The management of severe Crohn’s disease
Professor D. P. Jewell, Gastroenterology Unit, Radcliffe Infirmary, Oxford, OX2 6HE, UK. E-mail: email@example.com
The treatment of severe and active Crohn’s disease is currently based on immunosuppression, but also involves the management of nutrition, appropriate selection of patients for surgery, and maintenance of remission in the long term. Corticosteroids remain the drug of the first choice, particularly in the acute setting. However, there is evolving understanding of the role of other immunosuppressants and immune modifiers, as major concerns regarding side-effects and efficacy of steroids in the medium to long-term drive the search for alternatives.
One difficulty in reviewing the treatment of severe Crohn’s disease is that, unlike severe ulcerative colitis, there is no established definition—partly reflecting the many guises of Crohn’s disease. Measures of severity used predominantly in a research setting, such as a Crohn’s disease activity index (CDAI) > 250 or Harvey Bradshaw index > 8 are rarely used in the clinic, but do incorporate parameters used in any thorough assessment, such as the number of stools per day and severity of abdominal pain. However, other factors, including malnutrition, disease chronicity and disease pattern, particularly related to the site and extent of intestinal involvement, might also reasonably be used to identify severe cases. Likewise, symptoms related to the sequaelae of Crohn’s disease might be severe—a tight fibrotic stricture, or short bowel due to multiple resections—without directly reflecting inflammatory activity of the Crohn’s disease itself.
For all the many and varied manifestations of Crohn’s disease, and for all the difficulties in categorizing disease severity using standardized scoring systems, most severe cases will be readily apparent to the experienced clinician. This review will focus primarily on severe disease in the acute setting, but will also describe treatment strategies for chronic active, and complex fistulating Crohn’s disease. After briefly defining each of these disease categories with clinical features and laboratory findings, medical and surgical management will be discussed. An overall strategy will be briefly described, followed by a more detailed discussion of specific therapies and evidence favouring their use. The article concludes with a few comments regarding maintenance of disease remission and possible future developments.
IDENTIFYING THE PATIENT WITH SEVERE CROHN’S DISEASE
Most cases of severe Crohn’s disease will be identified in the course of the clinical assessment, with confirmatory evidence coming from laboratory investigations, endoscopic and radiological studies.
The presentation clearly depends on the site of intestinal involvement. Obstructive symptoms of abdominal pain, bloating and weight loss predominate in ileal and small bowel disease, while colonic inflammation tends to cause diarrhoea, which may or may not be bloody. Malaise, anorexia and the presence of extra-intestinal manifestations are more suggestive of active inflammation, as opposed to fibrotic strictures or adhesions, for example.
Severe inflammation is reflected in constitutional upset. The patient may have lost weight, appear malnourished or possibly dehydrated. Fever should prompt the search for an abscess or perforation, but may simply indicate a marked inflammatory response. A tender inflammatory mass in the right ileac fossa indicates severe ileo–caecal disease. Colonic tenderness due to Crohn’s colitis is a warning sign. Plain abdominal X-ray is likely to show mucosal oedema and an empty colon in affected segments, and occasionally toxic dilatation in extensive severe colitis. Frank peritonitis indicates perforation which may or may not be localized in Crohn’s disease, or may be masked by current steroid therapy. Severe small bowel disease and occasionally colonic disease can lead to strictures presenting with symptoms and signs of bowel obstruction.
Laboratory investigation, particularly C-reactive protein, platelet count, ESR and albumin, and barium radiology usually help differentiate inflammatory from fibrotic or adhesional strictures. The isolated finding, for example, of apparently severe disease on a small bowel enema in the absence of corresponding symptoms, would not itself be a mandate for management of ‘severe’ disease. Conversely, severe symptoms in the absence of objective laboratory or radiological evidence should raise questions regarding other possible diagnoses, including coexistent irritable bowel syndrome, bile salt diarrhoea, dietary intolerance or bacterial overgrowth.
The impact of fistulating disease ranges from asymptomatic to severe, the latter including multiple fistulae, fistulous tracts ending in abscesses, or deep fistulae connecting to adjacent structures such as anal sphincters, bladder or vagina. Local symptoms of pain or faeculant discharge may occur, and the patient may be systemically unwell. Radiological investigation is required, and examination under anaesthesia is important in the assessment of perianal disease.
