Mechanism of action. By combining with intracellular glucocorticoid receptors, corticosteroids have many potentially beneficial actions on the inflammatory process (see Table 5.1), but which of these is, or are, of predominant importance in IBD is unclear.

Indications. The use of corticosteroids in IBD should be restricted to the treatment of patients with active disease, as there is no evidence that they are able to maintain remission. Corticosteroids continue to have a major role in active ulcerative colitis, but their therapeutic value in Crohn’s disease is limited because of their failure to induce mucosal healing and their side effects (see below). Further details are given in Chapters 7 and 8.

Side effects. The principal side effects of corticosteroids are listed in Table 5.1. They relate to both dose and duration, except for avascular osteonecrosis, which is unpredictable and may occur after only short courses of treatment. In patients with penetrating Crohn’s disease, corticosteroids increase the risk of intra-abdominal and pelvic sepsis and delayed postoperative recovery.

Monitoring treatment. The tiny proportion of patients with IBD who require long-term treatment with oral corticosteroids should have regular checks of their blood pressure and blood sugar and potassium concentrations. Those who exceed a cumulative dose of about 10 g of prednisolone should be assessed for osteoporosis by bone densitometry and treated accordingly (see Chapter 3).

Contraindications. In patients with poorly controlled diabetes mellitus or hypertension, and in those with established osteoporosis or peptic ulceration, alternative pharmacological treatments should be used when possible. As indicated above, steroids should be avoided in patients with penetrating Crohn’s disease. If steroid therapy is unavoidable, topical therapy or oral budesonide in those with ileocecal Crohn’s disease is preferable to oral prednisolone.

Aminosalicylates

Pharmacology. 5-Aminosalicylates (5-ASAs) are available in oral formulations (Table 5.2) and as enemas and suppositories (Table 5.3). The original compound, sulfasalazine, consists of 5-aminosalicylic acid linked by an azo bond to sulfapyridine (Figure 5.1; see Table 5.2). The sulfonamide moiety acts as a carrier to deliver 5-ASA, the active component, to the colon, where it is released by bacterial action. About 20% of patients cannot tolerate sulfasalazine because of side effects, most of which are due to sulfapyridine (see Table 5.3).

The newer oral 5-ASA formulations are better tolerated than sulfasalazine. The pH-dependent, delayed-release and, particularly, slow-release mesalazine (mesalamine) preparations release 5-ASA more proximally in the gut (Figure 5.2). In contrast, olsalazine and balsalazide, like sulfasalazine, release 5-ASA by bacterial azo reduction in the colon and are indicated for use only in colitis. It is now known that once-daily administration of 5-ASA drugs is as effective in ulcerative colitis as twice daily or three times daily regimens: the increased convenience of once-daily regimens increases treatment adherence.

Mechanism of action. Like corticosteroids, aminosalicylates have a wide variety of anti-inflammatory effects (see Table 5.3). However, it is not known which of these explains their efficacy.

Indications and choice of preparation. 5-ASA compounds have a therapeutic role in moderately active (although not acute severe) ulcerative colitis and, particularly, in the prevention of relapse in those with inactive disease. 5-ASA agents given by mouth and rectally (‘top and tail’) are more effective, although more expensive, in active ulcerative colitis than when given by either route alone.

