15.12 Ulcerative colitis 2937

15.12 Ulcerative colitis 2937

ESSENTIALS Ulcerative colitis is a chronic relapsing and remitting disease in which chronic inflammation affects the rectum and extends proximally to a variable extent. The precise aetiology remains unknown but involves an interplay between reduced diversity in the gut microbiota and a genetically dysregulated gut immune system and epithelial barrier. Typical presentation of mild or moderate disease is with a gradual onset of symptoms including diarrhoea, rectal bleeding, and the pas- sage of mucus. Severe disease is characterized by anorexia, nausea, weight loss, and severe diarrhoea (more than six motions daily), with the patient likely to look unwell with fever, tachycardia, and other signs of volume depletion, and the abdomen may be distended and tympanitic, with reduced bowel sounds and marked colonic tender- ness. Complications of acute disease include acute dilatation and perforation, and those of long-​standing disease include carcinoma. Extraintestinal manifestations are common, with some related to colitic activity (e.g. oral aphthous ulceration, erythema nodosum, and peripheral arthropathy) but others not (e.g. sacroiliitis and pri- mary sclerosing cholangitis). Diagnosis is usually made on the basis of exclusion of infective colitis by stool culture and the finding of typical diffuse inflammation in the rectum and above at sigmoidoscopy. Management requires rapid control of symptoms with induction therapy followed by maintenance of remission. Mild disease is typ- ically treated with 5-​aminosalicyclic acid delivered both orally and by enema, and moderate disease by 5-​aminosalicyclic acid and ster- oids. Patients with severe disease require hospital admission, intra- venous steroids, and daily review by both a physician and a surgeon experienced in the management of ulcerative colitis. Ciclosporin or infliximab are used as rescue therapies for steroid-​resistant acute se- vere ulcerative colitis, but colectomy should not be delayed when this is required. Maintenance therapy with immunomodulators, small molecules and biological therapies are both effective at maintaining remission, and several new drugs are in clinical trials. Introduction Ulcerative colitis is a chronic inflammatory disease of the colon, of uncertain cause. It almost always affects the rectum and extends proximally to involve the colon to a variable extent. It is character- ized by a relapsing and remitting course. The disease was first described in 1859 by Samuel Wilks, a physician at Guy’s Hospital, London, who recognized that ‘simple, idiopathic colitis’ could be distinguished from other forms of colitis, mainly bac- terial dysentery. It took many years for the concept to be accepted, but in 1931, Sir Arthur Hurst was able to give a complete description of the disease, including the sigmoidoscopic appearances. Nevertheless, he still considered the disease to be primarily infective, even though its chronic nature might be induced secondarily by other factors. Over recent decades, a greater understanding of disease pathogenesis has emerged, as for many other chronic inflammatory conditions, with ulcerative colitis thought to result from a dysregulated immune response to components of commensal gut bacteria with strong gen- etic and environmental influences in this interaction. Epidemiology Ulcerative colitis is a worldwide disease, although it may be difficult to diagnose in areas where infective colitis is prevalent. Published rates for incidence and prevalence vary considerably and while the disease remains most common in Westernized countries, it is in- creasingly apparent worldwide. Hence, annual incidence rates in Europe are as high as 30 per 100 000 population with similar rates reported in North America. An increase in incidence over the past three decades has been reported most for Asian populations while the condition is also becoming more common in South America and Africa. A north–​south gradient in incidence is well recognized in Europe where countries with a higher latitude such as Scandinavia report 15.12 Ulcerative colitis Jeremy Sanderson and Peter Irving Acknowledgement: the authors and editors gratefully acknowledge the inclusion in this chapter of material contributed to previous editions of the Oxford Textbook of Medicine by Emeritus Professor D.P. Jewell.

section 15  Gastroenterological disorders 2938 higher incidences than those closer to the Mediterranean. While this is likely to be multifactorial, the gradient has been used as an indicator for a role of vitamin D in disease pathogenesis. Both in North America and South Africa, Jewish individuals appear three to four times more prone to ulcerative colitis than those who are non-​Jewish. Within Israel, Ashkenazi Jews have a higher incidence than Sephardim Jews, but it is still less than the incidence in Jewish individ- uals in North America or, indeed, than the European incidence. This highlights the likely role of environmental factors in addition to genetic factors in pathogenesis. This is emphasized even more by studies of mi- gration which consistently show a higher incidence in second-​ as op- posed to first-​generation immigrants to areas of higher prevalence, best studied in migration from Asia to Europe. On the other hand, differences in incidence between urban as opposed to rural communities, or be- tween different socioeconomic groups, have been slight and inconstant. The age of onset peaks between 20 and 40 years, but the disease may present at all ages from the first few months of life to the eighties. Some series show a second peak of onset in the 60-​ to 70-​year-​old age group, but more recent studies suggest this has disappeared. Nonetheless, there are differences in course of disease at differing age of onset, with dis- ease severity, extension of disease, and likelihood of surgery all greater in those with a young age of onset. Earlier series suggested a female predominance of the disease but more recent studies show little sex difference. Aetiology The precise cause or causes of ulcerative colitis remain unknown. However, as outlined later in this section, a much greater under- standing of the pathogenesis of the disease has developed from re- search over the last 10 to 15 years, combining data from immunology, genetics, and molecular microbiology. The overarching theory pro- poses that ulcerative colitis represents a dysregulated gut immune response directed most likely at commensal bacteria resident in the gut lumen, with a loss of integrity in the epithelial barrier contrib- uting to this interaction. While there are associations with true auto- immune diseases, the concept of ulcerative colitis as an ‘autoimmune’ condition has largely been abandoned. External influences such as diet, smoking, psychological stress, and medication are important as secondary influences but unlikely to be primary triggers. Genetic factors The familial incidence of ulcerative colitis has long been recognized, with 2 to 14% of patients likely to have at least one other family member affected with inflammatory bowel disease, usually ulcerative colitis but occasionally Crohn’s disease. Most of this familial associ- ation is within first-​degree relatives. Within a multiply affected family, there is a high degree of concordance for disease characteristics (e.g. extent, severity, and presence of extraintestinal manifestations). Familial incidence may, of course, reflect that family members are often exposed to common environmental factors. However, the higher concordance in monozygotic compared to dizygotic twins provides strong evidence that genetic factors play a role in determining disease susceptibility. Nonetheless, the concordance rate for ulcerative colitis in monozygotic twins is still quite low at 6 to 12%, suggesting that the genetic component of an individual’s risk of developing the disease is much less than it is for Crohn’s disease, where the concordance rate for identical twins is 35 to 45%. Ulcerative colitis (and Crohn’s disease) is viewed as a polygenic disorder in which the influence of a considerable number of low-​risk alleles combine to promote the chances of an individual developing the disease. However, a monogenic model may explain some cases of early-​onset (<5 years old) or very early-​onset (<2 years old) disease. The most recent large genome-​wide association studies of inflamma- tory bowel diseases have expanded the number of genomic regions of interest to 241. Of these, most confer a risk of both ulcerative col- itis and Crohn’s disease. Contrary to earlier expectations, most of the variants identified are noncoding in nature and hence considered to be somehow involved in modulation of expression of genes at other sites. This fits well with the concept that epigenetic influences on gene expression are an important part of the genetic susceptibility to inflammatory bowel disease, occurring through mechanisms such as altered methylation or via microRNAs. At present, the cellular influence of such genetic variation in ulcerative colitis appears to be focused partly on gut immune cells and, interestingly, on the gut epithelial cell, supporting the concept that the disease occurs as a result of a dyregulated immune response, most likely to components of the gut microbiota but promoted by a loss of integrity in the epi- thelial barrier. Host genetics also has an influence on the phenotype of ulcera- tive colitis. For example, the occurrence of extraintestinal manifest- ations also appears to be related to genetic make-​up. For example, specific HLA variants confer altered risk to arthropathy, and eye and skin complications, and genome-​wide association studies have iden- tified separate genetic loci conferring a risk of primary sclerosing cholangitis. Microbial factors Earlier concepts in which the pathogenesis of ulcerative colitis in- volved certain pathogenic bacteria have now largely been aban- doned in favour of a more broad involvement of bacteria present in the gut. One compelling argument for this has been the consistent demonstration that most animal models of colitis are ameliorated by a germ-​free environment and augmented once re-​exposed to lu- minal bacteria. Likewise, as indicated in the following paragraphs, the various early-​age epidemiological factors thought to promote the development of colitis are likely to have their effect primarily through alterations in the gut bacteria. The gut microbiota in health comprises a vast number of bacterial species—​as many as 800—​most of which are unculturable and form a complex, balanced ecosystem which plays a key role in shaping host immune responses through interaction with the gut immune system. Importantly, through 16s ribosomal RNA-​based analysis, a loss of diversity in the gut microbiota has been consistently demon- strated in patients with ulcerative colitis. This loss of diversity alone is thought to allow a variety of proinflammatory bacteria, for ex- ample, Bacteroides spp., greater access to immune cells (including the epithelium) while the anti-​inflammatory effects of other bacteria (e.g. bifidobacteria) are diminished. An increase in certain types of bacteria may have more specific influences. For example, sulphate-​reducing bacteria are found more commonly in those with colitis. These possess the capacity to reduce sulphate to sulphide which, in turn, inhibits butyrate oxidation, a key energy reaction in epithelial cells. Hence, altered bacteria may have a direct effect on epithelial integrity. Manipulation of the microbiota in the gut is likely to represent a novel therapeutic area in ulcerative colitis in coming years. Fascinating recent trials confirm the efficacy