Severe Crohn’s disease should also include the group of patients with chronic active or refractory disease where symptoms fail to settle despite steroid therapy, or flair soon after stopping treatment. Nutrition may be compromised, as symptoms are often triggered by food, and quality of life suffers. Maintenance steroid therapy is poorly tolerated, causes significant side-effects, and is of questionable efficacy. A variety of alternatives are available, as will be discussed.
THE MULTIDISCIPLINARY TEAM
While the gastroenterologist or admitting surgical team is likely to be the first port of call for a patient with a severe flair of Crohn’s disease, their management requires a truly multidisciplinary approach. Surgeons and physicians with inflammatory bowel disease experience must both be involved at an early stage in order that an appropriate management plan can be devised and pro-active rather than reactive decisions made. A number of other team members have important roles:
• Adequate assessment of disease extent and severity requires the help of an experienced radiologist to interpret barium contrast studies of bowel lumen and fistulae, CT (computed tomography) and MRI (magnetic resonance imaging) scans, and white cell scans. The interventional radiologist also plays an important role for percutaneous drainage of intra-abdominal abscess cavities.
• Maintenance and restoration of nutrition by enteral and parenteral routes, and the use of elemental and polymeric diets as therapy for active Crohn’s disease indicate the need for an experienced dietician with expertise in this field.
• Stoma therapy nurses should be involved early for a number of reasons in patients with severe Crohn’s disease. Many patients have understandable fears of stoma devices, and they need somebody to discuss these with. The large majority of patients with Crohn’s disease will require surgery at some stage (90% of all patients with ileo-colonic disease; 58% of those with colonic or ano-rectal disease). The proportion will be higher in those with severe disease, as will the likelihood of requiring a stoma. In this context, the education can start early. Another advantage of introducing the stoma therapist early is the relative unpredictability of severe and particularly acute disease, and thus the higher risk of requiring surgery on an emergency or semi-urgent basis.
• The patient should clearly be involved in the decision processes. Many are young and well informed about their disease and the relative merits and side-effects of the different therapies available. Some patients will be very resistant to the idea of surgery and keen to try all available pharmacological options, some may be well motivated to persevere with dietary therapies, and others may see early surgery for limited disease as the modality which will least disrupt their lives. Hard decisions should not be ducked, but presenting and discussing the available options with the patients is a matter of common sense.
MEDICAL MANAGEMENT OF ACUTE SEVERE CROHN’S DISEASE
Patients presenting acutely with severe diarrhoea, abdominal pain, anorexia or fever should be admitted to hospital. Corticosteroids provide the mainstay of treatment, together with intravenous fluids and bowel rest in the form of nil by mouth or enteral nutrition with elemental or polymeric diet only.1, 2 Antibiotics (for example metronidazole) are also given if there is any suggestion of sepsis, in the form of fever, a palpable inflammatory mass, discharging fistula or severe perianal disease. Anti-emetics may be required, and opiate analgesia with pethidine can be given, albeit cautiously if there is any suggestion of toxic dilatation. DVT prophylaxis is important in view of the increased risk of thromboembolism in active inflammatory bowel disease.3, 4
Stool frequency should be recorded, as should temperature and pulse. Patients must be examined at least daily, and electrolytes (especially potassium), albumin and inflammatory markers [erythrocyte sedimentation rate (ESR) and C reactive protein (CRP)] should be monitored. Plain abdominal X-rays need repeating unless symptoms settle promptly. Most patients respond well within 5–7 days, after which treatment can be changed to an oral regimen and normal diet recommenced.
