This provides sodium 90 mmol/L, potassium 20 mmol/L, chloride 80 mmol/L, citrate 10 mmol/L, glucose 111 mmol/L (total osmolarity 311 mmol/L). Several other formulations exist, some with less sodium (see national formularies).

Of note, it can be seen that attempted rehydration therapy with commercial soft drinks alone will fail because their sodium content is too low (usually less than 4 mmol/L).

Most cases respond adequately with assiduous attention to oral intake but fluid and electrolyte depletion are especially dangerous in children and the elderly, who may need intravenous fluid replacement. Antimotility drugs are inappropriate for severe diarrhoea; hazardous adverse effects (see below) counterbalance any marginal benefit.

Antidiarrhoeal drugs

There are two types of drug which are often used in combination. They should only be considered in benign cases of diarrhoea for short-term symptomatic benefit; in infective or inflammatory diarrhoea their use may be harmful.

Antimotility drugs

Codeine, diphenoxylate and loperamide all activate opiate receptors on the smooth muscle of the bowel to reduce peristalsis and increase segmentation contractions. The actions of all three drugs are antagonised by naloxone. Loperamide and diphenoxylate are relatively enterospecific and do not cross the blood–brain barrier (except diphenoxylate in large doses). These drugs should also be avoided in patients with active inflammatory bowel disease, for they may cause paralytic ileus and toxic megacolon. The abdominal bloating produced by antimotility drugs may be less acceptable than the loose stools for which they are prescribed.

Drugs that directly increase the viscosity of gut contents

Kaolin and chalk are adsorbent powders. Their therapeutic efficacy is marginal as is shown by the fact that they are often combined with an opioid; they should not be used routinely. Bulk forming agents such as ispaghula, methylcellulose and sterculia ¹ (see above) are useful for diarrhoea in diverticular disease, and for reducing the fluidity of faeces in patients with ileostomy and colostomy.

Infectious diarrhoea

This includes travellers’ diarrhoea, where up to half of the diarrhoea that afflicts visitors to tropical and subtropical countries is associated with enterotoxigenic strains of Escherichia coli; other bacteria including Shigella and Salmonella spp., viruses including the Norwalk family, and parasites (particularly Giardia lamblia) have also been implicated.

Transmission is almost invariably by ingestion of contaminated food and water, which indicates the most effective way of reducing risk.

Infectious diarrhoea as a rule is self-limiting and oral rehydration is generally all that is required. Antimotility agents are relatively contraindicated due to concerns of reduced pathogen clearance and toxic megacolon but may be permissible in mild cases. The use of antibiotics is controversial as even in cases of bacterial dysentery they do not reduce duration of symptoms by more than 48 hours, and there is hard in vitro as well as anecdotal evidence that their use in patients with certain bacterial infections (e.g. E. coli O175) can precipitate haemolytic-uraemic syndrome (HUS), which can be life-threatening. Antibiotics may be indicated if the patient is toxic or immunosuppressed, or if invasive infections (e.g. Shigella) are suspected or confirmed. Many regimens are used (commonly ciprofloxacin) but macrolides are theoretically less prone to precipitating HUS in susceptible patients.

Chemotherapy is available for certain specific organisms if enteric infection is confirmed on stool culture, e.g. amoebiasis, giardiasis (see Index).

Diarrhoea due to Clostridium difficile (‘C. diff’)

C. diff infection may range from an offensive but limited diarrhoeal illness to a life-threatening toxic pseudomembranous colitis, and for this reason occupies such a prominent place in the public consciousness. The major risk factors for infection are older age, significant co-morbidites, recent antibiotic use and a history of recent (within 3 months) hospitalisation. Virtually all antibiotics have been implicated as a risk factor for C. diff infection (including, rarely, metronidazole, one of the mainstays of treatment), but clindamycin, quinolones, cephalosporins and other β-lactams are particularly notorious.

First-line treatment has traditionally consisted of 7–14 days of metronidazole by mouth. There is better evidence for a prolonged (4-week) tapering course of oral vancomycin, although this tends to be reserved for severe, refractory or relapsed infections. The tapering course allows the killing of reactivated spores which may have survived initial treatment. Vancomycin not absorbed from the GI tract is excreted renally; it must therefore be given orally (125 mg four times daily initially; occasionally doubled) and monitoring of serum levels is unnecessary.