15.12  Ulcerative colitis 2939 of faecal microbiota transplantation in some patients with ulcerative colitis and, whilst this may be thought of as a rather blunt instru- ment in terms of manipulation of the microbiome, it strongly sug- gests that this is an important area to explore therapeutically. Diet In contrast to Crohn’s disease, dietary factors have generally been considered to play little role in the aetiology or course of ulcerative colitis. The failure of active colitis to respond either to avoidance of oral food by intravenous nutrition, or to faecal diversion by means of a split ileostomy, are key examples of this. Nonetheless, many pa- tients report improvement on specific diets, particularly those redu- cing certain carbohydrates, which may be genuinely due to influence on factors involved in pathogenesis, particularly microbial factors, or be related to alteration of functional gut symptoms which exist frequently in patients with ulcerative colitis. Accordingly, interest is growing in investigating the role of diet in ulcerative colitis. Other environmental factors As well as microbial and dietary factors, smoking and certain drugs have an important influence on the development and course of the disease. The use of nonsteroidal anti-​inflammatory drugs (NSAIDs) is well established as a risk factor for ulcerative colitis, particularly as a trigger for disease flares. The risk is particularly evident at higher doses and appears to be related to nonselective cyclooxygenase in- hibition as selective cyclooxygenase-​2 inhibitors carry a lower risk. Patients with ulcerative colitis should therefore be advised generally to avoid NSAIDs where possible. The role of other medications such as oral contraceptives is more debatable. Smoking is clearly an important modifying factor in the patho- genesis of ulcerative colitis. Interestingly, in contrast to the strong negative influence on the course of Crohn’s disease, the effect on ul- cerative colitis is in the opposite direction. Numerous studies have shown that ulcerative colitis is more common in nonsmokers than smokers, with a relative risk of 2 to 6. Ex-​smokers have a particularly high incidence, and this is highest for former heavy smokers com- pared with light smokers. There is also evidence that smokers have a less aggressive disease course. Appendicectomy, or perhaps appendicitis, also appears protective against ulcerative colitis, particularly when undertaken at a young age. As for smoking, the influence of appendicectomy appears op- posite to the effect on Crohn’s disease. The mechanism of this effect remains unclear. Hygiene hypothesis Along with allergic disorders, both ulcerative colitis and Crohn’s disease are evolving as classic conditions which fit the hygiene hy- pothesis. Numerous studies have associated a risk of developing ulcerative colitis (and Crohn’s disease) with nonvaginal delivery, lack of breastfeeding, early antibiotic use, sibling count, and various other parameters. The underlying explanation for these associations is uncertain, but almost certainly demonstrates the critical import- ance of the gut microbiota in the pathogenesis of ulcerative colitis. One intriguing extension to the hygiene hypothesis proposes that inflammatory bowel disease is more prevalent in the West as a result of reduced helminthic infection rather than primarily altered bac- terial influences. Indeed, treatment with nonpathogenic helminths, proposed to promote a more regulatory T helper (Th)-​2 cell gut im- mune response, have shown clinical benefit in some studies. Immunopathogenesis In active ulcerative colitis, there is an intense infiltration of the in- flamed mucosa with neutrophils, plasma cells, B and T lymphocytes, and macrophages. The stimulus to this broad-​ranging immune ac- tivation is clearly complex and involves some primary immune re- sponses but undoubtedly a range of secondary immune activation as a consequence of the inflammation and disrupted get mucosa. While all components of the gut immune system are involved, the inflammation in ulcerative colitis, and Crohn’s disease, is predom- inantly T-​cell driven. The antigenic trigger to T-​cell-​driven inflam- mation arises from increased exposure to various bacterial antigens, either as a result of a breached epithelial barrier or a relative increase in proinflammatory bacteria arising from reduced microbial diver- sity in the gut microbiota. Until fairly recently, ulcerative colitis was felt to demonstrate a Th2 pattern of immune activation based on cytokine profiles, in contrast to Crohn’s disease, in which a more typ- ical Th1 profile was seen. However, with lessons learnt from inflam- matory bowel disease genetics research, this paradigm has changed with the emergence of the Th17/​IL-​23 pathway as a key component of the immune activation seen in both types of inflammatory bowel disease. In ulcerative colitis, evidence supports a role for each of these pathways. Hence, contrary to earlier studies, increased pro- duction of the Th1 cytokine, tumour necrosis factor (TNF)-​α, has been demonstrated, and anti-​TNFα antibody therapy has become an important treatment for refractory disease. The concept of differing T-​cell pathways is a rapidly evolving area of research. Hence, recently discovered T-​cell subsets may be important in ulcerative colitis, particularly Th9 cells, considered important in al- lergic disorders. Likewise, regulatory T cells (Tregs) are also likely to play an important role: they have an immunosuppressive influence, act as an important balance to control the otherwise proinflammatory response, and may emerge as an important therapeutic target in future. Several other pathways designed to contain the immune response and to avoid excessive tissue damage are also likely to be impaired in ul- cerative colitis and help explain chronic persistent inflammation. Elements of autoimmunity may play a role in ulcerative col- itis, a concept that would fit with the association with other clas- sical autoimmune conditions such as thyroid disease and diabetes. Likewise, the presence of antibodies to epithelial cell components and, for example, the consistent presence of circulating perinuclear antineutrophil cytoplasmic antibodies in ulcerative colitis, and not Crohn’s disease, support this concept. Pathology Macroscopic features Ulcerative colitis almost always involves the rectum, but in about 40% of patients the disease is limited to the rectum (proctitis) or rectum and sigmoid (proctosigmoiditis). In adults, only about 20% will have the whole colon involved (pancolitis), but this proportion rises to about 50% in cases of childhood-​onset ulcerative colitis. In mild disease, the mucosa is hyperaemic and granular, with oe- dema hiding the normal vascular pattern. Small punctate ulcers ap- pear as the disease becomes more marked, which may then enlarge and extend deeply into the lamina propria. In severe disease, the ul- ceration may become linear along the line of the taeniae coli and the

