Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac have been reported to exacerbate IBD (Felder et al., 2000). It is thought this may result from direct inhibition of the synthesis of cytoprotective prostaglandins. Antibiotics may also precipitate a relapse in disease due to a change in the enteric microflora. The risk of developing Crohn’s disease is thought to be increased in women taking the oral contraceptive pill, possibly caused by vascular changes.

MMR vaccine

There has been much debate about the link between bowel disease and measles, measles vaccine or combined measles, mumps and rubella (MMR) immunisation. However, current evidence has indicated no proven correlation.

Appendicectomy

Appendicectomy has a protective effect in both Crohn’s disease and ulcerative colitis (Radford-Smith et al., 2002). It is unclear whether this protective effect is immunologically based or whether individuals who develop appendicitis and consequently have an appendicectomy are physiologically, genetically or immunologically distinct from the population that is predisposed to IBD.

Stress

Some patients find that stress triggers a relapse in their IBD and this has been reproduced in animal models. It is thought that stress activates inflammatory mediators at enteric nerve endings in the gut wall. In addition to stress as a trigger factor, living with IBD can also be stressful. Its chronic nature, lack of curative treatment, distressing symptoms and impact on lifestyle make it difficult for patients to cope.

Genetic

Fifteen percent of first degree relatives have IBD. There is mounting evidence that Crohn’s disease and ulcerative colitis result from an inappropriate response of the immune system in the mucosa of the gastro-intestinal tract to normal enteric flora (Ahmad et al., 2004). Since the mid-1990s there has been considerable progress in understanding the contribution of genetics to IBD susceptibility and phenotype.

Mutations of the gene CARD15/NOD2 located on chromosome 16 have been associated with small intestinal Crohn’s disease in white but not oriental populations. Two other genes have been recently linked with Crohn’s disease (OCTN1 on chromosome 5 and DLG5 on chromosome 10).

Genetic studies in ulcerative colitis have shown human lymphocyte antibody (HLA) is more strongly linked. Genotype related to pattern of disease (HLA-DRI’103) is 5–11 times more common in patients who have undergone colectomy.

Ethnic and familial

Jews are more prone to IBD than non-Jews, with Ashkenazi Jews having a higher risk than Sephardic Jews. In North America, IBD is more common in whites than blacks. First-degree relatives of those with IBD have a 10-fold increase in risk of developing the disease. A familial link is supported from research showing a 15-fold greater concordance for IBD in monozygotic (identical) than dizygotic (non-identical) twins (Jess et al., 2005).

Pathophysiology

In individuals with IBD, trigger factors typically cause a severe, prolonged and inappropriate inflammatory response in the gastro-intestinal tract and the ongoing inflammatory reaction leads to an alteration in the normal architecture of the digestive tract. Genetically susceptible individuals seem unable to downregulate immune or antigen non-specific inflammatory responses. It is thought that chronic inflammation is characterised by increased activity of effector lymphocytes and pro-inflammatory cytokines that override normal control mechanisms. Others, however, have suggested that IBD may result from a primary failure of regulatory lymphocytes and cytokines, such as interleukin-10 and transforming growth factor-β, to control inflammation and effector pathways. In Crohn’s disease, it is also thought that T-cells are resistant to apoptosis after inactivation. Non-pathogenic bowel flora appears to be an essential factor.

Disease location

The character and distribution, both macroscopic and microscopic, of chronic inflammation define and distinguish ulcerative colitis and Crohn’s disease. Table 13.1 shows the differences in location and distribution of ulcerative colitis and Crohn’s disease. Figure 13.1 details the histological differences.

Table 13.1 Location and distribution of ulcerative colitis and Crohn’s disease

	Ulcerative colitis	Crohn’s disease
Location	Colon and rectum 40% proctitis 20% pancolitis 10–15% backwash ileitis	Entire gut (mouth to anus, rectal sparing) 45% ileocaecal disease 25% colitis only 20% terminal ileal disease 5% small bowel disease 5% anorectal, gastroduodenal, oral disease
Distribution	Continuous, diffuse	Often discontinuous and segmental ‘skip lesions’
		Full thickness (transmural)
	No granulomas	Granulomatous inflammation
	Inflammation of mucosa
	Ulceration if fine and superficial	Deep ulceration with mucosal extension
Fissures, fistulae and stricture	Absent	Common
Perianal disease	Absent	Present

Fig. 13.1 Histological features in the rectal biopsy that help to distinguish between ulcerative colitis and Crohn’s disease

(from Misiewicz et al., 1994, with kind permission from Blackwell Scientific Publications, Oxford).

Crohn’s disease

Crohn’s disease can affect any part of the gut from the mouth to the anus. Approximately 45% of patients have ileocaecal disease, 25% colitis only, 20% terminal ileal disease, 5% small bowel disease and 5% anorectal, gastroduodenal or oral disease. Crohn’s disease can involve one area of the gut or multiple areas, with unaffected areas in between being known as ‘skip lesions’. The areas of the small bowel affected are typically thickened and narrow. A ‘red ring’ is often the first visible abnormality seen on colonoscopy. This is a lymphoid follicular enlargement with a surrounding ring of erythema, which develops into aphthoid ulceration and may progress to deep fissuring ulcers with a cobblestone appearance, fibrosis and strictures. Intestinal strictures arise from chronic and extensive inflammation and fibrosis and bowel obstruction may arise. Local gut perforation may cause abscesses which may also lead to fistulae.

Microscopically, inflammation extends through all layers of the bowel. Inflammatory cells are seen throughout, resulting in ulceration and microabscess formation. Non-caseating epithelioid cells, sometimes with Langhans’ giant cells, are seen in about 25% of colonic biopsies and in 60% of surgically resected bowel. Chronic inflammation in the small intestine, colon, rectum and anus leads to an increased risk of carcinoma.

Ulcerative colitis

At first presentation, ulcerative colitis is confined to the rectum (proctitis) in 40% of cases, the sigmoid and descending colon (left-sided colitis) in 40% and the whole colon (total ulcerative colitis or pancolitis) in 20% of cases. Proctitis extends to involve more of the colon in a minority, with 15–30% of patients developing more extensive disease over 10 years. The reason why some patients have extensive disease and some have limited disease is unknown. In severe total ulcerative colitis, there may also be inflammation of the terminal ileum. This is known as ‘backwash ileitis’ but is not clinically significant. The colon appears mucopurulent, erythematous and granular with superficial ulceration that in severe cases leads to ulceration. As the colon heals by granulation, post-inflammatory polyps may form.

Microscopically, superficial inflammation is seen with inflammatory cells infiltrating the lamina propria and crypts. Crypt abscesses occur, the crypt structure is lost and goblet cell depletion arises as mucin is lost. Dysplasia, which can potentially progress to carcinoma, may be seen in biopsies taken from patients with long-standing total colitis.

Other types of colitis

Crohn’s disease yet to be classified (sometimes referred to indeterminate colitis) is when chronic colitis persists, yet the pathology of the disease has not been identified as either Crohn’s disease or ulcerative colitis. In microscopic colitis, the main feature is watery diarrhoea in the presence of a normal colonoscopy and chronic inflammation in the absence of crypt architectural distortion on mucosal biopsies. Drugs such as NSAIDs and proton pump inhibitors (PPIs) are implicated as the cause in up to 50% of cases of microscopic colitis. Diversion colitis is when inflammation occurs in the defunctioned loop of a colostomy causing a mucous discharge. Pseudomembraneous colitis is caused by Clostridium difficile, usually after prolonged or multiple antibiotics. The use of PPIs predisposes patients to infection. It is diagnosed by sigmoidoscopy and detection of C. difficile toxin in the stool.

Clinical manifestation

The clinical differences between Crohn’s disease and ulcerative colitis are described in Table 13.2.

Table 13.2 Clinical differences between ulcerative colitis and Crohn’s disease

Symptom	Ulcerative colitis	Crohn’s disease
Prominent symptom	Bloody diarrhoea	Diarrhoea, abdominal pain, weight loss 30%, no gross bleeding
Fever	++	++
Abdominal pain	Variable	++
Diarrhoea	+++	+++
Rectal bleeding	+++	++
Weight loss	+	++
Sign of malnutrition	+	++
Abdominal mass	−	++
Dehydration	+++	++
Iron-deficiency anaemia, raised CPR/ESR, hypoalbuminaemia	++	++

CPR, C-reactive protein; ESR, erythrocyte sedimentation rate; +, the likelihood this symptom will be present; −, symptom absent in patient.

