Management of Crohn's disease

Introduction

Over recent decades the incidence of Crohn's disease has increased in the United Kingdom and it now affects about 1 in 1500 people. Symptoms start at any age, with peaks in early and late adulthood. Although the disease is incurable its adverse effects on health and quality of life can be substantially reduced by appropriate treatment. This paper reviews the current management of adults with common presentations of Crohn's disease.

Summary points

• Morbidity from Crohn's disease can be lessened by meticulous specialist management

• New techniques for clarifying the site of disease, activity, and complications include scanning with radiolabelled leucocytes, ultrasound, computed tomography, and magnetic resonance imaging

• Budesonide, high dose mesalazine and, for refractory disease, methotrexate and antitumour necrosis factor α antibody are new therapeutic options

• Other new therapeutic possibilities include a liquid formula diet, endoscopic stricture dilatation, and laparoscopic surgery

• The most effective measure for maintenance of remission is stopping smoking

• Patients should participate in decisions about their treatment

Methods

I searched Medline with the key terms Crohn's disease, drug therapy, dietary therapy, surgery, and therapy. Pharmacotherapeutic advances were derived from peer reviewed controlled clinical trials and meta-analyses published since 1993. Recent data were from the annual meeting of the American Gastroenterological Association. Citations about other aspects of Crohn's disease were mainly from review articles.

Aetiopathogenesis

The progressive elucidation of the pathogenesis, if not yet the cause, of Crohn's disease has improved our understanding of the possible modes of action of conventional treatment and has led to the development of new anti-inflammatory agents aimed at specific pathophysiological targets.

Epidemiological and genetic studies suggest that Crohn's disease is a polygenic disorder without any single Mendelian pattern of inheritance. Susceptibility loci for the disease have been reported recently on chromosomes 16, 3, 7, and 12; the latter three being shared with ulcerative colitis.¹ Several environmental factors have been implicated.¹ Claims for initiating roles for gut flora, food constituents, or specific infections such as mycobacterium paratuberculosis and measles have not yet been substantiated. The pathogenic significance of the strong association between cigarette smoking and Crohn's disease, and why smoking worsens the clinical course of the disease,² remains unclear.

Whatever the initiating factors in Crohn's disease, excessive activation of mucosal T cells leads to transmural inflammation, which is amplified and perpetuated by the release of proinflammatory cytokines and soluble mediators (fig 1).¹

Figure 1.

Aetiopathogenesis of Crohn's disease. Genetic and environmental factors activate mucosal T lymphocytes causing cytokine driven inflammation; increased epithelial permeability and granulomatous vasculitis, leading to focal intestinal microinfarction, may also contribute to the inflammatory process¹

Assessment

Treatment of Crohn's disease depends not only on the site of the disease but also on the pathological process underlying the patient's presentation.³,⁴ Inflammation, obstruction, abscess, and fistula need to be distinguished by appropriate investigation (table).Clinical evaluation and blood tests⁵ remain central to the assessment of symptomatic Crohn's disease, but recently there have been changes in the subsequent diagnostic approach.

Conventional radiology and colonoscopy

Plain abdominal radiography is still essential if intestinal obstruction is suspected: as in ulcerative colitis it helps to estimate the extent and severity of Crohn's colitis. For imaging the small intestine a barium follow through is more comfortable for patients, is less likely to miss proximal disease, and is safer than a small bowel enema (enteroclysis).⁶ Colonoscopy with ileoscopy, because it allows detection of superficial disease, biopsy and, when necessary, dilatation of strictures is now usually preferred to barium enema for investigation of the lower bowel (fig 2).⁶ Colonoscopy may also have a role, as in ulcerative colitis, in surveillance for colorectal cancer in patients with longstanding extensive Crohn's colitis.⁷

Figure 2.

Superficial aphthoid erosions in sigmoid colon in patient with ileocolonic Crohn's disease. Subtle lesions such as these are more readily seen at ileocolonoscopy than on barium enema

Newer imaging techniques

Scanning with radiolabelled leucocytes identifies sites of intestinal inflammation and intra-abdominal abscess non-invasively. Labelling with ⁹⁹technetium-hexamethyl propylene amine oxime is superior to ¹¹¹indium tropolonate in ease of use, availability, image quality, and radiation dose.⁶ Scintigraphic scanning with monoclonal antibodies to upregulated cellular adhesion molecules such as E selectin represents an ingenious application of improved understanding of the pathogenesis of Crohn's disease.¹,⁸

Transabdominal ultrasound for the assessment of bowel wall abnormalities, abscess, and fistula is becoming more widespread.⁶ Changes in mucosal and superior mesenteric arterial blood flow indicating active Crohn's disease are detectable by colour Doppler ultrasound, whereas endoanal and transvaginal ultrasound can help to evaluate perianal disease. Although its non-invasive nature and lack of radiation exposure make ultrasound an appealing investigative technique results are dependent on operator skill and equipment quality.