section 15  Gastroenterological disorders 2940 mucosa can become intensely haemorrhagic. In long-​standing dis- ease, scarring and atrophy can be present, sometimes shortening the colon. Inflammatory polyps (pseudopolyps) may also develop in long-​ standing disease. While sometimes somewhat dramatic in appearance, these polyps have no malignant potential. When the disease goes into remission, the colonic appearance returns to normal in many cases, but—​especially in patients who have had recurrent or severe attacks—​the mucosa may become atrophic and featureless. There is often narrowing and shortening of the bowel. However, fibrous strictures complicating long-​standing disease are rare and should always raise the possibility of Crohn’s disease or malignant transformation. In acute severe disease, due to disruption of the muscle layer of the colon, acute colonic dilatation can occur and the bowel becomes thin and congested. There is usually severe ulceration, with only small islands of mucosa remaining, and the risk of colonic perforation is high. Microscopic features In ulcerative colitis, the inflammation is largely confined to the mucosa (in contrast to the transmural inflammation seen in Crohn’s disease). The lamina propria becomes oedematous, with dilated and congested capillaries, and extravasation of red blood cells. There is a mixed cellular infiltrate of acute and chronic inflammatory cells including neutrophils, lymphocytes, plasma cells, macrophages, mast cells, and eosinophils. Neutrophils invade the epithelium, often in the glandular crypts, giving rise to a cryptitis or crypt abscesses, a pathological hallmark of the disease. Damage to the crypts leads to increased epithelial cell turnover and discharge of mucus from goblet cells. With increasing inflammation, the surface epithelial cells become flattened and ir- regular, and eventually ulcerate. In severe disease, deeper ulcers may extend into the lamina propria, leading to inflammatory changes in the submucosa that creates the pathological setting for acute dilata- tion or perforation. Many of the acute changes of ulcerative colitis are nonspecific and may also be seen in infective colitis. However, the diagnosis of ul- cerative colitis can be made with some accuracy (>80% probability) if features of a chronic inflammatory process are present. These in- clude distorted crypt architecture, crypt atrophy, basal lymphoid ag- gregates, and a chronic inflammatory infiltrate. Histological appearances may return to normal once the disease has gone into remission, but there is frequently evidence of bifid or shortened crypts, hyperplasia of the muscularis mucosae, neuronal hypertrophy, and Paneth-​cell metaplasia at the base of the crypts. Cytomegalovirus (CMV) inclusions may be seen on occasions. In the setting of an acute flare in a patient receiving immunosup- pressive therapy, CMV-​colitis complicating ulcerative colitis needs to be considered as appropriate antiviral therapy may be effective and prevent colectomy. Clinical features Patients usually present with a gradual onset of symptoms, often intermittent, but becoming progressively more severe. Occasionally, ulcerative colitis can present much more rapidly and may mimic an infective colitis. Indeed, some patients begin with a genuine docu- mented acute infection such as campylobacter or salmonella enter- itis which then develops into more typical ulcerative colitis. The principal symptoms include diarrhoea, rectal bleeding, the passage of mucus, and—​less frequently—​abdominal pain. When the inflammation is confined to the rectum (proctitis), patients often pass fresh blood and mucus, which is often separate to a normal stool. Indeed, patients with proctitis can often complain of consti- pation rather than diarrhoea and, on clinical symptoms alone, may be mistakenly diagnosed as suffering from haemorrhoids. When the inflammation extends beyond the rectum, there is usually diarrhoea with mucus and a variable amount of blood. The diarrhoea is often accompanied by considerable urgency and tenesmus, and patients can be incontinent. Nocturnal diarrhoea is a common symptom in the presence of severe inflammation. Patients with severe ulcerative colitis affecting most or all of the colon are often anorexic and nauseated, and may have lost weight. They usually have severe diarrhoea (more than six motions daily) mixed with pus, and blood. In all presentations of ulcerative colitis, including proctitis, pa- tients may also complain of fatigue and may have symptoms re- ferable to some of the extraintestinal manifestations, especially recurrent oral aphthous ulceration. On examination, patients with mild or moderate attacks usually look well and exhibit few abnormal physical signs. Weight should al- ways be recorded and, for children and adolescents, both height and weight should be noted on growth charts. Abdominal examination may reveal a tender colon but is often normal. Bowel sounds are normal and rectal examination is also usually normal, but may reveal blood. Patients with a severe attack may also look deceptively well, with tachycardia or a tender colon sometimes the only abnormal signs. However, many of these patients are ob- viously unwell, with fever, salt and water depletion, anaemia, and evidence of weight loss. There may be oral candidiasis, aphthous ulceration, signs of iron deficiency, and finger clubbing. Rarely, the skin changes of hypoalbuminaemia and dependent oedema may occur. The abdomen may be distended and tympanitic, with reduced bowel sounds and marked colonic tenderness. Minor perianal disease, such as a fissure, may occur in patients with active ulcerative colitis, but this is never as severe as is seen in patients with Crohn’s disease. Investigation and diagnosis The diagnosis of ulcerative colitis is made on the basis of the history, the absence of faecal pathogens, and the endoscopic and histological appearances of the colon. Blood markers of inflammation Active disease is often accompanied by a neutrophil leucocytosis, thrombocytosis, and a rise in acute-​phase proteins (e.g. C-​reactive protein (CRP)) and in ESR). There may also be a fall in haemoglobin and albumin levels. Although the CRP is perhaps the most com- monly used marker, any of these markers of active inflammation can be measured serially during the course of treatment as an indicator of disease activity. This may be daily during the course of a severe attack requiring hospitalization, or intermittently during outpatient assessment and treatment. Patients with proctitis rarely have a rise in CRP unless the inflam- mation is particularly severe, hence symptom scoring is the main guide to activity in this setting.

15.12  Ulcerative colitis 2941 Faecal markers Faecal calprotectin or lactoferrin, both released from neutrophils present in the gut lumen as a consequence of gut mucosal inflam- mation, are excellent noninvasive markers of active gut inflamma- tion even in the absence of symptoms. They are useful in differential diagnosis (particularly between inflammatory bowel disease and irritable bowel syndrome) and are especially useful to monitor the response to therapy without the need for endoscopic assessment. Faecal samples for microbiological analysis should be obtained from all patients presenting for the first time and, ideally, all those presenting with a flare of established disease. This should include testing for Clostridium difficile toxin as well as for standard bacterial and other pathogens according to the clinical setting. For example, opportunistic infection should be considered in immunodeficiency syndromes and lymphogranuloma venereum should be tested (rectal swab) in men with proctitis who have sex with men. Sigmoidoscopy and colonoscopy Rigid sigmoidoscopy is considered safe, even in patients with a se- vere attack, and not only confirms rectal inflammation but also al- lows a biopsy specimen to be taken and an assessment of severity to be undertaken. An unprepared flexible sigmoidoscopy is preferable where available, but full colonoscopy is rarely necessary during an acute attack although many regard this procedure as safe despite the theoretical increased risk of perforation. The earliest signs of colitis on sigmoidoscopy are blurring of the vascular pattern associated with hyperaemia and oedema, leading to blunting of the valves of Houston. With increasing severity, the mucosa becomes granular and then friable. With more severe in- flammation, the mucosa shows spontaneous bleeding and ulcer- ation (Fig. 15.12.1). These changes begin in the rectum and extend proximally in a continuous manner to affect a variable length of the colon. The disease can, however, be associated with relative rectal sparing. The reason for this is not known, but the finding can be wrongly used to diagnose Crohn’s disease of the colon. Pseudopolyps (inflammatory polyps) often occur in patients with long-​standing disease and tend to be colonic rather than rectal: they have no ma- lignant potential and may even regress over many years if the disease remains in remission. Colonoscopy with multiple biopsies is important for assessing the full extent of disease. It is not critical at presentation (where sig- moidoscopy will often suffice in order to commence treatment), but it should be undertaken at some point early in the course of the dis- ease, particularly to exclude Crohn’s disease and ensure the treat- ment plan is appropriate. Colonoscopy is mandatory for patients with a colonic stricture. It is also required for cancer surveillance in long-​standing ulcerative colitis (see ‘Colorectal carcinoma’). Preparation of the colon should follow the normal methods, with osmotic laxative being the most satisfactory, but a gentler approach is needed if colonoscopy is done in the presence of severe inflamma- tion, but this is rarely indicated (unprepared flexible sigmoidoscopy should nearly always suffice in this setting). Biopsy specimens should always be taken at sigmoidoscopy or colonoscopy to permit accurate histological assessment which con- tributes to grading of severity as well as to the differential diagnosis. In the setting of acute severe colitis, biopsies should be processed urgently to look for CMV inclusion bodies which should be supple- mented by immunohistochemistry. Capsule endoscopy targetting the colon is available but not yet widely used in the management of ulcerative colitis. Radiology All patients with a severe attack must have a plain abdominal radio- graph. Not only does this exclude a dilated colon, but it may pro- vide some prognostic information (mucosal islands, distended small-​bowel loops) and demonstrate the extent of the disease. An abnormal haustral pattern, thickening of the bowel wall, and mu- cosal oedema can be detected on a plain film (Fig. 15.12.2). An in- flamed colon does not hold faecal material, hence the presence of faecal matter in the ascending or transverse colon usually indicates that the inflammation is distal. Plain abdominal radiographs should be repeated daily or every other day when severe colitis persists des- pite ongoing therapy. Fig. 15.12.1  Sigmoidoscopic appearances of severe ulcerative colitis showing spontaneous bleeding and ulceration. Fig. 15.12.2  Plain abdominal radiograph of a 24-​year-​old man presenting with severe ulcerative colitis. The ascending and transverse colon are grossly oedematous and diseased, with loss of the normal haustral pattern. In addition, there are multiple loops of dilated small intestine.