Crohn’s disease

The clinical features of Crohn’s disease depend largely on the site of the bowel affected, the extent, severity and the pathological process in each patient. Crohn’s disease tends to be more disabling than ulcerative colitis with 25% of patients unable to work 1 year after diagnosis. The predominant symptoms in Crohn’s disease are diarrhoea, abdominal pain and weight loss. Weight loss occurs in most patients, irrespective of disease location. Ten to twenty percent of patients will have weight loss greater than 20%. The main cause is decreased oral intake, although malnutrition is also common. There is a slight increase in mortality in patients with extensive Crohn’s disease.

Small bowel, ileocaecal and terminal ileal disease

Patients present with pain and/or a tender palpable mass in the right iliac fossa with weight loss and diarrhoea, which usually contains no blood. Diarrhoea is caused by mucosal inflammation, bile salt malabsorption that causes steatorrhoea or bacterial growth proximal to a stricture. Small bowel obstruction may also occur as a consequence of inflammation, fibrosis and stricture formation. Patients often describe a more generalised intermittent pain which is colicky with loud gurgling bowel sounds (borborygmi), abdominal distension, vomiting and constipation. When inflammation or abscesses are the predominant pathology, many patients present with constant pain and fever. Enteric fistulae occur and may involve the skin, bladder or vagina. Although rare, perforation of the gut may present with an acute abdomen and peritonitis. Vitamin B₁₂ and folic acid deficiencies predispose patients with disease of the terminal ileum to macrocytic anaemia, while bile acid malabsorption also occurs in such patients and predisposes them to cholesterol gallstones and oxalate renal stones.

Colitis

The main symptoms are abdominal pain, profuse and frequent diarrhoea (more than six loose stools per day) with or without blood, and weight loss. Patients also complain of lassitude, anorexia and nausea and appear thin, tachycardic, anaemic, malnourished and febrile. Colitis may present insidiously with minimal discomfort. Patients with severe involvement of the colon or the terminal ileum often have electrolyte abnormalities, hypoalbuminaemia and iron-deficiency anaemia. Extra-intestinal complications are more common in those patients with large bowel disease.

Perianal disease

Patients may present with an anal fissure, fistula or a perirectal abscess. These symptoms can have a significant impact on the patient’s lifestyle.

Gastroduodenal and oral disease

These are both rare conditions. Gastroduodenal Crohn’s disease presents as dyspepsia, pain, weight loss, anorexia, nausea and vomiting. Oral disease is very painful and may cause chronic ulceration resulting in anorexia.

Stricturing Crohn’s disease

Patients presenting with pain, vomiting and constipation and a diagnosis of stricturing disease can lead to perforation if not surgically treated, although this is rare (see Fig. 13.2)

Fig. 13.2 Stricture formation in Crohn’s disease.

Ulcerative colitis

Typical symptoms of ulcerative colitis include bloody diarrhoea (the most predominant symptom) with mucus, abdominal pain with fever, and weight loss in severe cases. The typical appearance of a patient diagnosed with Crohn’s disease is low BMI, malabasorption, weight loss and growth retardation. Frank blood loss is more common in ulcerative colitis than Crohn’s disease. The symptoms of ulcerative colitis are similar to Crohn’s colitis with patients being tachycardic, anaemic, febrile, fatigued, dehydrated and thin. Approximately 50% of patients with ulcerative colitis have some form of relapse each year, and severe attacks can be life-threatening. Up until the 1960s, one-third of ulcerative colitis patients died from the condition; with advances in medical and surgical treatment death is now extremely rare.

Acute severe disease

In addition to the typical symptoms of ulcerative colitis, patients with acute severe disease may present with more than six bloody stools per day (10–20 liquid stools per day is not unusual), with a fever (>37.8 °C), tachycardia (>90 bpm), anaemia (Hb < 10.5 g/dL) or elevated inflammatory markers (ESR > 30 mm/h; CRP > 8). Severity is commonly assessed using the Truelove and Witts criteria (see investigations).

Moderately active disease

Stool frequency is less than six motions each day with diarrhoea, mucus and rectal bleeding. Moderatively active disease is more common in ‘left-sided’ disease. Toxic megacolon is rare in patients with rectosigmoidal involvement, and the incidence of colon cancer is much lower in these patients than those with total colitis.

Proctitis

The manifestations of active proctitis are less severe. These are tenesmus, pruritus ani, rectal bleeding and mucous discharge. Patients are often constipated.

Toxic dilatation

This can occur in untreated severe ulcerative colitis. There is a high risk of perforation with a mortality of 50%.

Extra-intestinal complications of IBD

Around 20–30% of patients with IBD will present with extra-intestinal manifestations. They are more commonly seen in patients where IBD affects the colon. Complications affect the joints, skin, bone, eyes, liver and biliary tree and are more common in active disease. Figure 13.3 highlights some of the extra-intestinal features of IBD.

Fig. 13.3 Some of the extra-intestinal illnesses and features of malnutrition found in patients with inflammatory bowel disease

(from Misiewicz et al., 1994, with kind permission from Blackwell Scientific Publications, Oxford).

Joints and bones

Arthropathies occur in 10% of patients with IBD, are more common in women and are a well-recognised complication of IBD. Patients with pauciarticular disease, characterised by arthritis limited to five or fewer joints, often experience a flare in the arthropathy when there is an exacerbation of the IBD symptoms. When the IBD relapse is treated, the arthropathy improves. In contrast, in polyarticular arthropathy, a chronic condition which affects more than five joints, a flare of the IBD appears not to be temporally related to the activity of the arthropathy. About 5% of patients with IBD also have ankylosing spondylitis. This is thought to be immunologically mediated and not associated with IBD activity. Osteopenia, potentially leading to osteoporosis, is often seen in patients with IBD because of chronic steroid use (particularly when the cumulative dose of prednisolone exceeds 10 g) and/or malabsorption.

Skin

Both erythema nodosum and pyoderma gangrenosum are associated with IBD. Erythema nodosum appears as tender, hot, red nodules that subside over a few days to leave a brown skin discolouration. Disease flares are normally directly related to IBD activity in the 8% of patients affected.

Pyoderma gangrenosum presents as a discrete pustule that develops into an ulcer. In the 2% of patients affected, IBD activity does not appear to be directly related to the pyoderma gangrenosum, which may begin or worsen when the IBD is quiescent.

Sweet’s syndrome (an acute febrile neutrophillic dermatosis) which has some similarity to erythema nodosum may also be associated with IBD.

Eye

Ocular complications are infrequent, occurring in less than 10% of cases. Episcleritis (intense burning and itching with localised area of blood vessels) is the most common complication of IBD. Scleritis, which involves more of the eye, may impair vision. Uveitis (headache, burning red eye, blurred vision) is often associated with joint and skin manifestations of IBD. Conjunctivitis is frequently seen in IBD patients but is not specific and no true association has been demonstrated.

Hepatobiliary

Biliary complications of IBD are gallstones and sclerosing cholangitis which occurs in 5% of patients with ulcerative colitis but less frequently in those with Crohn’s disease. Conversely the prevalence of IBD (mostly ulcerativ colitis) in patients with sclerosing cholangitis is 70–80%. Sclerosing cholangitis, found predominantly in males, is a chronic cholestatic condition characterised by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. Patients present with obstructive jaundice, cholangitis and raised liver enzymes (alkaline phosphatase and γ-glutamyltranspeptidase). Endoscopic retrograde cholangiopancreatography (ERCP) is useful in diagnosing and aiding the stenting of strictures. There is an increased risk of cholangiocarcinoma, with a liver transplant the only cure. Hepatic complications of IBD include fatty liver, pericholangitis, chronic active hepatitis and cirrhosis.

Thromboembolic

Thromboembolic complications occur in around 1–2% of IBD patients. The most common cause of death in hospitalised IBD patients is pulmonary embolism (Solem et al., 2004).

Anaemia

Around one-third of patients have haemoglobin levels below 12 g/dL. The main causes are chronic intestinal bleeding with iron loss (bowel inflammation) which causes a microcytic anaemia whereas the chronic inflammatory disease can cause normocytic anaemia giving rise to mixed features anaemia. Folate, iron, vitamin B₁₂ malabsorption are also common. The side effects of commonly used drugs in IBD, for example, methotrexate and azathioprine can give rise to symptoms of anaemia.

Investigations

Radiological, pathological and clinical investigations help to confirm diagnosis, disease recurrence and response to treatment. Differential diagnoses of IBD include carcinoma, infection, drug-induced colitis, ischaemia, radiation damage, irritable bowel syndrome and diverticulitis.