For patients with acute severe disease who do not respond well to steroids, the options lie between surgery and possibly ciclosporin (4 mg per kg body weight per day as a continuous infusion). There are no controlled data available for the use of ciclosporin in this context, but anecdotal evidence suggests a response similar to that seen in ulcerative colitis—including the relatively high relapse rate on stopping oral therapy.5, 6 For patients with extensive disease, complex fistulae or possibly first presentation of steroid refractory Crohn’s colitis, its use is probably warranted although more data from randomized trials are required. Early hopes that intravenous azathioprine would be efficacious in inducing a rapid remission were not substantiated in a larger trial, and this expensive formulation cannot be recommended in this context.7 For patients with disease that is limited in extent, early surgery is often the preferred option, as it clearly is for those whose symptoms are of obstruction which has failed to settle. Following surgery, symptoms recur at a rate of approximately 15% per year, compared to a 30–40% relapse rate at 1 year following medically induced remission.8, 9
Corticosteroids are an effective first line therapy for active Crohn’s disease, inducing remission in approximately 70% of patients compared to 30% on placebo.1, 2 Although there is no evidence to guide the route of administration, intravenous hydrocortisone at least obviates concern regarding poor enteral absorption in patients with active Crohn’s disease or previous resections.10, 11
An optimal dose has also yet to be evaluated. It is our usual practice to give hydrocortisone 100 mg every 6 h until a response is observed, usually at 3–7 days, and then switch to oral prednisalone 40 mg/day for 1 week, 30 mg/day for 1 week, 20 mg/day for 4 weeks and then taper by 5 mg/day each week. Budesonide (9 mg/day) has recently been introduced as an alternative to oral prednisolone for the treatment of ileo-colic Crohn’s disease with relatively fewer steroid side-effects due to its high first pass metabolism in the liver. Trial data suggest near equivalence to oral prednisolone in the treatment of active Crohn’s disease, with remission rates of 52–60% at 8 weeks.12–14 Although most clinicians are reluctant to use budesonide as a first line treatment of severe disease, it may be considered as follow-on therapy after intravenous treatment for patients in whom steroid side-effects such as psychosis or osteoporosis are a particular concern. For patients with severe Crohn’s disease affecting the rectum and left colon (more common in the elderly), a topical steroid should also be used. In the acute setting, a rectal hydrocortisone drip (100 mg in 100 mL normal saline every 12 h via soft rectal cannula) is best tolerated.
These are clearly indicated where there is evidence of sepsis. They are also widely used in ‘non-septic’ flares of Crohn’s disease, although the evidence for benefit in this latter group is less convincing. The rationale comes from experimental evidence regarding the pathogenic role of antigens present in the gut flora of Crohn’s patients.15 Metronidazole (200–400 mg t.d.s.) is the antibiotic most frequently used for a 7–10 day course. However, two well designed trials have demonstrated that its effect is at best only marginally greater than placebo when used as monotherapy.16, 17 Ciprofloxacin (500 mg b.d.) is increasingly being used as an alternative due to better tolerability, and there are emerging data that the combination of these antibiotics may be an efficacious treatment for active Crohn’s disease.18, 19 Metronidazole has also been demonstrated to reduce post-operative relapse rates, but it is not widely used in this context and treatment for more than 3 months is limited by peripheral neuropathy.20
Mirroring the use of antibiotics is the increasing interest being shown in the use of probiotics as treatment for active disease.21 In the absence of any currently available commercial preparations and particularly for patients whose disease is complicated by recurrent small bowel overgrowth, live yoghurt may help and is unlikely to harm.
These can be divided into the maintenance or restoration of nutrition in a patient who may otherwise be at risk, and nutritional therapies.
Assessment by a dietician shows the impact that anorexia may have had on nutritional intake, and can allow appropriate advice for supplementation once the acute phase of the illness has passed. Specific dietary intolerances are relatively common and may also be identified. Many patients with Crohn’s disease are less symptomatic on a low lactose and low fibre diet, and should be advised accordingly. Otherwise, a normal diet should be recommended.
Specific deficiencies may be identified, commonly B12, less commonly fat soluble vitamins D and K if there is steatorrhoea, and rarely of zinc or selenium. Calcium intake must be adequate, particularly where low lactose diets have been recommended and in patients with osteopenia.
Malnutrition can clearly result from factors other than reduced intake. Malabsorption can occur due to small bowel overgrowth, loss of villous surface secondary to inflammation, and occasionally short bowel due to multiple resections. Active inflammation renders the patient catabolic, with reduced albumin synthesis in the liver, and there may also be significant protein loss into the intestine. Treating active Crohn’s inflammation thus plays an important role in restoring any nutritional deficit.
There are now strong data to support the use of an elemental or polymeric diet as an alternative to corticosteroids in the management of active Crohn’s disease, particularly of the small intestine.22–26 However, opinions vary widely as to when it should be introduced. Some centres use this as first line therapy for ileo-colonic, small bowel and upper gut (including oesophageal) Crohn’s disease even when severely active. Others use it as very much second line therapy, other than in the special situations outlined below.
