, and has been associated with an increased risk for relapse⁴⁰. Although many UC treatments are administered via injections or infusions, the availability of oral medications for UC¹ may help to improve treatment adherence^33,40.

Addressing unmet needs for improved treatment options in UC

To address unmet needs for achieving remission, limiting or avoiding surgery in people with severe disease and limiting corticosteroid use, numerous investigational biologics and small-molecule therapies are in development for UC^1,28,42. These include investigational biologic and small-molecule therapies, with therapeutic targets including pro-inflammatory cytokines, cell adhesion molecules and various inflammatory pathways¹.

Improved risk stratification

Risk stratification can be challenging when based on the clinical features of UC alone³⁴. However, the identification of objective biomarkers may help to inform more precise treatment approaches for people with UC in the future³⁴.

Individualised approaches to treatment selection

With heterogeneity in disease activity, presentation and disease course, there is substantial variation in treatment response among people with UC^34,43. Determining which patients will benefit most from more intensive therapy remains a challenge³⁴. Investigations are underway into potential biomarkers that may facilitate optimal treatment selection by predicting which patients are more likely to have treatment response or treatment-specific complications^34,43.

Improved communication with patients

People with UC have expressed a need for improved information and communication with healthcare professionals about their disease, treatment options, emotional wellbeing, and their uncertainties and fears¹⁴. They also expressed a need for greater psychosocial guidance and support¹⁴.

Patient engagement is an important consideration in the management of UC, ensuring that individual preferences and uncertainties are considered and discussed, while encouraging shared decision-making¹⁴

The pathophysiology of ulcerative colitis (UC) involves intestinal barrier dysfunction, a dysregulated immune response and altered gut microbiota, and is influenced by genetic and environmental factors²

An overview of UC pathophysiology is provided in Figure 4.

Figure 4. Pathophysiology of ulcerative colitis (Adapted^7,27 under Creative Commons CC BY 4.0 License). Disruption of tight junctions and the mucous layer increase permeability of the intestinal epithelium, leading to uptake of luminal antigens²⁷. Antigen-presenting cells, such as dendritic cells, are activated by exposure to non-pathogenic, commensal bacteria²⁷. This leads to release of pro-inflammatory cytokines, activation and differentiation of naive CD4+ T cells into Th2 effector cells, and production of more pro-inflammatory cytokines²⁷. Entry of more T cells into the lamina propria is facilitated by binding of integrin-α4β7-bearing T cells to mucosal adhesion molecules (e.g., MAdCAM-1)²⁷. Circulating leukocytes are also recruited via upregulation of inflammatory chemokines, perpetuating the inflammatory cycle²⁷. DC, dendritic cell; IL, interleukin; MAdCAM-1, mucosal addressin cell adhesion molecule 1; NF-κB, nuclear factor kappa B; NKT, natural killer T cell; TGF-β, transforming growth factor-beta; Th, T helper; TLR, toll-like receptor; TNF-α, tumour necrosis factor-alpha; Treg, regulatory T cell.

Initially, UC is driven by disruption in the intestinal barrier^2,27. This can arise from dysfunction in the epithelial cell layer or activation/production of inflammatory mediators and cells in the lamina propria^2,27. The potential causes of barrier disruption include primary genetic defects, environmental factors such as changes to the microbiota, or altered expression of tight junction proteins².

In UC, the disrupted epithelial barrier increases permeability of the intestinal lining to luminal antigens and pathogens, stimulating an inflammatory response and the release of pro-inflammatory mediators^2,6, including tumour necrosis factor alpha (TNF-α), interleukin (IL)-12 and IL-23, and intracellular proteins, such as Janus kinases (JAK)⁶

Subsequently, this leads to infiltration of more immune cells, which exacerbates the inflammatory process and contributes to the chronicity of UC².

UC can also involve dysregulation of the adaptive immune response via an imbalance between regulatory and effector T cells, which can disrupt the integrity of tight junctions⁶. Abnormal immune response in genetically susceptible individuals may also contribute to UC. Atypical T helper cells (Th), particularly Th2, can exert a cytotoxic response against epithelial cells in UC⁸.

Immune cells, such as T cells and B cells, and various cytokines play a crucial role in perpetuating the inflammatory process in UC. T cells release pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-17, which further activate immune cells and perpetuate inflammation^2,6,7.

However, the precise pathophysiology of UC is not yet fully elucidated², and research is ongoing to further uncover the underlying mechanisms, to inform development of more effective treatments for the condition^1,2,6.

Therapeutic targets in UC

  Advances in our understanding of UC pathophysiology have led to the development of new treatments², and the therapeutic arsenal for UC is continuing to expand¹. Many of the pro-inflammatory mediators involved in UC pathogenesis are targets for various current and investigational treatments for UC^1,6. These targets include¹:

• Interleukins
• TNF-α
• Cell adhesion molecules
• Other inflammatory pathways, such as sphingosine 1-phosphate receptor, Janus kinase, tyrosine kinase 2, and toll-like receptors

Pending results of further clinical trials, the development of investigational treatments may help to address major unmet needs in UC for achieving remission, reducing the requirement for surgery and limiting corticosteroid use, with the potential to improve outcomes and quality of life for people with UC^1,28,42 .

More about current and investigational treatments for UC