There are also some data supporting the use of more novel treatments, although solid evidence is lacking. Probiotics and faecal enemas (prepared using normal faeces from unaffected donors), for example, are thought to work by recolonising the bowel with non-pathogenic bacterial flora, whereas intravenous immunoglobulin probably works by neutralising pathogenic toxins.

Drug-induced diarrhoea

Innumerable drugs have diarrhoea as a side-effect. Antimicrobials are the commonest drugs that cause diarrhoea. This is usually due to a benign alteration of bowel flora, but occasionally this will allow latent C. diff colonisation to result in overt colitis (see above).

Secretory diarrhoea due to vasoactive peptides

Octreotide, a synthetic somatostatin analogue (see p. 549), inhibits the release of peptides that mediate certain alimentary secretions, and may be used to relieve diarrhoea due to neuroendocrine tumours such as carcinoids and VIPomas (tumours that produce VIP).

Bile acid malabsorption (BAM)

BAM is increasingly recognised as an important cause of irritable bowel syndrome (IBS) and other diarrhoeas of unknown aetiology. The diarrhoea is a result of osmotically active bile acids remaining in the GI tract.

Bile acids, synthesised in the liver, are necessary for the absorption of lipids from the small bowel. The distal small bowel (terminal ileum) reabsorbs and returns bile acids to the liver, forming a highly efficient enterohepatic recycling system. Primary, or idiopathic, BAM is thought to be due to dysregulated enterohepatic feedback resulting in increased bile acid secretion which saturates uptake absorption capability. Surgery or diseases affecting the small bowel mucosa (such as Crohn’s), or prior cholecystectomy resulting in constant bile acid release, can cause diarrhoea (secondary BAM).

If no treatable underlying cause of BAM is identified then a bile acid absorption resin such as colesevelam, colestipol or colestyramine may be given. These are awkward drugs to take, due to taste, consistency and to the fact that they bind numerous other drugs. They must therefore be given at least 1 hour before or several hours after the administration of other drugs. Bile acid sequestrants are also used as lipid-lowering drugs (see Ch. 26).

Microscopic colitis

This condition presents with diarrhoea; the colonic mucosa is macroscopically normal but histologically shows either lymphocytic infiltration of the mucosa (lymphocytic colitis) or subendothelial fibrosis (collagenous colitis). The condition is benign and spontaneous resolution occurs in a significant proportion. Treatment with aminosalicylates or corticosteroid may hasten this; alternatively, antidiarrhoeals may be attempted to control symptoms.

Constipation

Constipation means different things to different people, and is difficult to define formally. Generally it refers to infrequent, hard to pass bowel motions. Rome III criteria ²define constipation as 2 + of the following over 12 weeks: < 3 stools per week, straining > 1/4 of the time, passage of hard stools, incomplete evacuation, sensation of anorectal blockage.

There are multiple causes of constipation which should be excluded or treated. Symptomatic treatment involves the use of laxatives, which are medicines that promote defaecation, largely by reducing the viscosity of the contents of the lower colon. They are classified as follows:

• Stool bulking agents.

• Osmotic laxatives.

• Faecal softeners.

• Stimulant laxatives.

Stool bulking agents

Dietary fibre

comprises the cell walls and supporting structures of vegetables and fruits. Most of the fibre in our diet is in the form of non-starch polysaccharides (NSPs), which are not digestible by human enzymes. Fibre may be soluble (pectins, guar, ispaghula) or insoluble (cellulose, hemicelluloses, lignin). Insoluble fibre has less effect than soluble fibre on the viscosity of gut contents but is a stronger laxative because it resists digestion in the small bowel and so enters the colon intact. In addition it has a vast capacity for retaining water; thus 1 g of carrot fibre can hold 23 g of water. It has been proposed that as humans have refined the carbohydrates in their diet over the centuries, so they have deprived themselves of fibre, the ensuing under-filling of the colon being an important cause of constipation, haemorrhoids and diverticular disease.

Stool bulking agents, which add fibre to the diet, are the treatment of choice for simple constipation. They act by increasing the volume and lowering the viscosity of intestinal contents to produce a soft bulky stool, which encourages normal reflex bowel activity. The mode of action of stool bulking agents is thus more physiological than that of other types of laxative. They should be taken with liberal quantities of fluid (at least 2 L daily).