TABLE 5.3 Aminosalicylates in inflammatory bowel disease
Indications Active and inactive ulcerative colitis Mildly active Crohn’s disease (see Chapter 8)
Preparations
Oral	See Table 5.2
Enemas	Liquid: Pentasa, Salofalk, Rowasa, sulfasalazine Foam: Asacolfoam, Salofalk, Claversal
Suppositories	Asacol, Pentasa, Salofalk, Canasa, sulfasalazine
Side effects
General	Headache,* fever*
Gut	Nausea,* vomiting,* diarrhea, exacerbation of ulcerative colitis
Blood	Hemolysis,* folate deficiency,* agranulocytosis,* thrombocytopenia,* aplastic anemia,* methemoglobinemia*
Renal	Orange urine,* interstitial nephritis
Skin	Rashes,* toxic epidermal necrolysis,* Stevens–Johnson syndrome,* hair loss
Other	Oligospermia,* acute pancreatitis, hepatitis, lupus syndrome, myocarditis, pulmonary fibrosis
Monitoring
Sulfasalazine	Every 3 months: blood count, red-cell folate, serum urea/creatinine, liver function tests
Mesalazine (mesalamine)	Every 6–9 months: serum urea/creatinine
Contraindications
Sulfasalazine	Known salicylate or sulfonamide sensitivity, G6PDH deficiency, porphyria
Mesalazine (mesalamine)	Salicylate sensitivity, renal failure
Mechanisms of action
Leukocytes	Reduced migration, cytotoxicity Reduced activation of NF-κB Reduced synthesis of IL-1 and lipid mediators Reduced degradation of prostaglandins Antioxidant TNF antagonist Activation of PPAR-γ
Epithelium	Reduced MHC class II expression Induction of heat shock proteins Reduced apoptosis
*Side effects usually due to sulfonamide component of sulfasalazine. G6PDH, glucose-6-phosphate dehydrogenase; IL, interleukin; MHC, major histocompatibility complex; NF-κB, nuclear [transcription] factor κB; PPAR-γ, peroxisome proliferator-activated receptor-γ; TNF, tumor necrosis factor.

Figure 5.1 Chemistry of 5-aminosalicylate (5-ASA) preparations. The green dotted lines indicate cleavage of the azo-bond by colonic bacterial flora to release the active moiety, 5-ASA, of each drug from the carrier molecule. In the case of olsalazine, the 5-ASA serves both as active component and carrier molecule.

Figure 5.2 Intestinal release profiles of 5-aminosalicylate (5-ASA) formulations (see Table 5.2). There is some variability in the site of release of the various formulations (as indicated by the blue-colored areas above), depending on, for example, the precise pH at which 5-ASA is released from different pH-dependent preparations, intestinal intraluminal pH and intestinal transit rate. The multimatrix mesalazine (mesalamine) preparation has a pH-dependent coating, while hydrophilic and lipophilic excipients prolong the release of 5-ASA throughout the colon.

Taken long term, 5-ASA drugs may reduce the risk of development of colorectal cancer in patients with extensive ulcerative colitis, but current data are conflicting. Patients using sulfasalazine in the long term should also be prescribed folic acid to prevent folate deficiency: this may also help to reduce the risk of colonic cancer in chronic extensive ulcerative colitis.

Recent data suggest that although mesalazine preparations are of minor benefit in mildly active Crohn’s disease, they have little or no other role in patients with this condition (see Chapter 8).

Side effects. Although better tolerated than sulfasalazine, the newer 5-ASA formulations may cause rash, headache, nausea, diarrhea, exacerbation of ulcerative colitis, pancreatitis and/or blood dyscrasias in up to 5% of patients (see Table 5.3). Interstitial nephritis has been associated very rarely (about 1 in 500 patients) with mesalazine, while watery diarrhea due to active small-intestinal secretion occurs in about 5% of patients given olsalazine. The latter can usually be avoided by taking the drug with meals.

Monitoring treatment. Patients taking sulfasalazine require regular (every 3–6 months) blood counts, and serum folate and liver function tests. Those receiving any 5-ASA preparation should have occasional (e.g. every 6–9 months) checks of their serum urea and creatinine concentrations.

Contraindications. All 5-ASAs should be avoided in individuals with a history of hypersensitivity to salicylates, including acetylsalicylic acid (aspirin), or those with serious renal impairment. In addition, sulfasalazine should not be given to patients with sulfonamide sensitivity, porphyria or glucose-6-phosphate dehydrogenase deficiency.

Antibiotics

Metronidazole is a nitroimidazole compound with antimicrobial actions against gut anaerobes and protozoa. It also has immunomodulatory effects in vitro. The oral preparation is the most widely used in IBD.

