Understanding ulcerative colitis

Epidemiology

Prevalence and incidence

Ulcerative colitis has a higher prevalence than Crohn’s disease in adults^1,2. It is a chronic, progressive, relapsing and remitting condition characterised by continuous inflammation of the colonic mucosa^3–5. As in Crohn’s disease, there are regional variations in the prevalence and incidence of ulcerative colitis, but an overall global increase has been consistently reported^6–9.

A systematic review investigating the worldwide prevalence and incidence of ulcerative colitis revealed that the prevalence was highest in Europe (505 cases per 100,000 individuals) and North America (249 cases per 100,000 individuals) (Figure 1)¹⁰. Within these regions, the highest prevalence values have been reported in Norway and the United States¹¹.

Figure 1. Worldwide ulcerative colitis prevalence per 100,000, 1990–2016 (Adapted¹¹).

Overall, incidence of ulcerative colitis is increasing globally, though there is substantial variation between different populations and geographical regions, with estimates ranging from 0.5–31.5 cases per 100,000 individuals each year^9,12,13. In recent years, newly industrialised countries have experienced a particular surge in the number of new cases reported annually. In Brazil, for example, the annual percentage change has recently been calculated at 14.9% (95% confidence interval 10.4–19.6)¹¹.

Disease development

In contrast to Crohn’s disease, ulcerative colitis is generally thought to be equally as common in males as in females across all age groups⁵. It can develop at any age from infancy onwards, but most frequently presents in adolescents and other patients under 30 years of age³. Interestingly, there is a second, albeit less pronounced peak between the ages of 50 and 80 years old, with incidence of ulcerative colitis on the rise in patients over the age of 65 years^3,14.

Aetiology

Though the exact causes of ulcerative colitis are not well understood, experts have identified several important factors that are thought to contribute to the development of this disease^5,15.

Genetic susceptibility

A family history of IBD is considered the most important risk factor for developing ulcerative colitis and has been reported in 8–14% of patients^16,17. Indeed, first-degree relatives of patients with IBD are four times more likely to develop ulcerative colitis¹⁷. Rates of ulcerative colitis also vary between different ethnic groups and, like Crohn’s disease, it is particularly prevalent among Ashkenazi Jews, providing further evidence of a genetic component¹⁸.

In a 2017 review, it was reported that genome-wide associated studies (GWAS) have now identified over 200 susceptibility loci for IBD. Of these, 137 confer a higher risk of developing both ulcerative colitis and Crohn’s disease, while a further 27 are specific to ulcerative colitis¹⁹. These susceptibility loci include human leukocyte antigen and genes associated with barrier function¹⁷. However, these “identified genetic factors” can only account for around 8% of the disease variance and therefore have poor predictive capacity and are of little use in a clinical setting^17,19.

Gut flora

Reduced microbial diversity of the gut has been reported in patients with both ulcerative colitis, and Crohn’s disease²⁰. In genetically predisposed individuals, the resultant state of dysbiosis may lead to onset of disease^21,22. Loss of commensal bacteria, particularly those belonging to the Bacteroidetes and Firmicutes phyla, is accompanied by the loss of their protective benefits²². It remains to be seen whether the dysbiosis observed in patients with ulcerative colitis is the cause of their condition, or simply a consequence of chronic mucosal inflammation. However, it is worth noting that the extent of dysbiosis in these patients is less severe than in patients with Crohn’s disease¹⁷.

Interestingly, loss of Faecalibacterium has been consistently reported in patients with IBD. Early studies in mouse models suggest that this bacteria could be used in the treatment of patients with ulcerative colitis in the future²².

Environmental factors

Childhood exposure to enteric pathogens, such as with Campylobacter and Salmonella, has been shown to increase the risk of developing IBD²³.However, paradoxically the introduction of more stringent hygiene practices and increased antibiotic use in industrialised countries and resultant reduction in microbial exposure during childhood, may hamper the development of the innate immune system²⁴. As a result, the immune system may not be able to coordinate an appropriate response when challenged with unfamiliar microorganisms in adulthood, increasing ulcerative colitis risk²⁴.

Unlike in Crohn’s disease, active smoking has been shown to confer protection against ulcerative colitis⁵. Furthermore, it has been reported that smoking cessation increases risk of developing ulcerative colitis and that this state of elevated risk persisted for as long as 20 years³. However, it is worth noting that this observation has been called into question by Indian studies which found no association between current- or ex-smoker status and ulcerative colitis^5,25,26. 

Appendectomy is also thought to reduce ulcerative colitis risk, though its relationship with Crohn’s disease is less clear^5,27. Paradoxically, undergoing an appendectomy after receiving an ulcerative colitis diagnosis is thought to detrimentally affect the course of the disease⁵.

Host immunity

The mechanism by which the immune response results in development of ulcerative colitis is considered in the pathophysiology section in this part of the Learning Zone.

Pathophysiology

Pathogenesis

The exact pathogenesis of ulcerative colitis is not well understood; however, it is thought to be similar to that of Crohn’s disease, though some important differences have been identified¹⁷.

In ulcerative colitis, thinning of the mucus layer contributes to impairment of the epithelial mucosal barrier²¹.

A range of different factors contribute to ulcerative colitis pathogenesis⁵.