Abdominal computed tomography now has a major role in the diagnosis of abscess, fistula, and perianal and parastomal complications of Crohn's disease.⁶ The contribution of magnetic resonance imaging is evolving but it is already invaluable for the delineation of pelvic and perianal disease.⁹

Treatment of active ileocaecal Crohn's disease

General measures

Explanation, hospital care, and dietary advice

Patients need their illness fully explained, not least to enable them to participate in decisions about their therapy: discussion can be reinforced with information from support groups such as the National Association for Colitis and Crohn's disease. Hospital care is best undertaken by a team of medical and surgical gastroenterologists, dieticians, and nurse practitioners with a special interest in inflammatory bowel disease, nutrition, and stoma care. Undernourished patients need liquid protein supplements, whereas special nutritional measures are required for patients with short bowel syndrome due to extensive Crohn's disease or resection.¹⁰

Non-specific drugs

Codeine phosphate and loperamide remain useful antidiarrhoeal agents in Crohn's disease but may cause acute colonic dilatation in active colitis. By binding bile salts cholestyramine (4 g 1-3 times daily) reduces diarrhoea due to terminal ileal disease or resection. Haematinics, calcium, magnesium, zinc, and fat soluble vitamins may be needed for the replacement of particular deficiencies as may bisphosphonates, calcium, vitamin D, and hormone replacement therapy for osteoporosis. Sick inpatients may require intravenous fluid and electrolytes and blood transfusion, with subcutaneous heparin to reduce the risk of systemic venous thromboembolism.¹¹Non-steroidal anti-inflammatory drugs may precipitate relapse of inflammatory bowel disease¹² and should be avoided.

Specific drug therapy

Clinical trials in Crohn's disease are bedevilled by difficulties in defining outcome measures, and by the heterogeneity, fluctuating course, and unpredictable placebo response of the disease.¹³ Nevertheless, several new treatments have been introduced recently as a result of well conducted controlled trials.

Corticosteroids

In active disease oral steroids still provide the quickest and most reliable response; about 70% of patients improve within 4 weeks. Conventionally, prednisolone (40-60 mg/day) is used, the dose being tapered by 5 mg every 7-10 days once improvement has begun. Very ill patients, or those with intestinal obstruction, need intravenous hydrocortisone or methylprednisolone initially.

Budesonide is a new steroid with high topical potency; because of poor absorption and rapid first pass metabolism it causes less adrenocortical suppression than prednisolone. Formulated in a pH sensitive coating, which delivers the drug to the distal ileum and caecum, budesonide (Entocort CR (Astra) or Budenofalk (Cortecs), 9 mg/day) approaches oral prednisolone (40 mg/day) in efficacy in ileocaecal Crohn's disease.^14–16 It has become a useful although comparatively expensive option for patients in whom minimisation of steroid induced side effects is particularly important.

Aminosalicylates

The newer oral 5-aminosalicylate formulations are better tolerated than sulphasalazine and can be used in higher doses. The pH dependent delayed release (Asacol, Salofalk) and, particularly, slow release (Pentasa) mesalazine preparations release 5-aminosalicylate more proximally in the gut than sulphasalazine making them useful in small bowel disease as well as colitis. High dose oral mesalazine (Pentasa 2 g twice daily, Asacol 1.2 g three times daily) given for up to 4 months induces remission in about 40% of patients with moderately active ileocaecal Crohn's disease.^16–18 However, even mesalazine may cause rash, headache, nausea, diarrhoea, pancreatitis, or blood dyscrasias in up to 5% of patients; interstitial nephritis occurs in around 1 in 500.¹⁹

Antibiotics

Metronidazole alone³,⁴ or with ciprofloxacin²⁰ is moderately effective in active Crohn's disease. Treatment is given for up to 3 months but may be complicated by nausea, an unpleasant taste, alcohol intolerance, and a peripheral neuropathy, which can be irreversible. Preliminary reports have suggested possible therapeutic roles for ciprofloxacin, clarithromycin, rifabutin, and clofazimine, singly or in combination,³,⁴ but conventional antituberculous triple therapy is ineffective.²¹