Indications and side effects. Metronidazole, 10 mg/kg/day orally, has moderate benefit in ileocolonic, but not small-bowel, Crohn’s disease and in preventing recurrence when given for 3 months after ileal resection. Despite the lack of data from controlled trials, it is commonly used in perianal Crohn’s disease too. It is also sometimes given in combination with ciprofloxacin in refractory Crohn’s disease. Metronidazole has no primary therapeutic role in ulcerative colitis other than in patients with pouchitis following formation of an ileoanal pouch after colectomy (see Chapter 9). Treatment must be given for up to 3 months, but it may be confounded by nausea, vomiting, an unpleasant taste in the mouth and/or an individual’s unwillingness to abstain from alcohol during this time. The most serious side effect is peripheral neuropathy. This is dose related and is not always reversible when treatment ends.

Other antibiotics. Limited data suggest that oral tobramycin and trimethoprim–sulfamethoxazole could improve outcome in acute severe ulcerative colitis. However, most gastroenterologists restrict the use of broad-spectrum antibiotics to prophylaxis against bacteremia and endotoxic shock in severely ill patients with acute severe colitis.

Ciprofloxacin has a moderately beneficial effect in Crohn’s disease, particularly in perianal disease; it can also ameliorate pouchitis alone or in combination with metronidazole. Clarithromycin (sometimes in combination with rifabutin) is reported to have benefit in Crohn’s disease and, like metronidazole, has some immunomodulatory effects in vitro.

Antibiotics such as amoxicillin, trimethoprim, ciprofloxacin and metronidazole are sometimes useful for the treatment of diarrhea or steatorrhea due to bacterial overgrowth in patients with small-bowel Crohn’s disease, while broad-spectrum and often intravenous antibiotics may be needed, together with drainage, in the management of those with intra-abdominal or perianal abscesses complicating Crohn’s disease (see Chapter 8).

Probiotics

Probiotics are defined as live microorganisms which, when given orally in sufficient quantity, confer a health benefit on the host. Given the importance of intestinal bacterial flora in driving the mucosal inflammation characteristic of IBD (see Chapter 1), it is unsurprising that a range of probiotic organisms have been assessed for its treatment (listed in Table 5.8). To date, evidence of efficacy relates only to use of E. coli Nissle to prevent relapse of ulcerative colitis, and of VSL3, which contains a mixture of bifidobacteria, lactobacilli and streptococci, in pouchitis.

Despite the paucity of data confirming the benefits of probiotics and prebiotics in IBD, they are widely used by patients adopting a complementary or alternative medical approach to their illness (see pages 82–3): they are probably safe.

Immunomodulatory drugs

Immunomodulatory agents currently used in the treatment of IBD include azathioprine and its metabolite mercaptopurine (MP) and, less often, methotrexate, ciclosporin (cyclosporine) and tacrolimus.

Azathioprine and mercaptopurine. Azathioprine is a prodrug that undergoes rapid conversion to MP; both are purine analogs (thiopurines). The doses most commonly used in IBD are 2.0 and 1.0 mg/kg/day, respectively (Table 5.4). Both drugs are currently used only in oral formulations and take up to 4 months to exert their clinical benefit.

TABLE 5.4 Azathioprine and mercaptopurine in inflammatory bowel disease
Indications Steroid-dependent or -refractory ulcerative colitis and Crohn’s disease Fistulating and perianal Crohn’s disease
Formulations
Oral	Azathioprine (2.0–2.5 mg/kg/day) MP (1.0–1.5 mg/kg/day)
Side effects
General	Nausea, vomiting, headache, arthralgia, fever, rash, abdominal pain
Blood	Agranulocytosis, thrombocytopenia, macrocytosis
Infections	Opportunistic including cytomegalovirus, herpes zoster
Hepatobiliary	Cholestatic hepatitis, acute pancreatitis, nodular regenerative hyperplasia
Malignancy	Lymphoma, skin
Preparatory screening	Serology and vaccinations (see Chapter 6) Measure TPMT before starting thiopurine
Monitoring	Blood count, liver function tests every 2 weeks for the first 2 months, then every 2–3 months
	TGN and MMP – see text
Contraindications	Pregnancy (relative contraindication) Homozygous TPMT deficiency
Mechanism of action	Inhibition of DNA synthesis and induction of apoptosis in T cells
MP, mercaptopurine; MMP, methylmercaptopurine; TGN, thioguanine nucleotides; TPMT, thiopurine methyltransferase.

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