Endoscopy

The key diagnostic investigation in IBD is lower gastro-intestinal tract endoscopy (sigmoidoscopy and colonoscopy), which allows direct visualisation of the large bowel and histopathological assessment from biopsies. The risk of developing colorectal cancer is 7–10% after 20 years in patients with colonic disease. Therefore, routine surveillance colonoscopy is essential in the early detection of colorectal cancer. Treatment response to biologics, for example infliximab, can be assessed via mucosal healing seen at colonoscopy.

In patients with severe symptoms, it is sometimes necessary to delay a full colonoscopy because of the increased risk of perforation. Wireless capsule endoscopy is a relatively new procedure where the small bowel can be viewed and can be useful in patients with non-stricturing Crohn’s disease.

Radiology

Radiological imaging is complementary to clinical and endoscopic assessment. It is used in the initial evaluation or diagnosis, preoperative review, to highlight the presence of complications during exacerbations and to evaluate extra-intestinal manifestations. Radiological examination still plays a key role in IBD affecting the small bowel, although endoscopy has generally replaced conventional X-ray examinations of the colon.

Computed tomography (CT scan) and magnetic resonance imagery (MRI) are the best radiological methods for locating and defining fistulae and abscesses in active Crohn’s disease.

Radiolabelled leucocyte scans that utilise autologous leucocytes labelled with ⁹⁹technetium-hexamethylenamine oxime may provide further information of disease site and severity.

Laboratory findings

Although not diagnostic, active disease is suggested in patients with raised inflammatory markers that include erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in addition to a low haemoglobin and raised platelet count. Vitamin B₁₂ may be low in patients with chronic terminal ileal disease. Low red cell folate and serum albumin, magnesium, calcium, zinc and essential fatty acids also indicate chronic inflammation and malabsorption. Anti-Saccharomyces cerevisiae antibodies (ASCA) are more likely to be present in Crohn’s disease. Serology can be used to exclude infection as a cause of diarrhoea.

Malabsorption, indicated by low serum trace elements, for example, magnesium and zinc, is not seen in ulcerative colitis. Low albumin may indicate relapse in active disease. Patients with sclerosing cholangitis often present with altered liver function tests.

Stool tests

Red and white blood cells can be seen on microscopic examination of fresh stools. Microscopic identification of infective cells such as amoeba may also be visualised. C. difficile toxin can be assessed through culture and toxin assay. Stool tests do not diagnose IBD but contribute to excluding alternative diagnoses.

Clinical assessment tools

The Crohn’s Disease Activity Index (CDAI) or the Harvey–Bradshaw Index (HBI) is used in most clinical trials to define remission in Crohn’s disease. However, in clinical practice the CDAI is rarely used as it needs to be measured prospectively and is complex. The HBI is a simple measure of stool frequency, pain and other clinical features that is increasingly used to document selection for and response to biologic therapy. A CDAI of <150 or an HBI ≤3 suggests patient is in remission (NICE, 2010).

The Truelove and Witts criteria is a useful tool in defining the severity of ulcerative colitis (see Table 13.3). A severe attack is defined as more than six bloody stools a day plus one or more of the following: pulse > 90 beats/min, temperature >37.8 °C, haemoglobin <10.5 g/dL or ESR >30 mm/h. In this case, the patient should be admitted to hospital.

Table 13.3 Truelove and Witts criteria for assessing severity of ulcerative colitis (Travis et al., 2008)

Remission in ulcerative colitis is defined as complete resolution of symptoms with a normal bowel pattern (< 3 stools/day), no urgency and no visible bleeding. Mucosal healing is confirmed by endoscopy. Steroid-free remission is the goal of therapy.

Treatment of inflammatory bowel disease

At present there is no cure for IBD since the exact cause of the condition is unknown. A wide range of drugs and nutritional supplements are available to maintain the patient in long periods of remission in both Crohn’s disease and ulcerative colitis. However, surgical intervention will eventually become necessary when the patient relapses and fails to respond to drug therapy. Since the majority of people with IBD are diagnosed under the age of 30, effective treatment and avoidance of relapses is of paramount importance in this chronic long-term condition.

Nutritional therapy

Nutritional therapy can be considered as an adjunctive or primary treatment. Although a potential problem for all patients with IBD, patients with Crohn’s disease are at particular risk of becoming malnourished and developing a variety of nutritional deficiencies (Fig. 13.3). It is, therefore, important for patients to receive optimal nutrition and dietary manipulation as needed. Low-fibre diets help to reduce clinical symptoms of intestinal obstruction in Crohn’s disease (Fernandes-Banares et al., 1999). Functional and structural damage to the small bowel can cause malabsorption problems and occasionally patients may require a low-lactose diet. Patients with poor oral intake and loss of appetite often respond to supplemental enteral feeds. Enteral nutrition in the form of an elemental or polymeric diet can be used as primary therapy and is widely employed in paediatrics (Heuschkel and Walker-Smith, 1999).

Patients who have extensive small bowel resection may experience many nutritional deficiencies because of malabsorption. Iron depletion, hypoproteinaemia, deficiencies in water- and fat-soluble vitamins, trace elements and electrolytes may all occur and must be corrected using a suitable replacement regimen.

Where appropriate, and when enteral nutrition is not indicated or adequate, a total parenteral nutrition (TPN) regimen may be prescribed. Some patients receive concurrent enteral and parenteral feeding.

Drug treatment

The main goals of drug treatment are to treat acute attacks promptly and effectively, induce and maintain remission, limit drug toxicity, modify the pattern of disease, avoid and/or manage complications and select patients who will benefit from surgery. Morbidity and mortality can also be reduced by the prompt use of effective and appropriate drug therapy. The choice of drug and route of administration depends on the site, extent and severity of the disease together with the individual’s treatment history. Drug therapy is often required for many years and patient preference, acceptability and possible side effects not only affect choice but will impact on medication adherence. There is a need for therapeutic strategy and consistency in the management of patients with IBD.

Corticosteroids, aminosalicylates and immunosuppressive agents (immunomodulators) such as azathioprine are the mainstays of treatment. Immunomodulators are not licensed for use in IBD but are routinely used.

Modern advances in treatment, such as the use of humanised monoclonal antibody preparations and other biologic agents which modify the affected biochemical inflammatory pathways, now have a significant role in treatment of the disease. These are likely to be the main area of future development.

Other drugs such as antibiotics, for example, metronidazole, are helpful in some cases, while colestyramine, thalidomide, sodium cromoglicate, bismuth and arsenical salts, nicotine, lidocaine, sucralfate, new steroid entities, cytoprotective agents, aloe vera, probiotics and fish oils are rarely used. However, for some patients they provide alternative or supplemental therapy.

The choice of drug treatment is dependent on whether it is prescribed to induce remission or as maintenance therapy. The majority of patients are managed successfully as hospital outpatients or by their primary care doctor. Only severe extensive or fulminant disease requires hospitalisation and the use of parenteral therapy and/or surgical intervention. Oral medication can be given to most patients for maintenance of moderate disease.

The route of administration is a particularly important factor in IBD. In contrast to most other conditions, minimal systemic absorption and maximal intestinal wall drug levels are required with oral therapy. Several delivery strategies have been used to achieve this including the chemical modification of drug molecules, delayed and controlled-release formulations and the use of bioadhesive particles.

Disease confined to the anus, rectum or left side of the colon is more appropriately treated with rectally administered topical preparations where the drug is applied directly to the site of inflammation (Table 13.4).

Table 13.4 Comparison of commercially available preparations for rectal administration in inflammatory bowel disease

Generic name (proprietary name)	Formulation	Site of release
Sulfasalazine (Salazopyrin®)	Suppositories Retention enema	Rectum Transverse, descending colon and rectum
Mesalazine (Pentasa®, Salofalk®)	Retention enema	Transverse, descending colon and rectum
Mesalazine (Asacol®, Salofalk®)	Foam enema	Rectum and rectosigmoid colon
Mesalazine (Asacol©®, Pentasa®, Salofalk®)	Suppositories	Rectum
Prednisolone sodium phosphate (Predsol®)	Retention enema Suppositories	Transverse, descending colon and rectum Rectum
Prednisolone sodium metasulphobenzoate (Predenema®)	Retention enema	Transverse and descending colon
Prednisolone sodium metasulphobenzoate (Predfoam®)	Foam enema	Rectum and rectosigmoid colon
Prednisolone sodium phosphate (Predsol®)	Retention enema	Transverse and descending colon
Hydrocortisone acetate (Colifoam®)	Foam enema	Rectum and rectosigmoid colon
Budesonide (Entocort©®)	Retention enema	Rectum and rectosigmoid colon

These topical preparations have reduced systemic absorption and fewer side effects. Choice of formulation depends on the site of inflammation and also consideration of presentation, acceptability, patient preference and cost. Adherence to topical therapy is generally poor and good patient education is required for effective benefit.