section 15  Gastroenterological disorders 2942 Barium studies have been superseded by colonoscopy. However, in settings where colonoscopy is unavailable, double-​contrast barium enema can safely be given to patients with less severe disease, but the colon must not be overdistended and the procedure should be stopped if the patient complains of pain (Fig. 15.12.3). Cross-​sectional imaging is not used routinely for diagnosis in ulcerative colitis but has a role in the exclusion of complications (Figs. 15.12.4 and 15.12.5). In particular, an abdominal CT scan should be undertaken if there is clinical suspicion of perforation during severe colitis. The threshold for CT should be reasonably low in this setting as high-​dose steroid therapy can often mask the symptoms and signs of peritonitis. Ultrasound is increasingly used in some parts of the world both as a diagnostic tool and also to monitor disease activity. Other laboratory data Anaemia is common, particularly in more extensive active disease, and is often a mixture of chronic disorder and iron deficiency. Iron loss is common as a result of chronic blood loss; this can be exacer- bated by a severe attack, in which 0.5 g of elemental iron can be lost, hence a hypochromic, microcytic anaemia is frequently present. Biochemical abnormalities are rare in mild or moderate attacks, but hypokalaemia, hypoalbuminaemia, and a rise in gammaglobulin frequently accompany a severe attack. Minor elevations of the aspar- tate transaminase or alkaline phosphatase concentrations are also frequently seen in patients with a severe attack, but they return to normal when the disease goes into remission. Persistent elevation, however, may indicate underlying chronic liver disease, particularly primary sclerosing cholangitis, and needs investigating. Assessment of disease severity The severity of ulcerative colitis can be graded in a number of ways—​ clinically, biochemically, and endoscopically—​each providing an important guide to the treatment required and a marker of disease activity that can be followed over time in order to assess response. Many activity indices have been devised for the purpose of clinical trials, but these are rarely used in day-​to-​day practice apart from the following simple guide. Clinical grading In simple terms, it is useful to grade the clinical severity of ulcerative colitis according to the symptoms into mild, moderate, and severe: • Mild disease—​fewer than four stools daily, with or without blood, with no systemic disturbance Fig. 15.12.3  A double-​contrast barium enema in a patient with active ulcerative colitis. The figure is a close-​up view of the splenic flexure showing extensive mucosal ulceration, loss of haustration, and narrowing of the colon. The patient also has diverticula in the descending colon. Fig. 15.12.4  Acute ulcerative colitis: CT findings. Section through the rectosigmoid reveals a diffusely inflamed and thickened mucosa. The oedematous submucosal layer (arrows) is paralleled by the external layer of muscularis propria and the internal layer of submucosa, both of which have higher attenuation. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. Fig. 15.12.5  Chronic ulcerative colitis: CT features. Sagittal reformatted image of the descending colon shows narrowing of the lumen and a thickened submucosa infiltrated by fat (arrow), producing a ‘target’ sign. The splenic flexure appears normal in calibre and mural thickness. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

15.12  Ulcerative colitis 2943 • Moderate disease—​four to six stools daily • Severe disease—​at least six stools daily, with bleeding, and evi- dence of systemic illness as shown by fever and tachycardia Even in the clinic, it is useful to capture this into an objective clin- ical score, particularly for the purpose of monitoring the efficacy of treatment, and the Simple Clinical Colitis Activity Index represents a good way of doing this routinely, although many variations on a theme of this can be used (Table 15.12.1). Differential diagnosis Symptoms of gradual onset If the patient has a history of slow onset of symptoms, including blood and mucus, and has diffuse inflammation on sigmoidoscopy, a diagnosis of ulcerative colitis is highly probable. The main differen- tial diagnosis is Crohn’s disease (see Chapter 15.11). In some cases, a definite distinction is not possible, but if clinical, radiological, endo- scopic, and histological information are considered together, less than 10% of patients fall into the category of indeterminate colitis, a term originally used to describe an uncertain colitis based on the examination of a colectomy specimen and therefore inappropriate when only biopsy specimens are available. Hence, the recommended term is ‘inflammatory bowel disease—​unclassified’. Collagenous colitis usually has normal appearance at colono­ scopy and is diagnosed on the basis of a thickened subepithelial col- lagen band (wider than 15 μm) seen in a mucosal biopsy specimen. Microscopic or lymphocytic colitis has a normal endoscopic ap- pearance but shows a diffuse infiltration of the lamina propria with lymphocytes and eosinophils on histological examination. Although ischaemic colitis classically occurs around the splenic flexure, it may occur in the rectum, especially in older individuals, and frequently has typical histological features. Drugs can induce colitis. Those that have been implicated include NSAIDs, gold, penicillamine, and chemotherapy agents particularly the increasingly used checkpoint inhibitors which are frequently as- sociated with colonic inflammation which may be life threatening. Interestingly, 5-​aminosalicylic acid may also cause an allergic colitis, causing diagnostic confusion in patients beginning treatment for a recent diagnosis of ulcerative colitis. A careful history will usually identify this problem. Chronic infection mimicking colitis is rare. Occasionally, schistosomal colitis is seen with uniform inflammation, and travel to an endemic area should prompt careful histological examination for characteristic schistosomal lesions. Mycobacterial infections gener- ally mimic Crohn’s disease rather than ulcerative colitis. Radiation damage to the rectum may occur, especially in men who have had radiotherapy to the prostate. Occasionally, solitary rectal ulcer syndrome presents as circumferential inflammation mimicking ulcerative proctitis, but typical histology should avoid confusion. Symptoms of acute onset For those patients presenting with a much more abrupt onset, in- fective forms of colitis must be excluded by stool culture. A sudden onset of symptoms, the predominance of abdominal pain, the inges- tion of potentially infected food (chicken, shellfish), history of travel, and evidence of diarrhoeal disease in contacts are potential pointers towards infection. Sigmoidoscopic appearances can be very similar to ulcerative colitis, but histology can be useful in distinguishing an infective from a more chronic ulcerative colitis. Hence, the presence of a chronic inflammatory infiltrate, architectural disturbances of the glands, and basal lymphoid aggregates favour ulcerative colitis. The common organisms causing an infective colitis are salmon- ella, shigella, and campylobacter. Yersinial infections may also cause colitis and can pursue a chronic course over many months before resolving. Special culture conditions may isolate the organism from stool, but a rising titre of serum antibody is often the more reliable Table 15.12.1  Simple Clinical Colitis Activity Index (SCCAI) descriptors, threshold, and kappa statistic (a measure of interobserver variation in rating, with a value of 1.0 indicating perfect concordance) Descriptor Level Kappa (95% CI) Bowel frequency (day) 0.83 (0.78 to 0.88) 1–​3 0 4–​6 1 7–​9 2

9 3 Bowel frequency (night) 0.89 (0.81 to 0.97) 1–​3 0 4–​6 1 Urgency of defecation 0.76 (0.71 to 0.81) Nil 0 Hurry 1 Immediately 2 Incontinence 3 Blood in stool 0.77 (0.72 to 0.83) No 0 Trace 1 Occasionally frank 2 Usually frank 3 General well-​being 0.88 (0.83 to 0.94) Very well 0 Slightly below par 1 Poor 2 Very poor 3 Terrible 4 Extracolonic features 1 (per manifestation) 0.25 (0.18 to 0.32) Thresholds Remission ≤2 Mild 3 to 5 Moderate 6 to 11 Severe ≥12 Total score (Range 0–​19) 0.75 (0.70 to 0.81) CI, confidence interval. Components of the Simple Clinical Colitis Activity Index (SCCAI), indicating thresholds used to categorize into remission, mild, moderate, and severe disease activity. From Walsh AJ, et al. (2014). Comparing disease activity indices in ulcerative colitis. J Crohns Colitis, 8, 318–​25, by permission of Oxford University Press.