Immunosuppressive drugs

For patients refractory to, or dependent on, corticosteroids, who because of extensive disease or previous resection need to avoid surgery, adjunctive azathioprine (2-2.5 mg/kg/day) or 6-mercaptopurine (1-1.5 mg/kg/day) remain invaluable, the dose of steroids being tapered as improvement occurs.²² Response to the thiopurines may take up to 4 months, but hopes that intravenous azathioprine could be used to accelerate improvement have not been confirmed by a controlled trial.²³ Homozygous deficiency of 6-thiopurine methyltransferase, the enzyme responsible for the safe metabolic disposal of purine analogues, occurs in about 0.2% of people and may predispose to azathioprine's occasionally serious side effects (bone marrow depression,²⁴ acute pancreatitis, chronic hepatitis). Routine assay of 6-thiopurine methyltransferase is not yet available but in the future may help identify patients at particular risk. The British National Formulary recommends that patients starting a thiopurine require blood counts every week for the first 8 weeks of treatment and at least every 3 months thereafter. Existing data about the risk of malignancy in patients with Crohn's disease given thiopurines long term are reassuring.²⁵ It is not yet clear how long azathioprine or 6-mercaptopurine should be used in Crohn's disease. However, in patients maintained in remission on a thiopurine the risk of relapse after 4 years seems to be similar whether the drug is continued or stopped.²⁶

Methotrexate 25 mg intramuscularly weekly improves symptoms and reduces steroid requirements in about 40% of patients with chronically active steroid dependent Crohn's disease,²⁷ but its side effects (bone marrow depression, hepatic fibrosis, pneumonitis, opportunistic infections) restrict its use to patients with very refractory disease. A lower oral dose (12.5 mg weekly) may also have a beneficial effect and prove safer.²⁸ Patients given methotrexate need blood monitoring as for azathioprine and 6-mercaptopurine; the necessity for routine lung function tests, chest x ray, or liver biopsy is not clear.

Cyclosporin has not been confirmed as useful in ileocaecal Crohn's disease.³ However, data from an unblinded controlled trial show that mycophenolate mofetil, an immunosuppressive drug that inhibits purine synthesis in lymphocytes, produces a quicker response than azathioprine in patients taking steroids with active Crohn's disease, with few adverse effects²⁹: this report requires confirmation in a double blind controlled study.

Antitumour necrosis factor α antibody

The first specific cytokine related therapy to reach clinical application in Crohn's disease is infliximab, a mouse-human chimeric antibody (cA2) to tumour necrosis factor α; this preparation was launched in the United States in late 1998 and in the United Kingdom in September 1999.³⁰,³¹

In patients with Crohn's disease refractory to steroids or conventional immunosuppressive drugs a single infusion of infliximab at 4 weeks produced improvement in 64% of patients and remission in 33% compared with 17% and 4% respectively after placebo.³⁰ Relapse tended to occur in the ensuing months: repeated infusions at 4-8 weeks may produce more lasting remissions.³²

Infliximab is infused intravenously over 2 hours—each 5 mg/kg infusion costs about £1000. Infusion reactions occur in up to 20% of patients and mean that treatment should be given in hospital, albeit on a daycare basis, where full resuscitation facilities are available. Common minor side effects include headache, nausea, and upper respiratory tract infections. Serious, although not opportunistic, infections including salmonella enterocolitis, pneumonia, and cellulitis have been reported. The production of human antichimeric antibodies may cause delayed hypersensitivity reactions (arthralgia, fever, rash) in patients given a repeat infusion after an interval of 2 or more years; anti-double stranded DNA and cardiolipin antibodies may cause a lupus syndrome. Rapid healing and fibrosis of intestinal strictures may precipitate obstruction. Lastly, there are reports of lymphoma in patients given infliximab for Crohn's disease and rheumatoid arthritis, although it is not yet clear if these are a complication of the disease or due to the drug.

In the future, selection of patients to be treated with antitumour necrosis factor α antibody may depend on their genotype as well as disease phenotype: patients with particular tumour necrosis factor microsatellite haplotypes, for instance, may respond poorly to infliximab.³³ At present, because of uncertainties about its efficacy, safety and, cost-benefit ratio antitumour necrosis factor α antibody should be restricted to patients with very refractory inflammatory disease.