A considerable problem is with palatability and acceptability of these feeds as the sole dietary constituent, and hence compliance is frequently an issue. Polymeric diets, containing short-chain peptides together with glucose and triglycerides, are generally more palatable and cheaper than elemental foods, which contain simple amino acids and no peptides, and most studies suggest that they are of equivalent efficacy.23–25, 27, 28 Most success with dietary therapy is achieved in units where there is enthusiasm for this approach; where options are limited by disease which is extensive, or refractory to other medical therapies; and in the setting of paediatric and adolescent Crohn’s disease, where there are particular concerns about the impact of steroids on growth.
Patients must tolerate the feed for the 3–12 weeks required to achieve remission. Compliance problems have been ameliorated by the use of fine bore naso-gastric tubes inserted by the patient for overnight feeding, and by endoscopic placement of gastrostomy feeding tubes. Once in remission the patient can be restarted either on a normal diet or preferably an exclusion/hypoallergenic diet.29 Concern remains due to meta-analyses demonstrating that steroids are significantly more effective in treating active Crohn’s disease, and the suggestion of higher relapse rates if remission is achieved by dietary means.25, 30–32 There is some evidence that better therapeutic results are achieved by reducing the long-chain fatty acid composition of the diet.33 Azathioprine is frequently started at the same time as dietary therapy to reduce the 50% relapse rate.
MEDICAL MANAGEMENT OF SEVERE CHRONIC ACTIVE CROHN’S DISEASE
For patients whose Crohn’s disease relapses early or frequently on stopping steroids, or persists on review at 4–8 weeks in spite of these treatments, additional and alternative therapies are required. A variety of immunosuppressants are currently used, although for most this is not a licensed indication. Surgery may also have an important role to play.
Azathioprine is generally the preferred therapy, but there is growing recognition that methotrexate is efficacious in this context and infliximab now provides another option.
Consideration should also be given to use of elemental or polymeric diets in those in whom this has not already been tried, particularly where the disease is extensive and hence not readily amenable to resectional surgery. Even where these diets are not used exclusively, maintenance of nutrition is an important goal and calorie supplements may be required.
Azathioprine (1–2 mg per kg body weight per day) or its metabolite 6-mercaptopurine (dose 0.5–1 mg per kg body weight per day) are the most commonly used second line therapies for small and large bowel Crohn’s disease, including fistulating disease.34–36 These purine analogues have essentially the same mode of action and are effective long-term therapies in 42–60% of patients with chronic active disease. However, they take 8–16 weeks to achieve maximum effect and are thus usually started with a course of oral steroids or dietary therapy.37, 38 Some of the data favour early introduction, with Ewe et al. demonstrating a 76% response at 1 year in a group started on prednisolone and azathioprine vs. 38% on prednisolone alone.37 A recent meta-analysis of randomized controlled trials for the Cochrane foundation showed azathioprine to be effective both in inducing remission (number needed to treat=5) and steroid sparing (number needed to treat=3) in patients previously steroid dependent.39 Corticosteroids can be withdrawn as the immunosuppressants take effect.
The duration of therapy is not yet defined. Early concerns regarding an increased cancer risk with the use of azathioprine appear to be largely unfounded. A retrospective study from France suggests that benefit may continue for up to 4 years, but possibly diminishes after that.40 Our current practice is to continue for 2–4 years provided that the drug is well-tolerated and a good response is achieved. The blood count should be monitored at weeks 1, 2 and 4 and monthly thereafter for evidence of bone marrow suppression. This occurs particularly in individuals homozygous (one in 300) or heterozygous (one in eight) for a thiopurine methyl-transferase polymorphism, which results in reduced enzyme activity and hence reduced drug metabolism. The risk of leukopenia does not diminish with time. In most cases the leucocyte count becomes only mildly depressed, and a dose reduction is adequate. If neutropenia is severe the drug should be stopped and an alternative found. Patients who develop flu-like symptoms, gastrointestinal disturbance, rash or minor abnormalities of liver function tests on azathioprine may respond to dose reduction or switching to 6-mercaptopurine. Available data suggest that the drug is safe in pregnancy. Failure to respond to azathioprine mandates an increase in dose to the maximum 2–2.5 mg per kg body weight per day, and if this dose does not work, an alternative drug such as methotrexate should be considered.