section 15  Gastroenterological disorders 2944 method of identifying the infection. Escherichia coli 0157 is a recog- nized cause of an acute colitis, especially in institutions, and massive bleeding is often a characteristic feature. Children may develop a haemolytic uraemic syndrome. For patients who have travelled in endemic areas, amoebic colitis should be considered; stool exam- ination and histological demonstration of amoebae in rectal biopsy specimens make the diagnosis. An antibiotic history must be taken, but a pseudomembranous colitis secondary to C. difficile can occur in the absence of antibiotic usage, especially in older people. Furthermore, C. difficile infection is a relatively common cause of a flare of ulcerative colitis, hence testing all patients admitted to hospital with suspected acute colitis is best practice in this setting. Other causes of infective colitis can occur in immunosuppressed patients and include CMV and herpes simplex. Although these or- ganisms usually cause more focal discontinuous colonic inflamma- tion, they can be associated with a diffuse pattern of inflammation. As previously mentioned, CMV can be seen as a superimposed in- fection in patients with acute ulcerative colitis on high-​dose steroids and should always be looked for in a rectal biopsy in those failing to settle on treatment. While abrupt in onset, sexually transmitted causes of proctitis (gonorrhoea, chlamydia, lymphogranuloma) do not usually cause diarrhoea and, especially with gonorrhoea, are as- sociated with the passage of watery pus. Exclusion of sexually trans- mitted infection is often best managed by referral to the appropriate acute clinic as testing is more thorough and effective. Extraintestinal manifestations The extraintestinal manifestations of ulcerative colitis are listed in Box 15.12.1. Skin Erythema nodosum occurs in about 2 to 4% of patients and is usu- ally associated with active disease. The lesions occur most com- monly on the anterior aspect of the lower legs. Inflammatory joint and eye disease often coexist with erythema nodosum. Pyoderma gangrenosum is rare (1–​2%) and usually seen in pa- tients with active disease, but occasionally persists despite inactive colitis. The lesions usually begin as sterile pustules, most commonly on the limbs, which break down as they enlarge and finally coalesce. Ulceration leads to necrosis and the lesions become surrounded by a black, necrotic margin. Treatment of the colitis is usually followed by regression of the skin lesions, but pyoderma can be very resistant to therapy, including anti-​TNF agents, and may even persist following colectomy. Indeed, because of the predilection of pyoderma for sites of skin trauma, troublesome lesions can occur in laparotomy wounds and in the skin close to an ileostomy. Mouth Crops of aphthous ulcers are common in patients with active dis- ease. A sore tongue and angular stomatitis often accompany chronic iron deficiency. Focal ulceration on the lateral aspects of the tongue is a rare colitis-​associated lesion, as is a vivid gingivitis known as pyostomatitis vegetans. Eyes Episcleritis or anterior uveitis occurs in 5 to 8% of patients. Local cor- ticosteroids and treatment of active colitis usually lead to resolution. Joints An acute arthropathy occurs in 10 to 15% of patients with active dis- ease. It affects the larger joints (knees, hips, ankles, wrists, elbows) and is usually asymmetrical. It is a nonerosive condition and settles as the colitis goes into remission. A less common joint complication is a symmetrical small-​joint polyarthropathy, which is seronegative and is unrelated to the activity of the colitis. Low back pain and early morning stiffness is a common symptom and usually due to sacroiliitis, which can be seen by plain radiology in 12 to 15% of patients and in 30 to 35% by MRI. It is unrelated to the activity of the colitis, and is not strongly associated with HLA B27. Ankylosing spondylitis, conversely, occurs in only 1 to 2% of patients, more often men, with 60% having the HLA B27 pheno- type. Spondylitis may present before the colitis becomes apparent or may follow the intestinal symptoms. The natural history is inde- pendent to that of the colitis and the condition needs various treat- ment approaches under the guidance of a rheumatologist. NSAIDs are frequently required but need to be used cautiously because of the risk of flaring the colitis. Anti-​TNF agents are highly effective in relieving the pain and stiffness of both sacroiliitis and ankylosing spondylitis. Liver disease Patients with severe attacks of ulcerative colitis often have minor ele- vations of alkaline phosphatase or transaminases. The cause of these enzyme rises is probably multifactorial, including malnutrition, sepsis, and hepatic steatosis (fatty liver), which occurs in up to 60% of patients undergoing urgent colectomy. The liver enzymes return to normal when remission is achieved, but there may be persistent abnormalities in liver enzymes in about 3% of patients, usually a rise in alkaline phosphatase. The overwhelming majority of these patients will have primary sclerosing cholangitis when the bile duct is visualized by endoscopic cholangiography (see Chapter 15.22.4). Histologically, liver biopsy specimens show evidence of chronic liver disease, but the spectrum of appearances ranges from those of an autoimmune hepatitis to the classic picture of concentric periductular fibrosis with obliteration of bile ducts. Box 15.12.1  Extraintestinal manifestations of ulcerative colitis Related to activity of colitis • Oral aphthous ulceration • Fatty liver (hepatic steatosis) • Erythema nodosum • Peripheral arthropathy • Episcleritis • Anterior uveitis • Pyoderma gangrenosum (sometimes unrelated to disease activity) Unrelated to activity of colitis • Unrelated to colitis • Sacroiliitis • Ankylosing spondylitis • Primary sclerosing cholangitis • Cholangiocarcinoma

15.12  Ulcerative colitis 2945 Many patients with ulcerative colitis and sclerosing cholangitis remain well for many years. The colitis frequently runs a relatively mild course, though often affects the whole colon, but the liver dis- ease is progressive and ultimately leads to portal hypertension and liver failure. Sclerosing cholangitis is a premalignant condition and explains the well-​recognized association between ulcerative colitis and cholangiocarcinoma. Furthermore, there is a high incidence of colorectal cancer, especially of the right colon, in these patients. Colonoscopic surveillance is therefore mandatory. The mild nature of the colonic inflammation despite extensive disease, the frequently observed rectal sparing, and the right-​sided cancers have called into question whether the colonic disease is really the same as ulcerative colitis. Rare associations Pericarditis with or without an effusion has been described in associ- ation with an acute attack of colitis, but a true association is not proven. Autoimmune haemolytic anaemia has been reported in ulcerative col- itis and may recur when the colonic disease becomes active. Amyloid rarely occurs in ulcerative colitis and is much more likely to be asso- ciated with Crohn’s disease. A rapidly progressing bronchiectasis has also been described in some patients with ulcerative colitis. Medical management Optimal treatment of ulcerative colitis requires rapid control of symptoms with induction therapy followed by maintenance of re- mission. There is a move towards treating more aggressively, perhaps aiming for complete mucosal or even histological healing, although this remains controversial. Ensuring appropriate timing of surgical intervention remains a cornerstone of the management of ulcerative colitis. It is also important that patients are encouraged to be involved in their management where possible; self-​management protocols and access to patient support groups should be encouraged. There are several guidelines to support management, with only minor differences between them. The European Crohn’s and Colitis Organisation guidelines are generally representative and up to date. Induction of remission Proctitis Proctitis refers to disease limited to the rectum. This accounts for about a third of patients with ulcerative colitis and tends to pre- sent with rectal bleeding, frequency, and tenesmus, often without diarrhoea. Despite its limited extent, proctitis can be very difficult to treat. Initial treatment with 5-​aminosalicylic acid is best given topically and is most effective when combined with oral therapy. Suppositories may treat the rectum more effectively than enemas. Topical steroids can also be used but are less effective than 5-​ aminosalicylic acid, although the combination of the two is often used in refractory cases. When disease remains refractory to these treatments, systemic steroids, immunomodulators, and biological drugs are all appropriate and, on occasion, colectomy is required. Proximal constipation should be considered in patients with proctitis, particularly those who are refractory to treatment and in whom abdominal pain and bloating are prominent. Treatment with osmotic laxatives not only treats the constipation, but is often asso- ciated with improvement in rectal inflammation. It is also important to consider disease extension in patients whose proctitis is refrac- tory to treatment as this is often associated with a worse prognosis. Left-​sided and extensive ulcerative colitis Mild disease The most effective initial treatment is with 5-​aminosalicyclic acid delivered both orally and through an enema. Once-​daily dosing of 5-​aminosalicyclic acid is as effective as multiple-​daily dosing. Where 5-​aminosalicyclic acid is ineffective, topical steroids may be used instead. For refractory disease, systemic steroids in the form of prednisolone starting at 40 mg per day, decreasing gradually over 8 weeks, is appropriate. Moderate disease While initial treatment with 5-​aminosalicylic acid at doses greater than 2 g per day is an appropriate first-​line treatment, more pa- tients with moderate disease end up needing systemic steroids and these are sometimes used first line. Prevention of steroid-​induced bone thinning should be considered with, for example, calcium and vitamin D. When steroids are used first line, 5-​aminosalicyclic acid should also be given, although it is important to remember that a few patients experience worsening of symptoms with 5-​aminosalicyclic acid (see ‘Differential diagnosis’). Steroid-​refractory disease In those with severe symptoms (stool frequency of more than six per day with blood), failure to respond to oral prednisolone should prompt admission to hospital for treatment with intravenous steroids or escalation to biological therapy to induce remission. Treatment with thiopurines (mercaptopurine or azathioprine) is in- appropriate in this situation due to their slow onset of action. Three different anti-​TNF agents have been shown to be effective at inducing and maintaining remission in treatment-​refractory ulcera- tive colitis. Infliximab, adalimumab, and golimumab have all been shown to be superior to placebo in this setting. Unfortunately there are no head-​to-​head trials that directly compare their efficacy, and due to differences in trial design and in the subjects enrolled, it is dif- ficult to draw conclusions about which, if any, is the most effective. As with many drugs used in inflammatory bowel disease, real-​ world effectiveness of anti-​TNF in ulcerative colitis appears to be better than the efficacy demonstrated in the registration trials. The role of anti-​TNF drug level and antidrug antibody testing is likely to be of benefit in some scenarios, particularly in patients who are losing response, and, at least for infliximab, combining treatment with a thiopurine has been shown in a high-​quality randomized controlled trial to be more effective than using either drug alone. Screening for transmissible infections as well as for latent tubercu- losis with a chest radiograph and an interferon-​γ release assay or PPD test is regarded as good practice. Vedolizumab is an antibody to α4β7, an integrin expressed on white blood cells which home to the gut. It has been shown to be superior to placebo in treatment-​resistant ulcerative colitis although the effects are less marked in patients who have previously been ex- posed to anti-​TNF therapy. Its gut specificity means that the risk of systemic infection seen with nontargeted therapies appears to