Individual preparations

Bran

is the residue left when flour is made from cereals; it contains between 25% and 50% of fibre. The fibre content of a normal diet can be increased by eating wholemeal bread and bran cereals but over-zealous supplementation may cause troublesome flatulence (from bacterial fermentation in the colon).

Viscous (soluble) fibres, e.g. ispaghula, are effective and more palatable than bran. Ispaghula husk contains mucilage and hemicelluloses, which swell rapidly in water. Methylcellulose takes up water to swell to a colloid about 25 times its original volume, and sterculia (a tree gum, named after the Roman god of agricultural fertility and therefore manure), similarly, swells when mixed with water. These and others are available as a variety of proprietary preparations.

Drugs to stimulate colonic motility

Stimulant laxatives

These drugs increase intestinal motility by various mechanisms; they may cause abdominal cramps, and are contraindicated when intestinal obstruction is suspected.

Bisacodyl

stimulates sensory endings in the colon by direct action from the lumen. It is effective orally in 6–10 h and, as a suppository, acts within 1 h. In elderly patients, bisacodyl suppositories reduce the need for regular enemas. There are no important unwanted effects.

Sodium picosulfate

Glycerol

has a mild stimulant effect on the rectum when administered as a suppository.

The anthraquinone group

of laxatives includes senna, danthron, rhubarb³ and aloes. In the small intestine soluble anthraquinone derivates are liberated and absorbed. These are excreted into the colon and act there, along with those that have escaped absorption, probably after being chemically changed by bacterial action.

Senna,

available as a biologically standardised preparation, is widely used to relieve constipation and to empty the bowel for investigative procedures and surgery. It acts within 8–12 h.

Danthron

is available as a standardised preparation in combination with the faecal softeners poloxamer 188 (co-danthramer) and docusate sodium (as co-danthrusate). It acts within 6–12 h. Evidence from rodent studies indicates a possible carcinogenic risk, and long-term exposure to danthron should be avoided. It can be useful for treating constipation in terminally ill patients.

The 5-HT₄ agonist prucalopride has recently been licensed as second-line therapy for women with chronic constipation.

Osmotic laxatives

These are but little absorbed and increase the bulk and reduce viscosity of intestinal contents to promote a fluid stool.

Some inorganic salts

retain water in the intestinal lumen or, if given as hypertonic solution, withdraw it from the body. When constipation is mild, magnesium hydroxide will suffice but magnesium sulphate (Epsom salts) is used when a more powerful effect is needed. Both magnesium salts act within 2–4 h.

Lactulose

is a synthetic disaccharide. Taken orally, it is unaffected by small intestinal disaccharidases, is not absorbed and thus acts as an osmotic laxative. Tolerance may develop. Lactulose is also used in the treatment of hepatic encephalopathy (see Ch. 34).

Osmotic laxatives are frequently used to clear the colon for diagnostic procedures or surgery. Enemas containing phosphate or citrate effectively evacuate the distal colon and can be useful for treating obstinate constipation in elderly or debilitated patients. Oral formulations containing magnesium sulphate and citric acid (Citramag) or polyethylene glycol (Klean-Prep, Movicol) made up with water to create an isotonic solution are used in preparation for colonoscopy; some patients find the necessarily large volumes difficult to tolerate.

Excessive use of stimulant and/or osmotic laxatives may lead to severe water and electrolyte depletion, even to hypokalaemic paralysis and renal failure, especially in the elderly ⁴ or those with diabetes or pre-existing renal impairment. Where bowel cleansing is necessary in these patients (e.g. before surgery or endoscopy), a less aggressive laxative and/or bowel preparation under medical supervision (with electrolyte and fluid balance monitoring) should be considered.

Faecal softeners (emollients)

The softening properties of these agents are useful in the management of anal fissure (see below) and haemorrhoids.

Docusate sodium (dioctyl sodium sulphosuccinate) softens faeces by lowering the surface tension of fluids in the bowel. This allows more water to remain in the faeces. It appears also to have bowel stimulant properties but these are relatively weak. Docusate sodium acts in 1–2 days. Poloxamers, e.g. poloxalkol (poloxamer 188), act similarly and are used in combination with other agents.