Proctitis is best treated with suppositories. Where inflammation affects the rectum and sigmoid colon (up to 15–20 cm), foam enemas are preferred. In more extensive disease extending to the splenic flexure (30–60 cm), liquid enemas are the agents of choice. However, patients often require a combination of different rectal preparations because, for example, over 90% of liquid enemas bypass the rectum and thereby exert no therapeutic benefit at that site. As a consequence, a suppository may also be required to treat rectal inflammation. The propellant action of foam applicators also results in some preparations by-passing the rectal mucosa. Enemas or suppositories should be administered just before bedtime in a supine position as this allows a much longer retention time. Liquid enemas can be warmed and should be inserted while lying in the left lateral position.

An algorithm for drug treatment in IBD is shown in Fig. 13.4.

Fig. 13.4 Drug treatment algorithm for inflammatory bowel disease.

Corticosteroids

The glucocorticoid properties of hydrocortisone and prednisolone are the mainstay of treatment in active ulcerative colitis and Crohn’s disease. Prednisolone administered orally or rectally is the steroid of choice, although in emergency situations hydrocortisone or methylprednisolone is used when the parenteral route is required. Corticosteroids have direct anti-inflammatory and immunosuppressive actions which rapidly control symptoms. They can be used either alone or in combination, with a suitable mesalazine (5-aminosalicylic acid, 5-ASA) formulation or immunosuppressant, to induce remission.

Oral corticosteroids should not be used for maintenance treatment because of serious long-term side effects, and abrupt withdrawal should be avoided. Patients should be maintained on aminosalicylates or immunosuppressants, as appropriate, or referred for surgery.

Formulations

Oral prednisolone will control mild and moderate IBD and 70% of patients improve after 2–4 weeks of 40 mg/day. This is gradually reduced over the next 4–6 weeks to prevent acute adrenal insufficiency and early relapse. An example of a reducing oral prednisolone regime is detailed in Box 13.1.

Box 13.1 An example of a reducing regimen for oral steroids

40 mg/day for 1 week

30 mg/day for 1 week

20 mg/day for 4 weeks

15 mg/day for 1 week

10 mg/day for 1 week

5 mg/day for 1 week then stop

Local regimen used at the Oxford Radcliffe Hospitals NHS Trust

Oral corticosteroids should be taken in the morning to mimic the diurnal rhythm of the body’s cortisol secretion and prevent sleep disturbance. Uncoated steroid tablets are suitable for most patients while enteric-coated preparations do not offer any proven advantage and should be avoided in patients with short bowel or strictures because of poor absorption and bolus release at stricture sites.

Severe extensive or fulminant disease requires hospitalisation. Patients are given either hydrocortisone sodium succinate, administered intramuscularly or intravenously at doses of 100 mg three or four times a day, or methylprednisolone 15–20 mg three or four times a day, for 5 days. No additional benefit is gained after 7–10 days. Additional therapy used in severe disease may include intravenous fluid and electrolyte replacement, blood transfusion, topical therapy for rectal and/or colonic involvement, prophylactic heparin (IBD is associated with increased coagulopathy), antibiotics and nutritional support, including possible parenteral nutrition. Oral prednisolone therapy is normally introduced as soon as possible and withdrawn over the following 6–8 weeks. Too rapid reduction is associated with relapse.

Prednisolone at doses higher than 40 mg/day increases the incidence of adverse effects and has little therapeutic advantage. Short-term side effects include moon face, acne, sleep and mood disturbance, dyspepsia, hypokalamia, hypernatraemia and glucose intolerance. Prolonged use can cause cataracts, osteoporosis and increased risk of infection. Doses below 20 mg are not generally effective in active disease (St Clair Jones, 2006). A typical treatment algorithm for the management of an acute attack of IBD is presented in Fig. 13.5.

Fig. 13.5 Treatment algorithm for a severe attack of inflammatory bowel disease.

Rectal corticosteroid preparations are available as suppositories, foam and liquid enemas. In the acute setting, some hospitals make up their own liquid enemas using 100 mg hydrocortisone sodium succinate injection in 100 mL sodium chloride 0.9%. This unlicensed preparation is administered via a burette and soft catheter over 30 min. It is often well tolerated and gives better therapeutic results compared with commercial preparations.

The distribution and absorption characteristics of rectally administered steroids vary greatly. Hydrocortisone (e.g. Colifoam®) is readily absorbed from the rectal mucosa with high peak concentrations compared to prednisolone sodium metasulphobenzoate (e.g. Predenema®) and, to a lesser extent, Predfoam®. Topical preparations may play a role either alone or in combination with oral steroids.

Other steroids

Budesonide, available orally and rectally, is currently licensed for Crohn’s disease affecting the ileum and descending colon. It is less effective than conventional corticosteroids in inducing remission in active Crohn’s disease, but has fewer side effects than prednisolone because of its rapid and extensive first-pass metabolism. However, the absorbed drug has a higher affinity for glucocorticoid receptors 50–100 times that of prednisolone and so long-term treatment is not advocated. Budesonide has shown to be of benefit in microscopic colitis (Travis et al., 2005). Budesonide enemas are effective in inducing remission in distal ulcerative colitis and are comparable to conventional steroids but probably less effective than mesalazine enemas (Marshall and Irvine, 1997).

Aminosalicylates

The aminosalicylates currently licensed for the treatment of IBD include sulphasalazine, mesalazine, olsalazine and balsalazide. Their mode of action is unclear but a local effect on epithelial cells by a variety of mechanisms to moderate the release of lipid mediators, cytokines and reactive oxygen species is proposed. Different formulations deliver variable amounts of the active component, mesalazine (5-ASA), to the gut lumen where it exerts a predominantly local action independent of blood levels. The dissolution profile and site of ulceration determine the effectiveness of different preparations.

Diagnosis, disease location, activity, side effect profile, efficacy and cost all affect the choice of aminosalicylate. Available as oral or rectal preparations, aminosalicylates can be used in combination with steroids to induce and maintain remission, in mild to moderate ulcerative colitis. Sulfasalazine is considerably cheaper but the newer aminosalicylates are generally used (Sutherland and MacDonald, 2006). Aminosalicylate maintenance therapy with doses of 1.2 g and above appears to reduce the risk of colorectal cancer by up to 75% (Van Staa et al., 2005).

The use of aminosalicylates in Crohn’s disease is less well established (Dignass et al., 2010). There is evidence of patient benefit with high-dose mesalazine (over 2 g/day) in reducing relapse post-small bowel resection.

Sulfasalazine consists of sulfapyridine diazotised to mesalazine. It is broken down by bacterial azoreductase in the colon to mesalazine and sulfapyridine. Sulfapyridine is absorbed in the colon, metabolised by hepatic acetylation or hydroxylation followed by glucuronidation and excreted in urine. Mesalazine is partly absorbed, metabolised by the liver and excreted via the kidneys as n-acetyl 5-ASA. However, the majority is acetylated as it passes through the intestinal mucosa. Sulfasalazine itself is poorly absorbed and that which is absorbed is recycled back into the gut, via the bile, either unchanged or as the n-acetyl metabolite.

Elimination of sulfapyridine depends on the patient’s acetylator phenotype. Those who inherit the ‘slow’ acetylator phenotype experience more side effects. The dissolution profile of the drug and the site of ulceration determine effectiveness (Fig. 13.6). The optimal dose of sulfasalazine to achieve and maintain remission is usually in the range of 2–4 g per day in 2–4 divided doses. Acute attacks require 4–8 g per day in divided doses until remission occurs, but at these doses associated side effects are often observed.

Fig. 13.6 Physiological and formulation problems encountered with mesalazine and delivery systems.

About 30% of patients taking sulfasalazine experience adverse effects which are either dose related and dependent on acetylate phenotype or idiosyncratic and not dose related. Dose-related side effects include nausea, vomiting, abdominal pain, diarrhoea, headache, metallic taste, haemolytic anaemia, reticulocytosis and methaemoglobinaemia. Side effects which are not dose related include rashes, aplastic anaemia, agranulocytosis, pancreatitis, hepatic and pulmonary dysfunction, renal impairment, peripheral neuropathy and oligospermia. In 3% of patients, acute intolerance may be seen. This often resembles colitis and includes bloody diarrhoea. Adverse effects usually occur during the first 2 weeks of therapy, the majority being related to plasma sulfapyridine levels. Sulfasalazine metabolites are responsible for the yellow colouration of bodily fluids and staining of soft contact lenses.