section 15  Gastroenterological disorders 2946 be reduced. A recent trial comparing vedolizumab and anti-​TNF showed that adalimumab was less effective than vedolizumab in patients with moderate to severe ulcerative colitis. As more head- to-head studies become available, our understanding of treatment positioning will increase. Tofacitinib, an inhibitor of janus kinase, is an orally administered treatment that has recently been licensed for the treatment of ul- cerative colitis. It appears to be at least as effective as the available biological therapies. Early experience suggests that it may be the pre- ferred choice in patients who have failed biologics although it is also undoubtedly effective in biologic-naive patients. A whole host of biologic and non-biologic therapies are currently going through early and late phase trials with those targeting the Il-12/23 axis being the next to arrive on the market. Pharmaco­ economic considerations will undoubtedly influence treatment choice in many parts of the world particularly as patents expire allowing cheaper versions of new therapies to become available. Tacrolimus has also been used in patients who are refractory to oral corticosteroids. A randomized controlled trial demonstrated that response was more likely in tacrolimus-​treated patients than in those who received placebo. Overall, it must be remembered that a significant proportion of patients fail to respond to any of these therapies, in which case sur- gery remains an appropriate option. Steroid-​dependent disease Patients who fail to withdraw steroids without relapsing or who re- quire recurrent courses of steroids in quick succession are deemed steroid dependent. Because of the multiplicity of adverse outcomes associated with long-​term steroid use, as well as the inability of ster- oids to maintain remission, steroid-​sparing agents are introduced in steroid-​dependent patients. As a rule of thumb, up to one course of systemic steroids a year is thought to be acceptable. The options for steroid-​dependent patients include anti-​TNF therapy, anti-​integrin therapy and tofacitinib. However, as such pa- tients may not have active disease, it is also appropriate to consider using thiopurines. A Cochrane meta-​analysis has shown that these are effective steroid-​sparing agents in ulcerative colitis. They are usually initially given at a weight-​based dose of 1 to 1.5 mg/​kg of mercaptopurine or 2 to 2.5 mg/​kg of its prodrug azathioprine. Approximately one-​third of patients treated with thiopurines de- velop side effects that limit their use. Myelosuppression and liver dys- function can normally be identified with prospective monitoring of blood tests, unlike flu-​like symptoms and pancreatitis. Thiopurines are known to increase the risk of non-​Hodgkin’s lymphoma and nonmelanoma skin cancer although the absolute risk in patients aged under 50  years remains extremely low. Pharmacogenetic markers that allow prospective identification of patients who are more likely to develop side effects have been studied in recent years. One such pharmacogenetic marker has now entered routine clin- ical practice; measurement of the activity of the enzyme thiopurine methyltransferase (or genotypic assessment of TPMT) allows iden- tification of the 1 in 300 people with extremely low TPMT activity. Such patients are at extremely high risk of bone marrow suppres- sion if treated with thiopurines and should not receive azathioprine or mercaptopurine. However, equally importantly, approximately 1 in 10 people have intermediate activity of TPMT. While also at an increased risk of myelosuppression, they are also more likely to develop some of the other side effects commonly associated with thiopurines, such as flu-​like symptoms. Reduced dosing to ap- proximately 50% of the standard dose allows successful treatment in most of these patients. Thus, while TPMT testing is suggested in many guidelines, it is important to note that knowledge of TPMT phenotype or genotype does not negate the need for white blood cell count monitoring as non-​TPMT related myelosuppression also occurs. Another pharmacogenetic marker identifying non-TPMT related myelsuppression has recently been discovered such that NUDT15 genotyping may also soon enter clinical practice. In add- ition, whilst a recently identified marker for thiopurine-related pan- creatitis may not have great clinical utility, there is ongoing interest in pharmacogenetics in this field which may allow further person- alisation of therapy. Therapeutic drug monitoring with measure- ment of thiopurine metabolites such as the thioguanine nucleotides and methylated metabolites allows optimization of therapy, as well as identifying thiopurine-​resistant patients, and is becoming more widely used. Methotrexate has occasionally been used as an alternative immuno­ modulator to thiopurines although, unlike in Crohn’s disease, there is limited high-​quality evidence to support its use. Indeed, recent ran- domized controlled trials failed to reach their primary endpoints and with increasing alternative treatments available, the use of metho- trexate in this condition is likely to disappear. Severe disease The presence of more than six bloody stools a day in combination with any systemic systems such as fever, tachycardia, anaemia, or an ESR of more than 30 mm/​h defines severe disease and should prompt admission to hospital. Intercurrent infection is common and should be excluded by sending stool samples for microscopy and culture as well as for C. difficile toxin. A flexible sigmoidos- copy should be performed to confirm the diagnosis and to ex- clude intercurrent infection with cytomegalovirus. Treatment with high-​dose intravenous steroids, for example, 100 mg of hydrocortisone four times daily or 60 mg of methylprednisolone per day, should be initiated along with thromboprophylaxis with low molecular weight heparin as the risk of deep vein thrombosis and pulmonary embolism is greatly increased with active disease. The presence of rectal bleeding should not be used as a reason not to use thromboprophylaxis. Fluid and electrolytes should be replaced with particular attention being paid to potassium levels which are often low. Antibiotics are only needed if infection is considered likely. Nutritional supplementation should be given to malnourished patients. Patients should be reviewed daily by both a physician and a sur- geon experienced in the management of ulcerative colitis. After 3 days of treatment with intravenous steroids, an assessment of re- sponse should be undertaken. For those that are responding, who will have improvement in their stool frequency and rectal bleeding with an absence of systemic features, substituting the intravenous ster- oids with oral prednisolone is appropriate after 5 to 7 days. However, patients who have either more than eight stools a day, or who have three to eight stools per day and a CRP of greater than 45 mg/​litre after 72 h of intravenous steroids, have an 85% chance of requiring urgent surgery. Accordingly, colectomy or rescue therapy should be considered. The decision between ongoing medical therapy and sur- gery should involve a careful and thorough discussion between the