Possible new treatments

The place of other new approaches specifically targeting steps in the inflammatory process awaits clarification. Possible treatments include bone marrow transplant, lymphapheresis, antiCD4 and cellular adhesion molecule antibodies, interleukin 10, interleukin 11, and antisense oligonucleotides to nuclear transcription factors.^34–37

Dietary therapy

In patients with a poor response to, or preference for avoiding, corticosteroids, and particularly in children, a liquid formula diet is a valuable option. Elemental (amino acid based), oligomeric (containing peptides), and polymeric (containing whole protein) feeds all approach the efficacy of corticosteroids if taken for 4-6 weeks as the sole nutritional source.³⁸ The usefulness of enteral therapy is unfortunately limited by its cost, the difficulty many patients have in adhering to it, the need often to give the feed by nasogastric tube or percutaneous gastrostomy, and the high relapse rate that follows its discontinuation.¹⁰,³⁸

Surgery

Surgery is usually indicated for patients whose ileocaecal disease fails to respond to drug or dietary therapy. Resection is not curative: there is a 50% chance of recurrence requiring further surgery at 10 years. Some patients prefer surgery at presentation to pharmacological or nutritional treatment of indefinite duration, but there are no controlled data to confirm the best approach. Although right hemicolectomy and stricturoplasty can both now be undertaken laparoscopically trials are required to compare open and laparoscopic surgery in this setting.³⁹

Principles of treatment of active ileocaecal disease

• General measures

Explanation, multidisciplinary care

Nutritional support

Drugs—antidiarrhoeals, haematinics, heparin  (inpatients); avoid non-steroidal anti-inflammatory  drugs

• Specific pharmacological options

Intravenous corticosteroids then tapered oral  prednisolone or budesonide

High dose mesalazine

Metronidazole alone or with ciprofloxacin

Azathioprine or 6-mercaptopurine (steroid  non-responders)

Methotrexate (thiopurine and steroid non-responders)

Antitumour necrosis factor α antibody (thiopurine and  steroid non-responders)

• Nutritional therapy

Liquid formula diet

• Endoscopic treatment

Balloon dilatation of strictures

• Surgery

Resection or stricturoplasty

Treatment of other common presentations of active Crohn's disease

Obstructive small bowel disease

A raised platelet count, erythrocyte sedimentation rate, or C reactive protein concentration,⁵ and a positive radiolabelled leucocyte scan may distinguish active from fibrostenotic Crohn's disease, but usually a trial of intravenous corticosteroids is given. Parenteral nutrition is required if resumption of eating is unlikely within a week. Although patients not settling after 48-72 hours of conservative treatment usually need surgery, short upper jejunal, terminal ileal, or colonic strictures can now be treated by enteroscopic or colonoscopic balloon dilatation⁴⁰; the value of concomitant intralesional injection of triamcinolone is uncertain.⁴¹

Intra-abdominal abscess

Ultrasound and computed tomography are now used not only diagnostically but also to drain abscesses percutaneously. In patients whose abscesses have no enteric connection, this approach can obviate surgery.⁶

Intestinal fistula

Where there is no obstruction distal to the site of the fistula, enteral or parenteral nutrition, an oral thiopurine, or intravenous cyclosporin or antitumour necrosis factor α antibody cause some fistulae to heal.³,²²,³¹ Many patients, however, still require surgical resection of the fistula and involved intestine.

Perianal disease

Non-suppurative perianal Crohn's disease may respond to oral metronidazole or ciprofloxacin, or both, given for up to 3 months³,⁴ and to long term thiopurine.²² Successful healing of perianal fistulae was reported in 62% of patients treated with three intravenous infusions over 6 weeks of antitumour necrosis factor α antibody compared with 26% of those given placebo.³¹ Although reopening of fistulae was common in the 3 months after treatment was stopped, antitumour necrosis factor α antibody may prove a useful advance in patients with refractory perianal disease. Patients with suppurating perianal Crohn's disease need surgery, minimised as far as possible: abscesses are drained and loose (seton) sutures inserted to facilitate the continued drainage of chronic fistulae.⁴²

Crohn's colitis

Medical treatment of active Crohn's colitis resembles that of active ulcerative colitis. Oral or, in ill patients, intravenous corticosteroids remain the mainstay of treatment. Colonic release formulations of budesonide are under development. Oral aminosalicylates, including sulphasalazine, are an alternative in patients not acutely ill.³,⁴ In contrast with ulcerative colitis about 50% of patients with moderately active Crohn's colitis respond to oral metronidazole for up to 3 months,³ but there are no data about the efficacy of cyclosporin. Compliant patients with Crohn's colitis, like ileitis, may respond to a liquid formula diet.³⁸