Mesalazine is tolerated by 80% of patients who are intolerant of sulphasalazine. Many of the sulphonamide-related adverse effects of sulfasalazine are avoided by using one of the newer aminosalicylate formulations. However, mesalazine alone can still cause side effects, including blood disorders, pancreatitis, renal dysfunction and lupoid phenomenon. Patients should be counselled on how to recognise and report blood dyscrasias and if they occur, treatment should be stopped.

Formulations

Mesalazine is unstable in acid medium and rapidly absorbed from the gastro-intestinal tract. To increase stability and/or alter the site of release, 5-ASA is modified by different delivery systems (see Fig. 13.6). Mesalazine dose is more important than the delivery system and the lowest systemic absorption preparation should be used. The different delivery systems developed are:

• acrylic resin-coated mesalazine tablet that releases drug pH-dependently;

• ethyl cellulose-coated mesalazine granules that release drug in a time controlled manner;

• diazotisation of mesalazine to itself or to an inert carrier.

All mesalazine preparations are licensed for UC, however only Mesren® MR and Asacol® MR are licensed for Crohn’s disease. There are six modified release oral preparations currently licensed in the UK. Asacol® MR, Ipacol®, Mesren® MR and Mezavant® XL contain mesalazine coated with an acrylic resin, Eudragit-S. Mesren® MR and Ipacol® are generic versions of Asacol® MR. Mezavant® XL, recently licensed, is a modified release mesalazine formulation with a patented multi-matrix release system allowing less frequent dosing which may be beneficial in patients experiencing difficulty with a high tablet burden. Salofalk® contains mesalazine coated with Eudragit-L. All these preparations provide pH-dependant release of mesalazine at the mid to terminal ileum and the colon, at pH 7 (Asacol® MR, Mesren® MR, Mezavant® XL) and pH 6 (Ipacol®, Salofalk®). As dissolution occurs at a lower pH with Ipacol® and Salofalk®, this results in a lower ileocolonic mucosal concentration of mesalazine compared with the other pH-dependant release products. There is little clinical difference between the available pH-dependant products Asacol® MR, Mesren® MR and Mezavant® XL. However, cost may contribute to initiating new patients with the cheaper generic. Pentasa® tablets and granules comprise ethyl cellulose-coated granules of mesalazine which are released in the stomach. Mesalazine is leached slowly and continuously from the granules throughout the gastro-intestinal tract at all physiological pH.

It is very important to maintain patients on the same brand of mesalazine as some may relapse because of the different release profiles of the active drug. Therefore, mesalazine should always be prescribed by brand.

Evidence suggests that there is no difference in splitting the dose of mesalazine products as licensed, compared to taking the total dose once daily.

Dipentum® 250 mg capsules and 500 mg tablets contain olsalazine sodium, a dimer of mesalazine. Like sulfasalazine, it remains intact until it reaches the colon where it undergoes bacterial cleavage, releasing two molecules of mesalazine. Olsalazine-induced diarrhoea may help patients with distal disease and proximal constipation. Colazide® 750 mg capsules contain balsalazide sodium, a pro-drug of mesalazine, which relies on bacterial cleavage in the colon, releasing mesalazine from 4-aminobenzoyl β-alanine, the inert carrier molecule.

Table 13.5 compares the oral aminosalicylate preparations currently available.

Table 13.5 Comparison of available oral aminosalicylate preparations for patients with IBD

Mesalazine enemas (1 g in 100 mL), foam enemas (1 g per application) or suppositories (250 mg, 500 mg and 1 g) are effective alternatives for treating distal ulcerative colitis and proctitis. The optimum rectal dose is 1 g. Rectal administrations of 5-ASA formulations are significantly better than rectal corticosteroids in inducing remission in ulcerative colitis but steroids are considerably cheaper (Travis et al., 2008). In severe ulcerative colitis, oral and topical formulations should be combined to give prompt symptom relief. Topical and oral 5-ASA is better than either alone (Marteau et al., 2005).

Immunosuppressants

Azathioprine, 6-mercaptopurine, methotrexate, ciclosporin and mycophenolate are immunosuppressants used in patients unresponsive to steroids and aminosalicylates or who relapse when steroids are withdrawn. They are used to induce and maintain remission. All are unlicensed for use in IBD but are routinely used. Treatment may be for up to 5 years because earlier withdrawal increases the rate of relapse. They can take several weeks to work and require regular monitoring.

Thioguanines (azathioprine, mercaptopurine)

Azathioprine is metabolised to 6-mercaptopurine by the liver. Both azathioprine and 6-mercaptopurine have steroid-sparing properties. Although the action in IBD is unclear, their active metabolites inhibit purine ribonucleotide synthesis which may in turn inhibit lymphocyte function, primarily T-cells. Mercaptopurine is further metabolised to 6-thioguanine nucleotides.

The main indications for thioguanines are when patients

• require two or more steroid courses in 1 year;

• have chronic active disease unresponsive to steroids or 5-ASAs;

• relapse when steroids are withdrawn (within 3 months) or when the dose is reduced below 15 mg;

• require post-operative prophylaxis of complex Crohn’s disease (fistulising or extensive disease).

Oral maintenance doses for azathioprine are usually 2–2.5 mg/kg/day and for mercaptopurine, 1–1.5 mg/kg/day. Doses are adjusted to patient response, tolerance, white cell and platelet counts. Patients are usually prescribed a reducing dose of corticosteroid in addition because mercaptopurine and azathioprine can take several weeks to show a therapeutic benefit.

Seventy percent of patients will tolerate azathioprine. Of the remaining 30%, most will tolerate mercaptopurine. The most common side effects occur within 2–3 weeks of starting treatment and rapidly stop on withdrawal. These include flu-like symptoms (myalgia, headache), nausea and diarrhoea. Nausea is reduced by taking the medicine with food. Although rare (<3%), leucopenia can develop suddenly and unpredictably. Hepatotoxicity and pancreatitis have also been reported in less than 5% of patients. Thioguanine has been used but is associated with a greater risk of hepatotoxicity. There is no evidence that the incidence of lymphoma increases with the use of these agents (St Clair Jones, 2006).

The value of assessing thiopurine methyl transferase (TPMT) activity and genotype, especially prior to initiating treatment, is debatable. Patients who develop leucopenia and are TPMT deficient have a greater risk of myelotoxicity. However, this may not apply in IBD. Some gastroenterologists measure TPMT if a patient has relapsed on doses greater than 2 mg/kg/day to identify fast metabolisers who may respond to higher doses. Measuring TPMT activity to identify the 0.3% of non-metabolisers who are at high risk of rapid leucopenia has also been recommended (Carter et al., 2004).

One of the most significant drug interactions is with allopurinol which inhibits the principal pathway for detoxification of azathioprine and mercaptopurine. Patients receiving these drugs concomitantly should have their dose of azathioprine reduced to approximately one-third to a quarter of the usual dose.

Methotrexate

A low-dose regimen of methotrexate is effective in inducing and maintaining remission in patients with chronically active Crohn’s disease. Patients receive once-weekly doses of methotrexate ranging from 15 to 25 mg on the same day each week. These can be given orally or by subcutaneous or intramuscular injection. Oral medication is more practical, although parenteral administration may be more effective and better tolerated. Methotrexate is reserved for patients intolerant or unresponsive to thioguanines.

Methotrexate metabolites inhibit dihydrofolate reductase, although this cytotoxic action does not explain the drug’s anti-inflammatory effect. Inhibition of cytokine and eicosanoid synthesis and modification of adenosine levels probably contribute.

Adverse effects associated with methotrexate are essentially gastro-intestinal (nausea, vomiting, diarrhoea and stomatitis). These may also be reduced by prescribing weekly doses of folic acid 5 mg. Folic acid should not be taken on the same day as the methotrexate. Monitoring is undertaken because of the serious side effects of hepatotoxicity, bone marrow suppression and pneumonitis.

Methotrexate is teratogenic and all male and female patients should be counselled about using contraception while taking the medication and also for 3 months after therapy is withdrawn. Guidance to improve the safety of methotrexate use and minimise the potential risk of overdose has been issued (NPSA, 2006). Measures include the issue of patient hand-held monitoring cards detailing dose and blood test results, comprehensive written and verbal medicines information, dispensing one strength of tablet (2.5 mg) and ensuring inpatient medication charts clearly state once-weekly dosing and the number and strength of tablets routinely used. An aide memoire commonly recommended to patients to remember dose frequency is to take methotrexate on Mondays and folic acid on Fridays.

Ciclosporin

Ciclosporin is a calcineurin inhibitor that acts at an early stage on precursors of helper T-cells by interfering with the release of interleukin-2. This inhibits the formation of the cytotoxic lymphocytes which cause tissue damage. Both controlled and uncontrolled studies suggest that ciclosporin is effective rescue therapy for severe ulcerative colitis failing to respond to intravenous steroids (Campbell et al., 2005). Its use in Crohn’s disease is unproven.

