Current Overview and Management of Ulcerative Colitis

Written by Ashley Costello Bpharm, Mpharm, Graduate entry medical school, University of Limerick - Rosie Culhane B.Sc. Graduate entry medical school, University of Limerick and Gerard Clarke MD FRCPI, Graduate entry medical school, University of Limerick

Ashley Costello Bpharm, Mpharm, Graduate entry medical school, University of Limerick

Rosie Culhane B.Sc. Graduate entry medical school, University of Limerick

Gerard Clarke MD FRCPI Graduate entry medical school, University of Limerick

Introduction

Ulcerative colitis (UC), a subcategory of inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disorder of the bowel and the most common form of IBD worldwide. It is characterised by continuous inflammation of colonic mucosa and follows a relapsing-remitting course. Typically, inflammation in UC starts in the rectum and may extend proximally resulting in inflammation affecting a variable length of colon. 1-3 Depending on the site and extent of anatomical involvement UC can be classified as proctitis, left-sided colitis or pancolitis. 2, 4 The Montreal classification categorises UC patients based on maximal disease extent; with E1 or proctitis representing disease limited to the rectum, E2 representing a leftsided colitis and E3 representing extensive colitis which extends proximally to the splenic flexure. 5

Epidemiology

UC was the first subcategory of IBD to be characterised as a separate entity and was first described by Samuel Wilks in 1859. 6, 7

The prevalence of IBD has been trending upwards on a global scale; from 3.7 million affected individuals in 1990 to 6.8 million in 2017. 8 UC is more common than Crohn’s disease with an incidence of 9 to 20 cases per 100,00 persons per year and a prevalence of 156 to 291 cases per 100,000 per year. 9, 10 Highest incidences of UC have been reported in northern Europe, Canada and Australia with incidences of 24.3 per 100,000, 19.2 per 100,000 and 17.4 per 100,000 respectively. 11-13 Furthermore, geographical locations previously considered as “low-risk” such as India and Japan have been experiencing a rise in the incidence of UC. 14

Etiology and Risk Factors

While the exact cause of UC remains unknown, the pathogenesis appears to be multifactorial; related to a combination of genetic predisposition, altered immune responses, defects in epithelial barriers along with environmental factors. Studies have reported a number of risk factors for UC:

Age: The most common age of onset for UC is between 15 and 30 years of age. However, a second peak occurs between 50-80 years of age representing a bimodal age distribution.

Sex: Whilst several studies suggest there is no sex predominance in UC, 11, 16, 17 other studies have shown higher incidence rates of UC amongst males versus their female counterparts.

Ethnicity and race: UC is more common in Jewish populations than other ethnicities. Earlier studies reported a lower prevalence of IBD in African- American and Hispanic ethnicities compared to white population, however, more recent studies have shown that the difference in incidence between white and non white populations is much smaller than previously thought. 3

Genetics: Previous studies have identified 200 risk loci for IBD, with most genes contributing to both UC and Crohn’s disease phenotypes. 21,

Of note, many of these IBD loci are implicated in other immune disorders such as ankylosing spondylitis and psoriasis. 22

Human leukocyte antigen (HLA) and genes associated with barrier functionality such as HNF4A and CHH1 have been associated with an increased risk of UC.

Despite this, genetics have very little predictive capacity for phenotype and are of limited clinical use.

Family history: Individuals with UC have a family history of UC from 7 to 11% and a family history of any type of IBD ranging from 8-14%. 24

Smoking: While previous cigarette smoking is an important risk factor associated with UC, active cigarette smoking confers a protective effect against development of UC compared to non-smokers and tend to have a milder course of disease. However, nicotine replacement therapy in individuals with UC has not been shown to reduce disease severity which suggesting a tobacco effect on UC rather than nicotine alone.

Appendectomy: Appendectomy, in particular when performed for acute appendicitis in young patients appears to confer a protective effect against development of UC, suggesting that the appendix may have a role in the development of IBD. 29 Findings from a large cohort study suggested that the inverse relationship between appendectomy and the risk of UC was found only for those who underwent surgery before the age of 20 (p<0.001) (N=212,963). 30 Despite this association, this is not proof of causality nor is there any evidence of a therapeutic utility for it in established UC.

Dietary factors: Findings from epidemiology studies have suggested that dietary factors may play a role as factors for developing IBD. Consumption of a Westernstyle diet has been postulated to increase the risk of UC.

Ingestion of a diet high in total fat, animal fat and polyunsaturated fatty acids has been correlated with an increased incidence of UC as well as Crohn’s disease while a diet high in vegetables was associated with a reduced risk of UC. 31-33

Gut microbiota: A twin study described a loss of interaction between the transcriptional profile of the mucosa with the colonic microbiota in patients with UC. 34

Infection and Immune system: Studies have suggested that episodes of infectious gastroenteritis such as Salmonella or Campylobacter gastroenteritis may play a role in the initiation and/or exacerbation of IBD.

Other: Breast feeding has been shown to decrease the risk of developing UC. 37

Pathophysiology

Epithelial cells of the colon (colonocytes), mucous and epithelial barrier defects are implicated in the pathogenesis of UC. There is reduced expression of peroxisome proliferator-activated receptor gamma (PPAR-y) in the colonocytes of patients with UC, which normally functions as a negative regulator of NF-kB dependent inflammation.