Drastic purgatives

(castor oil, cascara, jalap,⁵ colocynth, phenolphthalein and podophyllum) are obsolete.

Suppositories and enemas

Suppositories (bisacodyl, glycerin) may be used to obtain a bowel action within about 1 h. Enemas produce defaecation by softening faeces and distending the bowel. They are used in preparation for surgery, radiological examination and endoscopy. Preparations with sodium phosphate, which is poorly absorbed and so retains water in the gut, are generally used. Arachis oil is included in enemas to soften impacted faeces.

Contraindications

Do not give laxatives to patients with undiagnosed abdominal pain, inflammatory bowel disease or obstruction. Likewise, laxatives should not be used to empty the rectum of hardened faeces, for they will fail and cause pain. Initial treatment should be with enemas, but digital removal, traditionally ordered by a senior and performed by a junior doctor, may occasionally be required. A bulking agent or a faecal softener will help to prevent recurrence.

Inflammatory bowel disease (IBD)

The inflammatory bowel diseases ulcerative colitis (UC) and Crohn’s disease ⁶ are chronic relapsing/remitting diseases of the GI tract characterised by intestinal mucosal inflammation. The pathogenesis of inflammatory bowel disease (IBD) remains incompletely understood. IBD can be thought of as an inappropriate immunological response to non-pathogenic luminal antigens. This can be either an overenthusiastic damaging pro-inflammatory response to an innocuous stimulus or an underwhelming protective anti-inflammatory response which fails to keep an appropriate inflammatory reaction in check. A combination of genetic predisposition and environmental factors produces either Crohn’s disease, which can affect any part of the GI tract, or UC, which is confined to the colon. Classically, UC is thought to result from dysregulation of the Th1/cell-mediated immune pathway while Crohn’s results from disorders of Th2/humoral immunity, but this is almost certainly an oversimplification.

Although Crohn’s and UC are different diseases, their medical management shares many similarities. The goal of pharmacological therapy is to induce and then maintain remission. The maintenance of remission is important not only for the patient’s general well-being, but also because of the risk of complications such as colorectal cancer, which is directly related to disease activity over a long period of time. There is also increasing evidence that mucosal healing, and not just clinical remission, may be an important factor in determining long-term prognosis.

5-ASA and corticosteroids have been the mainstay of treatment of IBD for decades; indeed, the use of corticosteroids in UC has a particular place in the history of the randomised controlled clinical trial.⁷

More recently, immunosuppressive therapy has found an important role. In the last few years biological therapy has been introduced and this is likely to produce a number of new therapies in the coming years.

Antidiarrhoeals should be used only with extreme caution in active colitis and are contraindicated if the disease is severe. They can lead to toxic dilatation of the colon, with perforation.

Drugs to induce remission in UC

Aminosalicylates

5-Aminosalicylate (5-ASA) maintains remission in patients with ulcerative colitis (relapses are reduced by a factor of three), and may also be used for treatment of an acute attack (with or without a corticosteroid, depending on severity). There is increasing evidence that they have a protective effect against colorectal cancer in UC which is independent of its ability to maintain remission.

Its exact mechanism of action remains unclear; putative mechanisms include inhibition of pro-inflammatory prostaglandin synthesis, scavenging of free radicals, inhibition of inflammatory cell recruitment and inhibition of production of pro-inflammatory cytokines and protein mediators such as NFκB, IL1 and TNFα.

Sulfasalazine

has been used to treat rheumatoid arthritis since the 1930s (see p. 252). It was subsequently noted to have activity against ulcerative colitis. It consists of two compounds, sulfapyridine and 5-aminosalicylic acid, joined by an azo bond. Sulfasalazine is poorly absorbed from the small intestine, and colonic bacteria split the azo bond to release the component parts. Sulfapyridine is well absorbed, acetylated in the liver and excreted in the urine; it has no therapeutic action in colitis and functions solely to deliver 5-ASA to the colon.

Sulfasalazine is available as a tablet, retention enema (for disease extending up to the splenic flexure) or suppository (for treating proctitis). It can be particularly useful in treating patients with enteropathic arthritis associated with IBD, due to its rheumatological activity.