Following increased intestinal epithelial permeability, innate immune cells, such as macrophages, recognise bacterial antigens via toll-like receptors (TLRs) and NOD-like receptors (NLRs) and become activated²⁸. This leads to increased production of pro-inflammatory cytokines – tumour necrosis factor α (TNFα), interleukin (IL)-1β, IL-6, IL-12 and IL-23^28,29. Processed antigens are presented to T helper (Th) cells via T cell receptors (TCRs), facilitating an adaptive immune response and production of IL-4, while natural killer T (NKT) cells produce IL-13 and IL-5, further disrupting the epithelial barrier²⁹. Furthermore, leucocyte recruitment increases through mechanisms such as upregulation of pro-inflammatory chemokines (CXCL) and binding of integrin (α4β7)-bearing T cells to colonic endothelial cells via mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) (Figure 2)³⁰.

Figure 2. Pathogenesis of ulcerative colitis (Adapted²⁹). α4β7, Integrin α4β7; CXCL, Chemokine (C-X-C motif) ligand; HLA-2, Human leukocyte antigen 2; IL, Interleukin; MAdCAM-1, mucosal vascular addressin cell adhesion molecule 1; NF-κB, Nuclear factor- κB; NKT, Natural killer cell; TCR, T cell receptor; Th2, T helper 2 cell; TLR, Toll-like receptor; TNFα, Tumour necrosis factor α; Treg, Regulatory T cell.

Clinical presentation

Ulcerative colitis is a chronic disease that involves relapsing and remitting inflammation of the colon¹⁷. Unlike in Crohn’s disease, this inflammation is confined to the mucosa and sub-mucosa and tends to be continuous rather than patchy³¹.

The symptoms of ulcerative colitis vary depending on the extent of colonic involvement, with bloody diarrhoea the most common symptom¹⁷. Other common symptoms include urgency, incontinence, fatigue, increased frequency of bowel movements, mucus discharge, nocturnal defecations and abdominal discomfort³².

It has been estimated that around 16% of ulcerative colitis patients experience disease progression over the course of 9 years (Figure 3)³³.

Figure 3. Montreal Classification of ulcerative colitis, showing disease phenotype and disease progression over 9 years (Adapted^17,33,34).

Treatment goals

Evolution of treatment goals and treat-to-target

In the past, the goal of treatment in IBD was to achieve symptomatic relief, preferably without the need for glucocorticoids³⁵. More recently, it has been established that absence of symptoms does not necessarily indicate absence of inflammation, leading to the introduction of more stringent treatment targets^35,36.

The concept of a treat-to-target approach in ulcerative colitis is still relatively new, having first been defined in 2015³⁷. The treat-to-target strategy involves adjusting therapy based on whether or not patients meet predefined treatment response targets, encouraging personalisation of care and earlier intervention^36,38.

Despite being met with enthusiasm by experts around the world, many physicians have been slow to adopt this new disease management style and still consider symptomatic control an adequate treatment target³⁶.

Consensus definition of targets in ulcerative colitis: STRIDE

The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) programme assessed potential treatment targets for patients with IBD to facilitate a treat-to-target strategy. As in Crohn’s disease, the expert-consensus definition of treatment targets in ulcerative colitis combines clinical (patient-reported) remission and endoscopic (clinician-reported) remission. In ulcerative colitis, clinical/patient-reported outcome (PRO) remission is defined as resolution of rectal bleeding and diarrhoea or altered bowel habit, while endoscopic remission is defined as a Mayo endoscopic sub-score of 0–1 (Figure 4)^37,39.

Figure 4 . Understanding Mayo endoscopic sub-scores (a) Score 0, normal mucosa; (b) Score 1, mild disease with erythema, decreased vascular pattern and mild friability; (c) Score 2, moderate disease with marked erythema, absent vascular pattern, friability and erosions; (d) Score 3, severe disease with spontaneous bleeding and ulceration⁴⁰.

The STRIDE statements were recently updated to reflect new evidence regarding treatment optimisation in IBD³⁹. STRIDE-II provides confirmation of the long-term treatment targets identified in STRIDE-I, with the addition of absence of disability, restoration of quality of life and normal growth in paediatric patients³⁹. STRIDE-II also lists symptomatic relief and normalisation of serum and faecal markers as suitable short-term targets³⁹.

Role of mucosal healing

Mucosal healing is now considered an important treatment target in ulcerative colitis, consistently predicting favourable patient outcomes across a number of studies⁴¹. In the past, mucosal healing was assessed endoscopically. Today, a revised definition of mucosal healing incorporates both endoscopic and histologic healing^42,43.

Mucosal healing is defined as endoscopic healing plus histologic healing^42,43.

A recent European Crohn’s and Colitis Organisation (ECCO) position paper highlighted the lack of standardised histological procedures, definitions and scoring systems in ulcerative colitis⁴⁴. Though the authors recognised that further research will be required to fully understand the relevance of histologic disease activity in this field, they proposed absence of intra-epithelial neutrophils, erosion and ulceration as the minimum requirement for histological remission⁴⁴. Given the association between persistent histological inflammation and adverse outcomes in ulcerative colitis, histological remission is now considered a treatment target for patients with this disease⁴⁴.

Role of early intervention

The benefits of early intervention with biological therapy are less well-established in ulcerative colitis as compared to Crohn’s disease^43,45–47. This is reflected in the continued use of a “step-up” approach when treating ulcerative colitis, whereby treatment is escalated based on the severity of clinical symptoms⁴³.

Current evidence does not support early intervention with biological therapy for patients with ulcerative colitis, but research is ongoing⁴³.

Research into the efficacy of top-down versus step-up approaches in ulcerative colitis is ongoing, with the SPRINT study among those set to shed light on the long-term implications of early intervention. However, as yet early intervention with a biologic therapy is not supported by available evidence⁴³.

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