In patients who require total panproctocolectomy permanent ileostomy is usually preferred to ileoanal pouch because of a high incidence of pouch breakdown and sepsis in Crohn's disease. However, a recent series suggests that ileoanal pouches may be viable in patients with Crohn's disease without perianal or small bowel disease.⁴³

Current management of other common presentations of Crohn's disease

• Subacute obstruction

Intravenous corticosteroids, fluids, nasogastric suction

Endoscopic balloon dilatation (if accessible)

Surgery

• Intra-abdominal abscess

Antibiotics

Percutaneous drainage

Surgery

• Intestinal fistula

Enteral or parenteral nutrition

Azathioprine, 6-mercaptopurine, or intravenous  cyclosporin

Antitumour necrosis factor α antibody

Surgery

• Perianal disease

Metronidazole or ciprofloxacin, or both

Azathioprine or 6-mercaptopurine

Antitumour necrosis factor α antibody

Surgery

• Colitis

Corticosteroids

Aminosalicylates

Metronidazole

Liquid formula diet

Surgery

Maintenance of remission of Crohn's disease

The most effective prophylactic measure in patients who smoke is to stop: the risk of relapse in non-smokers at 5 years is about 30% lower than in smokers.² The efficacy of drug prophylaxis is limited and depends on whether remission has been achieved by medical or surgical treatment.

Patients in remission after medical treatment

Meta-analysis shows that, unlike in ulcerative colitis, long term aminosalicylates have little or no prophylactic effect in this setting.⁴⁴ Prednisolone in safe doses has no routine prophylactic role.³,⁴ Unfortunately long term budesonide (6 mg/day), although less likely to cause steroid related complications, delays time to relapse without increasing the remission rate at 1 year.⁴⁵,⁴⁶ Thiopurines are of proved value in maintaining remission and reducing steroid requirements in the minority of patients dependent on long term corticosteroids in whom symptoms recur whenever their dose is reduced.²²

High potency ileal release fish oil capsules (Purepa), if commercially available, would be an attractive option should their prophylactic efficacy in one study⁴⁷ be confirmed.

Patients in remission after surgical treatment

Long term aminosalicylates (at least 3 g/day mesalazine) reduce the risk of symptomatic relapse after resection by less than 15%.⁴⁴ Oral budesonide (6 mg/day) halves endoscopic, although not symptomatic, recurrence rate at 1 year after resection for active but not fibrostenotic Crohn's disease.⁴⁸ Oral metronidazole given for 3 months postoperatively reduces symptomatic as well as endoscopic recurrence rate at 1 year although not over a longer period⁴⁹: it may be a useful option in patients reluctant to take drugs long term.

Maintenance of remission in Crohn's disease

• Remission achieved medically

Stop smoking

Azathioprine or 6-mercaptopurine (patients  dependent on steroids)

• Remission achieved surgically

Stop smoking

Mesalazine

Metronidazole (3 months only)

The future

Advances in medical treatment are likely to take several directions. Efforts are being made to formulate corticosteroids, aminosalicylates, and azathioprine in ways that focus delivery more accurately to the site of the disease. Our improved understanding of the aetiopathogenesis of Crohn's disease will lead to the development of further drugs, of which antitumour necrosis factor α antibody has been the first to reach the bedside, that are selectively targeted at specific points in the inflammatory pathway. The choice of treatment will depend increasingly not only on the phenotypic expression of patients' disease but also on their genotype. Finally, gene therapy, for example, applied topically to inflamed gut mucosa is an imminent possibility.

In view of the increasing variety and complexity of therapeutic options it will be essential to ensure that the patient remains at the centre of the decision making process as the fully informed and final arbiter of the type of treatment he or she is to be given.

Table.

Usefulness of imaging techniques for assessment of Crohn's disease

	Information obtained
	Site	Activity	Complications*
Conventional radiology:
Plain abdominal film	+	+	−
Barium follow through	++	++	+
Ileocolonoscopy and biopsy	++	++	+
Newer imaging techniques:
Radiolabelled leucocyte scan	+	++	+
Ultrasound	+	−	+
Computed tomography	+	−	++
Magnetic resonance imaging	−	−	++

^*Abscess, fistula, perianal disease.