Adverse effects are due largely to the sulfonamide moiety and include headache, malaise, anorexia, nausea and vomiting; these are dose related and commoner in slow acetylators (of the sulfonamide). Allergic reactions include rash, fever and lymphadenitis; rarely leucopenia and agranulocytosis occur. Males may suffer from reversible oligospermia and reduced sperm motility. Body secretions may have an orange discoloration, which can stain soft contact lenses.

Mesalazine

Patients intolerant of sulfasalazine usually tolerate mesalazine, which is 5-ASA. Mesalazine is absorbed rapidly and completely in the upper jejunum, and is presented in various formulations that delay its release. Asacol tablets are coated in a resin, which dissolves only at pH 7 or higher, favouring its release in the distal ileum and colon. In contrast, Pentasa has a slow-release but pH-independent coating so that 5-ASA is liberated throughout the gastrointestinal tract. Mesalazine preparations are available in oral, enema and suppository forms.

Other 5-ASA

Balsalazide (a 5-ASA prodrug) and olsalazine (a 5-ASA dimer which is cleaved by colonic bacteria yielding active 5-ASA) are the other available aminosalicylates, obtainable in oral forms only.

5-ASA that enters the blood is rapidly cleared by acetylation in the liver and renal excretion. In comparison to sulfasalazine, the newer 5-ASAs are generally well tolerated and very safe. Patients should be counselled about the rare risk of blood dyscrasias and renal impairment, and occasional blood monitoring is required. Patients being initiated on 5-ASAs rarely experience a paradoxical flare in their symptoms.

Corticosteroid

Enemas and suppositories

These can be used in left-sided or distal UC. 5-ASA therapy is more effective in cases not requiring systemic corticosteroid so corticosteroid enemas/suppositories should not be used as first-line treatment. When UC is restricted to the left hemicolon, exacerbations that do not respond to an aminosalicylate alone often benefit from the addition of corticosteroid enemas. Foam-based preparations appear to coat the colonic mucosa more efficiently than the aqueous formulations.

Patients with distal colitis are prone to faecal loading proximal to the inflamed segment and this can lead to overflow diarrhoea and worsening of inflammation. Faecal loading can be detected on straight abdominal radiograph and is treated with laxatives; this is safe provided the inflammatory process is restricted to the distal colon. On no account should antidiarrhoeals be used as these will exacerbate the problem. Adequate quantities of dietary fibre and fluid should be encouraged, and stool bulking agents can also be helpful in protecting against faecal loading.

Systemic corticosteroid

Severe attacks of ulcerative colitis or Crohn’s, or flares that are unresponsive to 5-ASA therapy, should be treated with systemic corticosteroid, and oral preparations usually suffice. It is important to start with a dose that will bring the inflammatory process under control, e.g. prednisolone 40 mg/day by mouth. Clinical response should be rapid (within 1 week). Once remission has been attained the dose can be tailed down very slowly over a period of 6–8 weeks. This gradual decrease is important, as stopping treatment too abruptly may result in a further flare; this is in contrast, for example, to acute asthma where rapidly tailing regimens are appropriate.

Very severe attacks of ulcerative colitis necessitate hospital treatment with intravenous corticosteroid; parenteral corticosteroid should also be considered in patients unresponsive to other medical management.

The main danger is toxic dilatation of the colon and perforation, which can occur insidiously. Significant clinical improvement should be seen within 72 h. If there is no improvement a trial of ciclosporin or an anti-TNF (see below) may induce response. Treatment otherwise is by emergency colectomy.

Ciclosporin

The calcineurin inhibitor ciclosporin will induce remission in some patients with severe ulcerative colitis unresponsive to intravenous corticosteroid, but is currently unlicensed for this indication in the UK. Give 2 mg/kg i.v., titrated to plasma levels, until remission is attained. Available oral preparations have different pharmacokinetic properties such that equivalence between them can not be assumed.

Doses used in UC are lower than those used in transplant recipients. Renal function and blood pressure must be monitored closely. Ciclosporin is epileptogenic and this effect is enhanced in patients with electrolyte disturbances (particularly calcium and magnesium) and hypocholesterolaemia; it should also be avoided if there is a history of fits. Ciclosporin is ineffective in maintaining remission so maintenance immunosuppressive therapy (see below) is generally required.