Alterations in goblet-cell derived proteins which contribute to the integrity of the mucosal barrier have also been described in UC.

Gut dysbiosis has also been reported in individuals with UC. 42 Reduced biodiversity, in particular lower proportions of Firmicutes and increased proportions of Gamma-proteobacteria and Enterobacteriaceae. 43 Although, it remains unclear whether dysbiosis is the cause or effect of mucosal inflammation.

Clinical presentation

Abdominal pain, bloody diarrhoea, urgency and tenesmus are typical presenting features. 1, 3

Diagnostics

Diagnosis of UC is based on clinical presentation, endoscopic findings and histological evaluation. 44 Stool assessments should include stool culture and a Clostridium difficile assay to rule out superimposed infectious agents. Fecal calprotectin, a biomarker more specific for intestinal inflammation can be useful for ruling out IBD as individuals with low levels have a <1% chance of having IBD.

Endoscopy with biopsies is the only definitive method to establish the diagnosis of UC. Classical endoscopic findings consistent with UC include erythema, oedematous mucosa, friability, bleeding and ulcerations.

Treatment – pharmacological versus surgical interventions

The goals of therapy encompass induction and maintenance of remission, risk reduction of complications and improvement of quality of life. The choice of therapy can be decided based on the extent and severity of disease. The modified Truelove and Witts criteria incorporates both clinical and laboratory parameters as a measurement of disease severity. 5

Induction treatment for mildmoderate distal ulcerative colitis e.g. mild to moderate proctitis or proctosigmoiditis, includes mesalazine that can be administered as a foam enema usually at a dose of 2g once daily at bedtime. 49 Emerging data suggests that a Multimatrix ® (MMX ® ) mesalazine formulation may be just as effective at inducing remission in these UC patients. This drug formulation facilitates homogenous delivery of high concentrations of drug into the colon, particularly to distal segments which is often difficult to achieve using normal oral delivery. 50 Maintenance can be achieved by 1g mesalazine suppositories each night. 51 While the mechanism of action of mesalazine is unknown, it is closely related to salicylic acid which has anti-inflammatory properties mediated by inhibition of prostaglandin synthesis.

More extensive or proximal disease, including left-sided colitis and colitis extending proximal to the splenic flexure, can be treated with oral 5-aminosalycylic acid (5-ASA) at maintenance doses of 3.0 to 3.2 g daily and induction doses of 4.8 to 5 g daily. 52 In terms of treating moderate to severe ulcerative colitis systemic glucocorticoids were once the mainstay of therapy, but are avoided now due to significant toxicity; major adverse effects arise from the suppression of the hypothalamic–pituitary–adrenal axis and involve metabolism, bone, central nervous system, skin, arterial pressure and the gastrointestinal tract. 50 There is positive data to suggest advance MMX ® technology could encourage glucocorticoid use as it becomes more targeted to the distal colon, trials have shown that MMX ® budesonide has been particularly useful in treating mild to moderate left sided UC. 53

There are a growing number of effective biologic agents for moderate to severe UC, including anti-tumor necrosis factor (TNF) therapy (infliximab, adalimumab), anti-integrin therapy (vedolizumab), and anti-interleukin 12/23 therapy (ustekinumab). 54-56 Small molecules including tofacitinib (an oral Janus kinase [JAK] inhibitor), upadacitinib (an oral JAK inhibitor), and ozanimod (an oral sphingosine-1-phosphate [S1P] receptor modulator), have also shown effectiveness as induction therapies in UC. 57-60 However, due to possible risks associated with these medications (thromboembolic, cardiovascular, and malignancy risks with JAK inhibitors, and cardiovascular risks with ozanimod), they are reserved as second-line options in patients who do not achieve remission with anti-TNF-based therapy. 61

Surgery remains a valuable option in UC. Surgical management of ulcerative colitis is required when patients fail medical therapy or when serious complications arise.

Emergency surgery is indicated in patients with colonic perforation, life-threatening gastrointestinal hemorrhage, or toxic megacolon. 62 Urgent surgery during the same hospital admission is indicated in patients with acute fulminant colitis that is refractory to medical therapy. 63 A total abdominal colectomy with end ileostomy is the procedure of choice in both situations. Elective surgery is indicated in patients with persistent symptoms despite best medical management and in those with increased cancer risk. 64 Most patients undergo a restorative proctocolectomy with ileal pouchanal anastomosis (RPC-IPAA). The overall mortality rate associated with surgical treatment of ulcerative colitis is less than 1 percent; the overall morbidity is about 30 percent. 65 Major complications include stricture, pelvic sepsis, pouch failure, fecal incontinence, pouch dysplasia/cancer development, sexual dysfunction, and female infertility. 66-69

Future developments

Although the likes of biologics and novel small molecule drugs targeting different immune pathways have revolutionised the treatment of autoimmune disorders including IBD in recent decades, unmet needs remain. Novel treatment concepts such as bispecific biologics and biologic/ small molecule drug combination therapies are also being developed (70, 71). Numerous head-to-head trials are underway to investigate what combinations of biologics can induce clinical response and remission. 72 A new generation of drugs for IBD are in clinical development, including S1P modulators, IL-23 inhibitors, leukocyte adhesion inhibitors, and preferential JAK1 inhibitors. In parallel, the clinical management of IBD is being improved through introducing personalised treat-to target strategies, biomarker-based disease activity monitoring, along with empowerment of patients through better education.