The effectiveness of ciclosporin at doses of 2–5 mg/kg/day in treating IBD has been studied in patients refractory to conventional drug therapy (Van Assche et al., 2003). A dose of 2 mg/kg has been shown to be as effective as 4 mg/kg. Patient response to this treatment has varied, with adverse effects causing withdrawal of treatment in some cases. However, some patients have stopped concurrent steroid therapy and have remained in remission for some time.

When patients with severe colitis fail to show a response to treatment with parenteral steroids, then ciclosporin at an intravenous dose of 2 mg/kg/day should be considered. If patients respond to parenteral ciclosporin they can subsequently be maintained on an oral dose for 3–6 months. If the patient has a low plasma magnesium (< 0.5 mmol/L) or low cholesterol (<3 mmol/L), they are at an increased risk of ciclosporin-induced seizures when given intravenously. In these circumstances, treatment with an oral ciclosporin preparation, for example, Neoral®, at a dose of 5 mg/kg/day is preferred. Ciclosporin therapy is used for many patients, but normally as a bridge to colectomy or starting maintenance treatment with azathioprine or mercaptopurine. Infliximab is an alternative ‘rescue therapy’ for acute severe colitis (NICE, 2008a) if ciclosporin is contraindicated or clinically inappropriate. A multi-centre randomised controlled trial (CONSTRUCT) is underway comparing the clinical and cost-effectiveness of infliximab and ciclosporin in the treatment of steroid resistant acute severe colitis.

Forty percent of patients who receive ciclosporin develop minor side effects such as tremor, paraesthesia, headache, gum hyperplasia, burning sensations of the hands and feet and hirsutism. Major complications include nephrotoxicity, neurotoxicity, hepatotoxicity and hypertension. There has been 1–2% mortality reported in some case series. Ciclosporin blood levels should be monitored and maintained within the range of 100–200 ng/mL. Grapefruit juice, macrolide antibiotics (mainly erythromycin and clarithromycin), ketoconazole, fluconazole, itraconazole, diltiazem, verapamil, oral contraceptives and protease inhibitors are just some of the drugs that increase ciclosporin levels and toxicity.

In severe proctitis, refractory to standard treatments, ciclosporin enemas have been used with some success at a dose of 250 mg at night for 1 month. No commercial preparation is available.

Tacrolimus

Tacrolimus is an alternative calcineurin inhibitor to ciclosporin that has shown some benefit in inducing remission in ulcerative colitis. It is of limited value in Crohn’s disease.

Mycophenolate

It has been suggested that mycophenolate mofetil is effective and well tolerated in IBD. Although used if other treatments have failed, there is little evidence regarding its use in clinical practice.

Monitoring of immunosuppressants

Major concerns about the use of immunosuppressive agents are related to bone marrow suppression and hepatotoxicity. Therefore, patients should be monitored regularly and have routine blood counts and liver function tests including plasma bilirubin and alkaline phosphatase. These should be undertaken every 2–3 weeks for the first 2–3 months and then bimonthly. Although often advised, there is no evidence that more frequent monitoring is more effective. Patients should be taught to recognise the signs of bone marrow suppression and educated about the need for earlier blood tests and the increased risk of infection due to immunosuppression. It is recommended that all patients initiated or maintained on immunosuppressants are provided with a record card detailing current dose and blood test results. This should be shown to their doctor and pharmacist at each visit. There should be good shared care policies in place between primary and secondary care in the management of patients on immunomodulators.

The incidence of lymphomas in patients receiving immunosuppressants when compared with other treatments is of concern. Patients should be advised to avoid live vaccines while taking immunosuppressants, including corticosteroids. Guidance on appropriate action following abnormal blood results is provided in Box 13.2.

Box 13.2 Guidance on dealing with abnormal blood results for patients on immunosuppressant therapy

Baseline U&Es, LFTs and FBC should be carried out prior to initiation of therapy. These should be repeated at 2 weeks, 4 weeks then every 2–3 months.

Methotrexate should be stopped and the relevant expert advice obtained if any of the following occur:

WBC	<4 × 10⁹ L⁻¹
Neutrophils	<2 × 10⁹ L⁻¹
Platelets	<150 × 10⁹ L⁻¹
AST/ALT	>3 × normal range

• Unexplained respiratory symptoms, for example, dyspnea, dry cough, especially if accompanied by fever and sweats

• Renal impairment

• Mouth or throat ulceration/rash/unexplained bleeding/fever/alopecia/recurrent sore throats, infections, fever or chills/nausea/vomiting/diarrhoea

Azathioprine or mercaptopurine should be stopped and the relevant expert advice obtained if any of the following occur:

WBC	<4 × 10⁹ L⁻¹
Neutrophils	<2 × 10⁹ L⁻¹
Platelets	<150 × 10⁹ L⁻¹
AST/ALT	>3 × normal range

• Significant reduction in renal function

• Mouth or throat ulceration/rash/unexplained bleeding/fever/upper abdominal or back pain/alopecia/recurrent sore throats, infections, fever or chills/nausea/vomiting/diarrhoea

• Nausea may be relieved by taking the dose with/after food or in divided doses

Ciclosporin should be stopped and the relevant expert advice obtained if any of the following occur:

• High blood levels (will require dose adjustment)

• Significant reduction in renal function

• Uncontrolled hypertension

Drug blood levels should be done at similar intervals to FBC. A 12-h trough level should be taken, that is, before a dose. Target level within the range of 100–200 ng/mL. It takes 2–3 days to reach steady state after dose change

U&Es, urea and electrolytes; LFTs, liver function tests; FBC, full blood count; WBC, white blood cells; ALT, alanine transaminase; AST, aspartate transaminase.

Biologic agents

Since their introduction over a decade ago, biological therapy targeting tumour necrosis factor alpha (TNF-α) has revolutionised the management of IBD. These agents are efficacious in treating signs and symptoms of Crohn’s disease and ulcerative colitis, reducing corticosteroid requirements and draining fistulae, achieving mucosal healing and reducing the need for major abdominal surgery or hospitilisation. They are indicated for patients who have failed or are intolerant or who have contraindications to conventional therapy including corticosteroids and immunomodulators. Not all patients will require biological therapy which is expensive and is a significant cost to the Health Service. Some patients may derive greater benefit from early use of these agents such as patients who are steroid dependant or who have complex fistulising disease.

Biologic agents that are licensed for use in IBD are infliximab (Remicade®) and adalimumab (Humira®). At present there are no direct comparative studies of the two agents. Certolizumab pegol (Cimzia®) has also shown benefit and is an alternative in some cases; however, it is currently not licensed for use in IBD. All these monoclonal antibodies inhibit the functional activity of the pro-inflammatory cytokine TNF-α which damages cells lining the gut, causing pain, cramping and diarrhoea. Colonic biopsies post-treatment with these agents show a substantial reduction in TNF-α and a reduction in the commonly elevated plasma inflammatory marker C-reactive protein. Table 13.6 summarises the anti-TNF agents used. All appear to have similar efficacy, although there are more data on infliximab than adalimumab or certolizumab. Natalizumab, another monoclonal antibody, has also shown promise in treating active Crohn’s disease. It works by inhibiting the migration of leucocytes into the CNS thereby reducing inflammation. It is unlicensed in IBD.

Table 13.6 Summary of anti-TNF agents used in IBD

Agent	Licensed/(unlicensed) indication	Dose
Infliximab	*Crohn’s disease*
	Induction of remission in severe active disease	5 mg/kg intravenously at weeks 0 and 2
	Maintenance treatment	5 mg/kg intravenously 6 weeks after initial dose then every 8 weeks or further dose of 5 mg/kg if signs and symptoms recur
	Fistulising	5 mg/kg intravenously at weeks 0, 2 and 6 (consult product literature)
Infliximab	*Ulcerative colitis*
	Induction of remission in moderate to severe active disease	5 mg/kg intravenously at weeks 0, 2 and 6
	Maintenance of remission in severe active disease	5 mg/kg intravenously every 8 weeks; discontinue if no response 14 weeks after initial dose
	Extra-intestinal manifestations (unlicensed)	5 mg/kg intravenously
Adalimumab	*Crohn’s disease*
	Induction of remission in severe active disease	80 mg subcutaneously at week 0, 40 mg at week 2 and or accelerated regime of 160 mg at week 0, 80 mg at week 2
	Maintenance treatment	40 mg subcutaneously on alternate weeks, increasing to weekly if loss of response
Certolizumab pegol	*Crohn’s disease (unlicensed)*
	Used in moderate to severe disease when patients who have lost response to or are intolerant of infliximab or adalimumab
	Induction	400 mg subcutaneously at weeks 0, 2 and 4
	Maintenance treatment	400 mg subcutaneously every 4 weeks

National guidance has been issued on the use of infliximab in ulcerative colitis (NICE, 2008a,b) and infliximab and adalimumab in the treatment of Crohn’s disease (NICE, 2010). The latter guidance indicates treatment should be started with the less expensive drug, taking into account drug administration costs, required dose and product price per dose. This may need to be varied for individual patients due to differences in the method of administration and treatment schedules.