There is evidence that liquid diets based on amino acids (elemental diets) or oligopeptides (semi-elemental diets) for 4–6 weeks are as effective as corticosteroids in controlling Crohn’s disease, although relapse is common when the treatment stops. Elemental preparations are notoriously unpalatable even with flavourings and they often have to be administered through a nasogastric tube, which is unpopular with patients. Furthermore, the beneficial effect is lost if non-elemental/semi-elemental dietary components are included. They are worth trying in steroid-resistant cases and are particularly favoured by paediatricians, who prefer to avoid systemic steroids because of their adverse effects on growth.

Corticosteroids

Corticosteroids are effective in active Crohn’s disease. Budesonide, a potent topically active corticosteroid, is an alternative to prednisolone. As a delayed-release formulation it delivers drug to the ileum and ascending colon and is therefore particularly useful in small bowel and ileocaecal Crohn’s, where it has comparable (but inferior) efficacy to prednisolone. Extensive first-pass metabolism in the liver limits its systemic availability and potential for adverse effects.

Topical steroid preparations are generally not useful in Crohn’s disease due to the intermittent nature of mucosal involvement.

Ciclosporin

Ciclosporin is ineffective in Crohn’s disease.

Biological therapies

There is much more extensive experience of biological therapies in Crohn’s disease, in particular with the use of anti-TNFα therapy. These have been demonstrated to be effective in the induction and maintenance of remission of active Crohn’s disease, including perianal and fistulating disease.

Maintenance of remission in IBD

Corticosteroids

are ineffective in maintaining remission of UC or Crohn’s, largely due to significant adverse effects associated with long-term use.

In UC, maintenance therapy with an aminosalicylate should be started as corticosteroids are being weaned. 5-ASA has limited, if any, efficacy in the maintenance of remission of Crohn’s disease.

If the disease is corticosteroid dependent despite adequate 5-ASA therapy, azathioprine or another immunosuppressive agent may be used (see below). Surgery is indicated if medical therapy fails to control the disease or is associated with unacceptable adverse effects.

Azathioprine

is effective as a steroid-sparing agent in maintenance therapy in UC and Crohn’s, and is used when 5-ASA is insufficient to maintain adequate remission. Azathioprine is converted to 6-mercaptopurine (6-MP) and then to tioguanine, an inhibitor of purine synthesis, which causes a degree of immunosuppression; in this pathway the thiopurine methyltransferase (TPMT) enzyme is rate-limiting. TPMT activity is inherited as a Mendelian trait, with low levels carrying an increased risk of myelotoxicity and mandating lower doses or selection of a different agent. TPMT activity assays are now widely available and differentiate between patients with low or absent TPMT activity (mutant homozygotes) at high risk of complications, intermediate activity (heterozygotes) in whom thiopurines may be used with caution, and normal activity (normal homozygotes) who are at low risk of toxic effects; with the latter 2–2.5 mg/kg is therapeutic. Azathioprine is not an appropriate drug for inducing remission as its onset of action takes 8–12 weeks; corticosteroid (or occasionally ciclosporin in the case of steroid failure in UC) is used as a ‘bridge’ to allow its therapeutic action to take effect.

Allopurinol can cause dangerous toxicity at therapeutic doses by inhibiting xanthine oxidase and preventing the conversion of azathioprine to 6-MP.

Adverse effects, in particular myelosuppression, are much more common in TPMT-deficient patients but those with normal enzymatic activity are also at risk. As azathioprine can cause bone marrow suppression and hepatitis, the blood count and liver function should be monitored weekly for the first 2 months of therapy and every 2–3 months thereafter for as long as the drug is taken. Pancreatitis occurs in up to 5% of patients. Intolerance to azathioprine is fairly common, for example malaise, abdominal discomfort and nausea. These effects are usually due to the imidazole side-chain of the molecule, and mercaptopurine (which is azathioprine without the side-chain) may be better tolerated (1–1.5 mg/kg daily). Mercaptopurine is not an alternative to azathioprine in patients who have suffered pancreatitis or myelosuppression with the latter, as these effects are due to the active part of the drug.

Methotrexate,

a folic acid antagonist, can be helpful in controlling relapses of Crohn’s disease unresponsive to corticosteroid or azathioprine. It has also been used with benefit in ulcerative colitis. Its short- and long-term use are limited by a wide profile of adverse effects including bone marrow suppression and pulmonary and hepatic fibrosis (see p. 248). It is given once weekly, with folic acid supplements on the days on which it is not taken. It is severely teratogenic and is contraindicated in both men and women trying to conceive.