15.12  Ulcerative colitis 2947 patient, their physician, and the surgeon. Numerous factors weigh into this including the potential risks of each of the options, the quality of life experienced prior to the current attack, which thera- peutic options for maintenance of remission remain should rescue therapy be successful, and the patient’s personal preference. Rescue therapy Randomized controlled trial evidence supports the use of either ciclosporin or infliximab as rescue therapies for steroid-​resistant acute severe ulcerative colitis. Ciclosporin Ciclosporin should be given at a dose of 2 mg/​kg per day, usually as an intravenous infusion. Higher doses (e.g. 4 mg/​kg as was used in the original trial) are no more effective but are likely to be asso- ciated with a greater risk of side effects. Hypomagnesaemia should be corrected prior to use, and intravenous ciclosporin should be avoided in the presence of hypocholesterolaemia. An alternative in this situation may be to use oral ciclosporin (5 mg/​kg) which may be just as effective as the intravenous preparation having excellent bioavailability. Response should be assessed over 4 to 7 days. In the short term, response rates are in the region of 80%, although the likelihood of avoiding colectomy in the long term may be as low as 50% over 5 years. Infliximab Infliximab is more effective than placebo in patients with steroid-​ resistant acute severe colitis. While the initial trial demonstrating this used a single infusion of 5 mg/​kg, it has subsequently become apparent that the optimal regimen requires higher dosing. Indeed, preliminary data suggests that levels of infliximab can drop rapidly after dosing in acute severe colitis, perhaps due to loss into the bowel lumen, such that doses higher than 5 mg/​kg at weeks 0, 2, and 6 (the standard regimen for ulcerative colitis) may be needed to maximize the response. Poor response is associated with low serum albumin levels. While not supported by data in this setting, it is likely that in the longer term, the response to infliximab is likely to be improved when it is combined with a thiopurine, albeit at a higher risk of side effects. As for ciclosporin, of those patients that respond, many undergo colectomy over the ensuing years and patients should be made aware of this fact when deciding whether to receive rescue therapy or not. Ciclosporin or infliximab? Two randomized controlled trials have compared the use of ciclosporin and infliximab in patients with acute severe ulcerative colitis. One used a combined clinical endpoint, while the other had a quality-​adjusted outcome as its primary measure. Neither demon- strated a significant advantage of one drug over the other. Currently, the convenience of administering infliximab is probably its greatest advantage over ciclosporin. Whereas previously the lack of main- tenance options in azathioprine-​experienced patients drove the use of infliximab in this patient group, the advent of newer maintenance therapies makes this decision less clear. While it is unclear whether one drug is superior to the other in the setting of acute severe ulcerative colitis, case series suggest that sequential use of infliximab and ciclosporin or vice versa is inappropriate, being associated with an increased risk of morbidity and mortality. For patients who do not respond to rescue therapy after 4 to 7 days, or for those who deteriorate despite treatment, subtotal col- ectomy is mandated. Inappropriately delaying surgery is dangerous and best avoided by ensuring that decisions are taken at appropriate time points using a multidisciplinary approach. Maintenance therapy Once remission is achieved with 5-​aminosalicylic acid, mainten- ance is with continued treatment. Sulfasalazine was the first 5-​ aminosalicyic acid-​containing drug to be used in ulcerative colitis. Its use is limited by side effects related to the sulfapyridine component, which is released once the drug reaches the colon where bacteria act on the azo-​bond linking it to 5-​aminosalicylic acid. Common side effects include nausea and headache, but more serious side effects include agranulocytosis and reversible male infertility. Sulfasalazine, however, maintains a role in patients with coexistent enteropathic arthropathy, which may respond well to this drug. For most patients, however, newer preparations of 5-​aminosalicylic acid are available. As the drug is partially absorbed in the upper gastrointestinal tract, preparations which either delay its release until the distal small bowel or rely on bacteria to release the active com- ponent in the colon are generally used. Tolerance is usually excel- lent. Rare but serious side effects include pancreatitis and interstitial nephritis, which can lead to end-​stage renal failure. Accordingly, monitoring of renal function should be performed in patients taking 5-​aminosalicylic acid with the serum creatinine measured soon after starting and yearly thereafter. However, the most frequent side effect limiting its use is worsening of diarrhoea, which may occur in up to 10% of patients. Whichever preparation is used, once-​daily therapy has been shown to be at least as effective as multiple-​daily dosing and is likely to improve adherence. There is limited evidence to suggest that one preparation is better than another, although swapping to alterna- tive release preparation can on occasion be successful in cases of nonresponse. For patients with proctitis, topical maintenance therapy with sup- positories can be extremely effective and often does not necessarily require daily dosing. Maintenance therapy with steroids is inappropriate and as- sociated with a wide range of side effects. As described earlier, immunomodulators and biological therapies are both effective at maintaining remission. The cost associated with newer agents has been the greatest barrier to expanding use of these agents as mainten- ance therapy although the advent of biosimilar versions of anti-TNF has greatly decreased the economic burden associated with their use. The effectiveness as maintenance agents of biologics and tofacitinib and their long-​term safety profile (albeit limited for tofacitinib) ap- pears to be at worst comparable with immunomodulators. Thus, withdrawal of therapy is an area of increasing interest. Limited data are available for anti-​TNF withdrawal in ulcerative colitis where the greatest risk of stopping treatment probably relates to the risk of antibody production which may compromise subsequent reintro- duction. By comparison, withdrawal of thiopurine is probably suc- cessful in about half of patients who have been in remission in the long term; reassuringly, reintroduction of thiopurines is normally effective in patients who relapse.

section 15  Gastroenterological disorders 2948 Surgical management The need for surgery in patients with ulcerative colitis is driven by one of several scenarios: first, patients with acute severe colitis not responding to medical therapy; second, in the context of complica- tions of severe colitis such as toxic megacolon; third, patients with chronic disease activity; and, fourth, patients who have dysplasia or cancer. Particularly in the setting of active disease, a subtotal colectomy is usually performed initially. Restorative proctocolectomy with for- mation of an ileoanal pouch may then be offered. The J-​pouch is the preferred configuration as it involves a shorter operation time and has similar long-​term outcomes in terms of pouch function compared to larger-​volume configurations. Either a stapled pouch-​ anal anastomosis leaving a short cuff of rectal mucosa, or a hand-​ sewn pouch in association with a mucosectomy, can be performed (Fig. 15.12.6). In general, the former is associated with better con- tinence, although the latter prevents recurrence of dysplasia and the possibility of developing cuffitis. There is an increasing vogue for performing colectomy and pouch surgery using minimal access techniques resulting in an improved cosmetic appearance and a shorter length of stay. Pouch surgery is associated with a decrease in fecundity among females and with a risk of impotence and ejaculatory dysfunction in men. On rare occasions, ileorectal anastomosis is performed, although careful surveillance of the remnant rectum is required. Pouch function is generally good in most patients, with better outcomes being associated with high-​volume pouch centres. On average, patients with pouches open their bowels between four and six times a day and often once at night. Complications after pouch surgery include small-​bowel obstruction, which occurs in up to 30% of patients but usually responds to conservative management. Pouchitis occurs in approximately half of patients over a 10-​year period. Endoscopic assessment helps to exclude other conditions such as irritable pouches, cuffitis, ischaemia, Crohn’s disease, or in- fection. In assessing the pouch endoscopically, it is also important to inspect the prepouch ileum for inflammation or stenosis. Pouchitis normally responds to antibiotics such as ciprofloxacin and metronidazole, although long-​term treatment is sometimes needed. There is some evidence that VSL#3, a probiotic, is able to improve maintenance of antibiotic-​induced remission in patients with pouchitis. Approximately 5% of patients experience pouch failure resulting in a long-​term nonfunctioning pouch, pouch excision and per- manent end ileostomy, or a redo pouch operation. Prognosis/​outcome The outcome of ulcerative colitis is varied. A few patients have a single attack which responds to treatment without any subsequent relapses. At the other end of the spectrum, approximately 5% of pa- tients will have a severe attack at presentation necessitating colec- tomy. The remainder have a disease course somewhere in between. Most patients relapse within their first year after diagnosis and then go on to have regular relapses, but with a frequency of less than once per year. Approximately 10% will have more than one relapse per year and some have unremitting disease activity. Active inflammation, even in the absence of symptoms is a pre- dictive factor for future relapse. In addition, both macroscopic and microscopic inflammation are known to drive the risk of dysplasia and cancer. It is also likely that chronically active disease contrib- utes to the colonic dysfunction that is characteristic of long-​standing ‘burnt-​out’ colitis. The risk of requiring colectomy is difficult to determine but is probably in the region of 10%. Having extensive disease or disease extension is known to increase the risk of colectomy, and admission to hospital with an attack of acute severe colitis increases the like- lihood of subsequent colectomy fivefold. By comparison, patients with proctitis have a much lower risk of colectomy. Whether the ad- vent of new therapeutic options will dramatically alter the long-​term requirement for colectomy remains to be seen. Complications Acute complications Toxic dilatation Acute severe colitis can be associated with toxic dilatation of the colon, also known as toxic megacolon. It occurs in approximately 5% of cases of acute severe colitis and is recognized by radio- logical dilatation of the colon to 5.5 cm associated with signs of systemic toxicity. The use of antimotility drugs and opiates may precipitate toxic dilatation, as may electrolyte disturbances such as hypokalaemia and hypomagnesaemia. While patients who pre- sent with dilatation may respond to medical therapy, failure to re- spond within 24 h of intensive medical therapy or the development (a) (b) Fig. 15.12.6  Different methods to fashion an ileal pouch anal anastomosis. A double-​stapled technique leaves the anal transition zone intact and may be associated with better pouch function (a). A mucosectomy and hand-​sewn anastomosis removes all the colonic mucosa, is felt to reduce the long-​term risk of cancer in the rectal stump, but may be associated with an increased likelihood of faecal leakage (b). Reproduced from MacKay GJ, Dorrance HR, Molloy RG, O'Dwyer PJ (eds) (2010). Colorectal surgery (Oxford Specialist Handbooks in Surgery) with permission from Oxford University Press.