A combination of infliximab with azathioprine has been shown to be superior to monotherapy in inducing remission and mucosal healing in Crohn’s patients naïve to both agents. The rate of infliximab-related infusion reactions was also less with combination treatment and there was no significant difference seen with the rate of serious infection (Colombel et al., 2010). For scheduled treatment, the concomitant immunomodulator should be reviewed and stopped after 6–12 months. It remains unclear whether the same applies to other anti-TNF agents. In practice, the same principles apply with other immunomodulators such as methotrextate. Natalizumab should not be combined with an immunosuppressant or prolonged steroids as this may increase the risks of progressive multifocal leucoencephalopathy (D’Haens et al., 2010).

There is currently no specific guidance on how long anti-TNF agents should be continued for. Preliminary evidence suggests that many patients in clinical remission for greater than 1 year, with a normal C-reactive protein and complete mucosal healing on endoscopy will remain in remission during the following year after stopping treatment. Whether remission is then sustained or whether the behaviour of disease is altered in the long term is currently unknown (D’Haens et al., 2010). NICE guidance on the treatment of Crohn’s disease recommends that infliximab or adalimumab treatment should be given until treatment failure (including the need for surgery) or until 12 months after initiation of treatment, whichever is shorter. Patients should then have their disease reassessed and continue treatment if there is clear evidence of ongoing active disease and treatment is still clinically appropriate. Treatment can be restarted if patients subsequently relapse.

Loss of response or intolerance to anti-TNF agents can be managed by optimising dosing regimes, switching to agents or switching class, for example, to natalizumab. Reasons for a loss of response should be assessed.

Monoclonal antibodies are contraindicated in patients with tuberculosis (TB) and, therefore, all patients should have a chest X-ray prior to administration to exclude latent TB. Infliximab increases the risk of TB five-fold. Other contraindications include moderate to severe cardiac failure, history of malignancy (excluding non-melanoma skin cancer), sepsis (including pelvic or perianal), optic neuritis. Intestinal stricturing is a relative contraindication (obstruction may be exacerbated through rapid healing at the stricture site) along with chronic hepatitis B/C carriers, primary failure or absence of inflammatory activity (normal C-reactive protein). Patients who receive live vaccines should not receive biological therapy for 3 months. Patients on biologics should be vaccinated against tetanus, pneumococcus species, influenza and hepatitis B. Young females should also be vaccinated for the human papilloma virus.

Anti-TNF agents should only be prescribed by a gastroenterologist with experience of IBD, and in the case of infliximab, administered in a setting where there are adequate resuscitation facilities available and patients are closely monitored. Patients self-administering adalimumab at home should be counselled on how to recognise signs of infection, for example, fever, productive cough, toothache, stinging on passing urine or if neurological symptoms develop.

Infliximab

Infliximab is a chimeric human murine monoclonal antibody, licensed for treating severe active Crohn’s disease (with or without fistulae) which is refractory or intolerant to corticosteroids or conventional immunosuppressants alone or if surgery is inappropriate. Treatment may be repeated if the condition responded to the initial course but subsequently relapsed. Infliximab is also licensed for moderate to severe active ulcerative colitis (acute exacerbation) requiring hospitilisation and/or possible surgical intervention and if unresponsive to conventional treatments. Infliximab may half the need for colectomy in steroid refractory patients with acute ulcerative colitis. It remains to be determined whether infliximab is superior to ciclosporin (D’Haens et al., 2010).

In severe active Crohn’s disease, infliximab is administered by intravenous infusion, at a dose of 5 mg/kg over a 2-h period, repeated after 2 weeks. If a clinical response is seen, then a maintenance dose of 5 mg/kg every 8 weeks should be given. Alternatively, a dose could be given when signs and symptoms recur. Fixed interval dosing may be superior to intermittent dosing because of the reduced risk of immunogenicity (NICE, 2010).

In active fistulising Crohn’s disease where disease has not responded to conventional therapy (including antibiotics, drainage and immunosuppressive therapy) or who are intolerant or have contraindications to conventional therapy, an initial dose of 5 mg/kg is given, repeated at 2 and 6 weeks after the first infusion is given. If no response is seen after three doses, no further treatment should be given (NICE, 2010).

Trials in inflammatory Crohn’s disease have shown an 81% response rate at 4 weeks. After 12 weeks, 48% of patients still had a response. In fistulising disease, 68% of patients experienced a 50% reduction in the number of draining fistulas at two or more consecutive visits. If a loss of response is seen the dose can be increased to 10 mg/kg (unlicensed) or the dosing interval shortened. An alternative is to switch treatment to adalimumab.

In treatment-refractory, moderate to severe acute exacerbation of ulcerative colitis, the licensed dose regimen is 5 mg/kg at weeks 0, 2 and 6. The optimal maintenance strategy after induction therapy is currently unknown. Treatment should be discontinued if no response is seen after 14 weeks. In azathioprine naïve patients responding to infliximab induction, azathioprine is an option instead of infliximab for maintenance (Travis et al., 2008). Although unlicensed, infliximab has shown to be of benefit in extra-intestinal manifestations such as pyoderma gangrenosum and peripheral and axial naturopathies

All doses should be preceded with intravenous corticosteroid (hydrocortisone 200 mg) unless the patient has been taking an immunosuppressant for more than 3 months.

In some patients, infliximab has been associated with either infusion (during or shortly after infusion) or delayed hypersensitivity reactions. It may also affect the normal body immune responses in a significant number of patients. Other side effects include headache, dizziness, nausea, rash, raised liver function tests, abdominal pain, fatigue, etc.

Adalimumab

Adalimumab is a fully humanised anti-TNF monoclonal antibody which is licensed for the treatment of severe active Crohn’s disease in patients who are refractory or intolerant to corticosteroids and conventional immunomodulators. It may also be used in those patients who have primary or secondary non-response to infliximab or developed a hypersensitivity reaction. Unlike infliximab it is not licensed for acute ulcerative colitis.

As adalimumab is fully humanised it is less immunogenic than infliximab. It also has the advantage of being given as a subcutaneous injection which enables patients to self-administer at home, therefore reducing nursing time and hospital bed occupancy. This also lends itself to supply by home delivery services. The licensed dose is an initial induction of 80 mg followed by 40 mg at week 2 and then 40 mg on alternate weeks thereafter as maintenance. An accelerated dose of 160 mg followed by 80 mg and then 40 mg on alternate weeks maintenance is more commonly used, particularly in those patients who have previously been on infliximab. The maintenance dose can be increased to 40 mg weekly if a diminished or suboptimal response is seen but treatment should be stopped if no response is seen within 12 weeks of the initial dose.

Infliximab may be of benefit in patients initiated on adalimumab as the first-line anti-TNF agent but who lose response to, or develop adverse effects. The efficacy of infliximab in patients with no initial response to adalimumab needs to be evaluated.

Certolizumab

Certolizumab is a pegylated monoclonal antibody fragment TNF-α antibody. It is currently used for those patients who have lost response to or have become intolerant to infliximab or adalimumab. It is given at an induction dose of 400 mg subcutaneously at weeks 0, 2 and 4 and then if a response is seen, once every 4 weeks as maintenance.

Antibiotics

Metronidazole has been used in Crohn’s disease associated with perianal disease, sepsis associated with fistulae, perforation and bacterial overgrowth in the small bowel. Doses of 0.6–1.5 g/day are typically used and well tolerated. Metronidazole appears to be ineffective in ulcerative colitis. The associated paraesthesia appears to be dose related, occurring frequently with treatment of greater than 3 months duration. In such patients, doses should be gradually reduced or the drug alternated with another antibiotic, for example, ciprofloxacin, tetracycline or rifabutin, which have shown some limited benefit. The metabolite of metronidazole has a free nitro group and this is probably responsible for the drug’s local activity. It also inhibits phospholipase A, contributing to a reduction in damage induced by polymorphonuclear leucocytes.

Other antibacterials are used if specifically indicated, especially when the causative bacterial agents have been identified.