Biological therapies

TNFα causes activation of immune cells and release of inflammatory mediators by binding surface TNF receptors. Following in vitro demonstration that inhibition of TNFα activity resulted in reduced mucosal inflammation, several anti-TNFα have come to market. Infliximab, adalimumab and certolizumab-PEGol are recombinant monoclonal anti-TNFα-receptor antibodies. Infliximab, the first to come to market, is mouse-human chimaeric antibody and is given as an intravenous infusion of 5 mg/kg at 0, 2 and 6 weeks initially and then at 8-weekly intervals. Adalimumab is a fully human monoclonal antibody and has the advantage of being given subcutaneously at 160 mg at week 0, 80 mg at week 2, and 40 mg every 2 weeks thereafter. Certolizumab-PEGol is also a humanised monoclonal antibody with a PEGylated Fab′ fragment. It is also given subcutaneously at a dose of 400 mg at weeks 0, 2 and 4, and at 4-weekly intervals thereafter.

These drugs are effective in inducing and maintaining remission in Crohn’s disease. Most experience has been gained with infliximab (certolizumab does not currently have a licence in the UK). Infliximab and adalimumab appear to be effective in penetrating (fistulating) disease.

There is evidence that infliximab is also effective in inducing and maintaining remission in UC, although this is an unlicensed indication.

Anti-TNFα are given as a long-term course over at least a year if effective. Controversial issues include whether to co-administer another immunosuppressant (such as azathioprine) to improve efficacy and whether to institute them early in the course of disease (‘top-down’) or only after failure of other treatment modalities (‘bottom-up’).

Adverse effects include hypersensitivity reactions. There is a significant risk of potentially fatal reactivation of TB, which must therefore be excluded before initiating treatment. There is a theoretical risk of increased susceptibility to other atypical infections and cancers, particularly lymphoproliferative disease, but long-term follow-up data are not yet available. Screening for infections such as hepatitis B and C viruses, and HIV is commonplace without as yet definite evidence that TNFα therapy worsens these conditions if coexistent.

Maintenance of remission following surgery for Crohn’s disease

An additional difficulty in the medical management of Crohn’s disease is prophylaxis against recurrence after surgical resection. Of the drugs studied, antibiotics are effective but cannot be given for longer than 3 months because of toxicity and unwanted effects with long-term use. 5-ASA and azathioprine provide some benefit but emerging evidence suggests that infliximab (and potentially other anti-TNFα) are much more effective.

Irritable bowel syndrome (IBS)

This condition affects 20% of the population and is the commonest reason for referral to a gastroenterologist. It is manifested by a variety of gastrointestinal symptoms including disordered bowel habit (constipation, diarrhoea, or both), abdominal pain and bloating. Upper gastrointestinal symptoms manifest as non-ulcer dyspepsia (see Ch. 32). All of these symptoms occur in the absence of demonstrable pathology in the gastrointestinal tract, although patients with IBS often have abnormalities of gut motility. Another feature of the condition is visceral hypersensitivity; patients with IBS have lower thresholds for pain from colonic distension induced by inflating balloons placed in the bowel. A proportion of patients develop their IBS symptoms after an episode of gastroenteritis and, in many, emotional stress is an important precipitating factor. Associated psychopathology, with anxiety and sometimes depression, is common.

The mainstay of treatment, after investigation when appropriate, is to reassure the patient of the entirely benign nature of the disorder and the good prognosis. Those with predominant constipation should be encouraged to increase the fluid and fibre content of their diet. Unprocessed bran can lead to troublesome bloating and wind, and a bulking agent such as ispaghula husk is often better tolerated.

Diarrhoea may respond to an antimotility drug such as loperamide, the dose being adjusted to symptoms. Codeine phosphate is effective but may cause sedation.

Low-dose tricyclic antidepressants, i.e. at doses ineffective as antidepressant, and antispasmodics (see below) are given for abdominal pain, but there is little objective evidence for their therapeutic efficacy. The generation of evidence is complicated by the variable nature of IBS symptoms, the patients who suffer from them, and the high rate of placebo response in this condition. There are two main classes of antispasmodic, the antimuscarinic drugs and drugs that are direct smooth muscle relaxants.