15.12  Ulcerative colitis 2949 of dilatation in the context of intensive therapy requires surgical intervention. Perforation Perforation is, fortunately, rare in the context of appropriately man- aged acute severe ulcerative colitis but can occur in the absence of toxic dilatation. It carries a high risk of mortality and can be the result of inappropriately delayed surgery. As the vast majority of patients who experience perforation are on high-​dose steroids to manage their colitis, it is important to remember that steroids can mask the signs of peritonitis. Colectomy is mandatory in the setting of ulcerative colitis-​associated perforation. Massive haemorrhage Uncontrollable colonic blood loss is rare in patients with ulcerative colitis. However, when it does occur, if medical therapy and resusci- tation fails, surgical intervention is required. Thromboembolism Pulmonary embolism remains an important cause of mortality in patients with ulcerative colitis. The risk is highest in patients who are hospitalized with acute colitis and those undergoing surgery. A wide range of venous and arterial thromboses are reported in association with ulcerative colitis, highlighting the importance of adequate thromboprophylaxis in this setting. Long-​term complications Colonic structural effects Strictures rarely form in people with chronic ulcerative colitis. They are associated with an increased risk of colorectal carcinoma and, if severe, prevent adequate colorectal cancer surveillance. Similarly, extensive pseudopolyp formation may make cancer surveillance more challenging. Patients who develop strictures or who have ex- tensive pseudopolyp formation should have a discussion about the risk:benefit balance of surveillance and colectomy. Colonic functional effects Chronic active disease is associated with colonic dysfunction. The typical appearance of a ‘lead pipe’ colon with a lack of haustration and a tubular structure provides a visual illustration of the effects of chronic activity on colonic function. Impaired motility and a lack of compliance can have devastating effects on colonic function, ex- plaining the greatly increased risk of faecal incontinence in patients with ulcerative colitis. Colorectal carcinoma There is a clear association between long-​standing ulcerative colitis and an increased risk of colorectal cancer, except in patients with proctitis. The risk is low during the first 8 years of disease, apart from in patients with specific risk factors such as primary sclerosing chol- angitis, advanced age, or a strong family history. Disease activity is probably the biggest risk factor and there is some evidence that the use of medications decreases the risk of colitis-​associated cancer. Estimates of the risk of developing cancer vary widely, but for pa- tients with extensive disease, the risk is probably lower than previ- ously thought; one of the original meta-​analyses suggested the risk of colorectal cancer was as high as 18% at 30 years, whereas more recent estimates have been as low as 2% at the same time point. Because of the risk of colitis-​associated colorectal cancer, screening is recommended. Current guidelines suggest that an index colonoscopy should be performed approximately 8  years after diagnosis to define microscopic and macroscopic disease ex- tent. It is important to note, however, that up to one in five colitis-​ associated cancers present before this time point. Subsequent colonoscopy should be performed at an interval of 1 to 5 years, depending on risk factors such as inflammation, family history, and disease extent. Patients with concomitant primary sclerosing cholangitis are at particularly high risk of developing colorectal cancer and should have an annual colonoscopy from the time of diagnosis of primary sclerosing cholangitis. Patients with proc- titis (and no past history of more extensive disease) do not re- quire screening. The presence of pseudopolyps makes screening more challenging and should be taken into consideration when determining the screening interval, or even the possibility of prophylactic colectomy. Screening colonoscopy is best performed by experienced colonoscopists familiar with techniques to enhance the detection of dysplasia. For example, chromoendoscopy employing pancolonic dye spray with targeted biopsies is now regarded as the gold standard. However, where this is not available, four random biop- sies taken every 10 cm has been shown to increase the chance of detecting dysplasia. Special circumstances Ulcerative colitis in pregnancy Fertility is unaffected by ulcerative colitis although voluntary child- lessness is increased in inflammatory bowel disease. Women who conceive while in remission are no more likely to relapse than nonpregnant women. However, if conception occurs during an ac- tive disease flare, this is associated with an increased risk of active disease throughout pregnancy. Most medications used to treat ulcerative colitis are considered low risk in pregnancy; the risk of active disease is greater than that associated with medication use with the exception of metho- trexate, which is teratogenic, and vedolizumab and tofacitinib, where there is not yet enough data to understand the risks of its use. 5-​aminosalicyclic acid, steroids, thiopurines, and anti-​TNF therapy are all used in pregnancy. The risk to the infant of infection in the first year of life associated with maternal anti-​TNF exposure ap- pears to be very small if, indeed, it exists. Nevertheless, because of the fact that anti-​TNF is actively transported across the pla- centa, therapy is sometimes withdrawn towards the end of the second trimester, although the risks of drug withdrawal need to be considered in this situation. Anti-​TNF-​exposed babies should not receive live vaccines until their serum levels of anti-​TNF have dropped. Ulcerative colitis does not necessitate caesarean section, although the presence of an ileoanal pouch is a relative contraindication to vaginal delivery. Breastfeeding is considered safe with standard ul- cerative colitis medications. Ulcerative colitis in childhood Onset of ulcerative colitis before the age of 10 years is unusual. However, when it does present in children, it probably has a more

section 15  Gastroenterological disorders 2950 severe phenotype than that seen in adults. Extensive disease is more common, accounting for up to 80% of colitis in children. Furthermore, failure to respond to steroids is more frequently encountered than in adult onset ulcerative colitis. It is probably for this reason that colectomy rates are significantly higher in children than in adults, reportedly being as high as 40% after 10 years of disease. Treatment principles are similar to adult-​onset ulcerative colitis although particular attention to steroid exposure and its effects on growth are required. Due to the higher incidence of steroid resist- ance, exposure to immunomodulating and/​or biological therapies is increased in childhood-​onset ulcerative colitis; dose adjustments may be necessary depending on the preparations used. Future developments The treatment of ulcerative colitis has been through a marked change over recent years. The availability of treatments with new modes of action as well as adaptation of traditional treatments to improve their effectiveness and tolerability has improved our ability to treat the condition. Several new treatments are likely to become available over the next few years. Accordingly, there is a need to identify ways in which patients can be profiled in order to treat them with the most effective medication. Such personaliza- tion of medicine is one of the ways in which the ever-​increasing challenges of the pharmacoeconomic impact of new, often ex- pensive, drugs can be addressed. Similarly, with increasing recog- nition of the relevance of mucosal healing and the possibility of long-​term complications arising from chronically active disease, it is imperative that research addresses long-​term benefits and safety, as well as the cost-​effectiveness, of more aggressive treat- ment strategies. FURTHER READING Duijvestein M, et al. (2018). Novel therapies and treatment strategies for patients with inflammatory bowel disease. Curr Treat Options Gastroenterol, 16, 129–​46. Harbord M, et al. (2017). Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management. Journal of Crohn’s and Colitis, 11, 769–84. Imdad A, et al. (2018). Fecal transplantation for treatment of inflam- matory bowel disease. Cochrane Database Syst Rev, 11, CD012774. Khalili H, et al. (2018). The role of diet in the aetiopathogenesis of inflammatory bowel. Nat Rev Gastroenterol Hepatol, 15, 525–35. Lamb CA, et al. (2019). British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut, Sep 27. pii: gutjnl-2019-318484. Lee SH, Kwon JE, Cho ML (2018). Immunological pathogenesis of inflammatory bowel disease. Intest Res, 16, 26–​42. Limketkai BN, Wolf A, Parian AM (2018). Nutritional interventions in the patient with inflammatory bowel disease. Gastroenterol Clin North Am, 47, 155–​77. Magro F, et al. (2017). Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1:
Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders. Journal of Crohn’s and Colitis, 11, 649–70. Matsuoka K, et al. (2018). Evidence-​based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol, 53, 305–​53. Mosli MH, et al. (2017). Histologic scoring indices for evaluation of disease activity in ulcerative colitis. Cochrane Database Syst Rev, 5, CD011256. NG SC, et al. (2018). Worldwide incidence and prevalence of inflam- matory bowel disease in the 21st century: a systematic review of population-​based studies. Lancet, 23, 390, 2769–​78. Singh S, et al. (2019). AGA Technical Review on the Management of Mild-to-Moderate Ulcerative Colitis. Gastroenterology, 156, 769–808.