Pseudomembranous colitis caused by C. difficile usually occurs after prolonged or multiple antibiotics. This can be distinguished from other causes of colitis by biopsy and stool culture. If it is unclear whether a patient has pseudomembranous or acute colitis, treatment with metronidazole or vancomycin and steroids is advised. A colonoscopy can be performed once symptoms resolve.

Other treatments

Thalidomide

The use of thalidomide, under specialist supervision, is restricted to refractory cases of Crohn’s disease. Thalidomide acts as a TNF-α inhibitor and probably stabilises lysosomal membranes. At therapeutic doses it also inhibits the formation of superoxide and hydroxyl radicals, both potent oxidants capable of causing tissue damage. Daily doses in the range of 50–400 mg have proved beneficial when used for periods of 1 week to several months. Side effects during treatment include sedation, dry skin and reduced libido. Thalidomide is teratogenic and should never be used in women of child-bearing age.

Antidiarrhoeals

Codeine diphenoxylate and loperamide should be used with caution to treat diarrhoea and abdominal cramping in IBD. Their use may mask inflammation, infection, obstruction or colonic dilation, thereby delaying correct diagnosis.

Colestyramine

Colestyramine has been used in Crohn’s disease following ileal resection to reduce diarrhoea associated with bile acid malabsorption caused by the decrease in small bowel absorptive surface area and the cathartic effect of bile salts on the colon. Doses of up to 4 g three times a day inhibit the secretion of water and electrolytes stimulated by bile acids.

Fish oils (omega-3 fatty acids)

Fish liver oils containing eicosapentaenoic and docosahexaenoic acids have been used with some success in the treatment of both ulcerative colitis and Crohn’s disease. These products cause unpleasant regurgitation which renders them unpalatable in long-time use. Enteric-coated preparations have reduced this problem. It is thought that fish oils work by diverting fatty acid metabolism from leukotriene B4 to the formation of the less inflammatory leukotriene B5.

Miscellaneous treatments

There are many limited trials, studies and case series in the literature evaluating other therapies for ulcerative colitis and Crohn’s disease. These include probiotics, sodium cromoglicate, bismuth and arsenic salts, sucralfate, nicotine, oxygen-derived free radical scavengers, somatostatin analogues, lidocaine, chloroquine, d-penicillamine, carbomers, antituberculous agents, heparin, aloe vera, probiotics and worm therapy (helminths). In general, these treatments are not recommended, although the variety illustrates the limitations of current therapy. When a patient is not responding to conventional agents, consideration should be given to referral to a specialist centre for a review of current therapy and a plan of future management. Alternative and complementary treatments, for example, acupuncture, aromatherapy may have a role.

Leukapheresis has been shown to have some benefit in patients with IBD. It involves removal of leucocytes from the blood, either through an adsorptive system or by centrifugation. In each system, venous blood is removed in a continuous flow, anticoagulated, processed to deplete the leukocytes and returned to the circulation (see NICE, 2005). Table 13.7 summarises the pharmacological profile of drugs used in adults with IBD.

Table 13.7 Pharmacological profile of drugs used in adults with inflammatory bowel disease

Future treatments

Future therapy is focusing on the ability of drugs to target a specific point in the inflammatory process, such as TNF, interleukins (IL-10, 11, 12), T-cell surface antigens and stem cell transplantation.

Surgical treatment

Fifty to eighty percent of Crohn’s disease patients will require surgery within 5–10 years of diagnosis. In contrast, 20–30% of ulcerative colitis patients will usually undergo colectomy with 5 years.

In ulcerative colitis, surgical colectomy, temporary ileostomy and ileoanal pouch construction are all curative. These are the surgical interventions of choice, although proctocolectomy and permanent ileostomy also have a role. Curative surgery is not possible in Crohn’s disease as recurrence elsewhere in the gut is inevitable. Complications in the course of their illness result in about 70% of patients with Crohn’s disease requiring at least one surgical procedure. If a significant length of gut is removed this can result in short gut syndrome which may require long-term parenteral nutrition and medication to control a high-output stoma if present, for example, PPIs, loperamide, codeine phosphate, isotonic fluids.

Patient care

The impact of a diagnosis of IBD should not be underestimated. In general, most patients are diagnosed when they are relatively young and the disease can have a significant effect on the rest of their life. In addition to managing symptoms, the condition can result in loss of education and difficulty in gaining employment or insurance. In young patients, it can cause psychological problems and growth failure or retarded sexual development. Anxiety and loss of self-esteem are commonly described. In addition to pharmacological treatments, psychological support is also important. Medical treatment with corticosteroids and immunosuppressants causes secondary health problems such as infection and surgery may result in complications such as intestinal failure. The care of patients with IBD is, therefore, a challenge for the multidisciplinary team.

All patients should be educated about their illness and medication and reminded that even in periods of remission it is important to continue taking prescribed therapy. This should take the form of verbal and written information. Drug use is invariably lifelong and patients are likely to receive several different treatments during the course of their illness due to intolerance or lack of response. Certain patients such as female or those newly diagnosed patients may require more tailored information about the condition or treatment. Patients with poor dexterity may find the use of rectal preparations difficult and these preparations may, therefore, be poorly tolerated. Leaflets about IBD and insurance or employment for patients with IBD have been prepared by the National Association for Colitis and Crohn’s Disease (www.nacc.org.uk). Patients should also be warned about unreliable information sources.

Patients and primary care doctors may require additional reassurance as several of the treatments used, for example, azathioprine, are unlicensed for IBD. Regular blood monitoring of aminosalicylates and immunosuppressants is essential to ensure patients avoid toxicity associated with these drugs. All patients taking steroids must be issued with a steroid card. Shared care policies between primary care doctors, gastroenterologists and patients may also be appropriate.

If relapse occurs in some patients, they are advised to increase the dose of their current oral therapy and/or commence rectal administration of a corticosteroid before contacting their doctor. If symptoms do not improve within 48 h they should arrange a review with their specialist.

Effective home treatment of proctitis is important because tenesmus and occasional faecal incontinence, apart from being distressing, limit further treatment. Good counselling on the administration of topical therapy is important to ensure effectiveness and adherence.

IBD affects young adults, so pregnancy is not uncommon. Poorly controlled IBD can affect fertility and pregnancy. Good nutrition, stopping smoking and adherence to medication is important. Active disease is a risk factor for pre-term delivery and low birth weight. Infertility associated with sulfasalazine therapy would indicate the use of alternative aminosalicylate therapy. With the exception of methotrexate, which is contraindicated in pregnancy, most drugs used in the treatment of IBD do not present a significant hazard. However, patients are strongly advised to first discuss any plans for pregnancy with their gastroenterologist. Care of pregnant women should be done jointly by a gastroenterologist and obstetrician.

Encouraging patients to stop smoking, especially those with Crohn’s disease, can have a significant impact on the course of the disease.

Long-term steroid use and underlying IBD both contribute to a higher risk of developing osteoporosis. This is prevalent in up to 50% of the patient population with IBD. Patients with Crohn’s disease appear more susceptible to osteoporosis than those with ulcerative colitis. Regular DEXA-scanning should be considered and preventive treatment with bisphosphonate and/or calcium and vitamin D supplements may be necessary. Guidance for the treatment of osteoporosis in IBD has been published by the British Society of Gastroenterology.

IBD patients often develop microcytic anaemia because of malabsorption and chronic blood loss. Assessment of the blood film and serum ferritin can differentiate between iron deficiency and anaemia of chronic disease. Oral iron supplements are generally poorly tolerated and parenteral iron may be required. Guidance of the treatment of iron-deficiency anaemia in IBD has been published (Gasche et al., 2007). Megaloblastic anaemias are uncommon, although vitamin B₁₂ and folate deficiencies occur and may benefit from appropriate supplementation.

The European Crohn’s and Colitis Organisation have published evidence-based consensus guidelines on the prevention, diagnosis and management of opportunistic infections in IBD (Rahier et al., 2009). These highlight which vaccinations should be offered on diagnosis of IBD. UK practice currently recommends influenza, and pneumococcal vaccine in immunosupressed patients only, along with HPV vaccines for females aged 12–18 years in line with other national guidelines. IBD patients in the UK are also advised to receive the swine flu vaccine if immunocompromised.

In 2009, National IBD Standards were published by key stakeholders involved in the care of patients with IBD to improve the service provided for people with a diagnosis of IBD across the UK. The aim of the standards is to ensure patients receive consistent, high-quality care and that IBD services throughout the UK are evidence based, engaged in local and national networking, based on modern IT and audit, meet specific minimum standards. The delivery of patient-focused care requires a multidisciplinary approach which should comprise medical gastroenterologist, nurse specialist, pharmacist, dietician, psychologist, colorectal surgeon, primary care doctor, radiologist and histopathologist.

Case studies