Methotrexate (25 mg intramuscularly once a week) has now been shown in placebo controlled trials to induce remission in patients with chronic active steroid dependent disease, allowing steroid withdrawal in 39% vs. 19% in the placebo arm.41 Furthermore, in those patients who enter remission, it appears to be an effective maintenance therapy over at least 40 weeks.42 The drug is well-tolerated and may act slightly more rapidly than azathioprine. It is clearly contra-indicated in pregnancy. Many centres use oral methotrexate (20–25 mg once a week) for logistical reasons and this appears to have good effect, although no trial data are available for the oral preparation and there are some concerns regarding variable absorption. In our practice, methotrexate is generally used in patients who fail to respond or who are intolerant of azathioprine. We have observed a response rate of approximately 65%.
Infliximab (anti-TNF antibody).
Infusion of infliximab 5 mg per kg body weight over 2 h has recently been licensed for use in severe refractory Crohn’s disease.43–45 At this dose, trial data showed a response rate (fall of CDAI > 70 points) of 81% by 4 weeks, and remission (CDAI < 150) in 33% vs. 4% in the placebo arm.43 Although well-tolerated the drug is expensive and its effects are probably not maintained beyond 12 weeks. Repeated treatments may thus be required and are effective in maintaining remission.46 However, some patients develop human anti-chimeric antibodies (HACAs) if given infliximab after a drug-free interval of 1 year, and these can limit efficacy and cause delayed hypersensitivity reactions. Although a valuable addition to the armamentarium, the place of infliximab in the management of severe refractory disease has yet to be fully worked out. It is clear that this novel therapy alone does not provide a long-term solution to Crohn’s disease, and further immunosuppression or surgery must continue to be considered.
Limited data are available for a number of other immunosuppressants. A recent study suggests that mycophenolate may be useful, although more trial data are required.47 In a multicentre European study, oral ciclosporin (5 mg per kg body weight per day) did not appear to help chronic active Crohn’s disease.48, 49 Studies of tacrolimus to date have been small and uncontrolled.50, 51
SURGICAL TREATMENT OF SEVERE ACUTE AND CHRONIC ACTIVE CROHN’S DISEASE
The predominant role for surgery in Crohn’s disease is as treatment for those patients in whom medical therapies have failed to produce a satisfactory response, and to treat complications. For acute or chronic disease which is neither unduly extensive nor complex, it is generally a case of attempting medical therapies first and if these fail to produce a satisfactory response then offering surgery. For the more complex and extensive cases, the physician and surgeon more frequently manage the patient simultaneously. Timely surgery in the patient with severe inflammatory disease who is failing to settle plays an important role in preventing the development of complications such as perforation, fistulae and abscess formation—features which clearly magnify the complexity of future medical and surgical management.52 For patients with chronic active disease, outcomes are improved by optimizing the patients’ condition prior to surgery. This includes the treatment of any malnutrition (which may require a few weeks of parenteral nutrition), control of sepsis with antibiotics and radiological drainage of abscesses, blood transfusions as required, and so on.
A conservative approach is the abiding principle of surgery for inflammatory Crohn’s disease, with resection of the least amount of bowel possible to reduce future risk of short bowel syndrome. Microscopic disease at the resection margins does not appear to affect relapse rates.54
• Gastroduodenal disease is rare. Medical therapy with corticosteroids and a proton pump blocker may help, although there are no controlled data regarding the latter. Stenosis in the first or second parts of the duodenum is the most common surgical problem, managed by strictureplasty where possible, or by gastro-jejunoscopy.
• Jejunal disease is rare in isolation and usually found in association with ileal disease. Stenosis is the most common indication for surgery and multiple strictures may be present (usually two or three, but occasionally as many as 20). Rather than resection, with its attendant risks for short bowel, strictureplasty is now the preferred surgical method where possible. A catheter or balloon is passed the length of the small bowel to ensure no strictures are missed. Strictureplasty produces very satisfactory symptom response in over 95% of patients. Five percent are complicated by sepsis and 5% by bleeding, which usually settle with conservative therapy.52
• Ileo-colonic disease. Up to 90% of patients with ileo-colonic disease will eventually require surgery, usually for symptoms of obstruction and right ileac fossa pain which have failed to respond satisfactorily to medical therapy. Right hemicolectomy is clearly the operation of choice, and provides an extremely effective means of relieving symptoms and restoring health. Relapse rates are modest even with conservative surgery, and two-thirds of patients undergoing this operation for ileal disease will not require further surgery.53, 55 A right hemicolectomy can be extended if the more distal colon is involved. There are some advocates for the use of endoscopic balloon dilatation of strictures, with or without injection of steroids such as triamcinolone, but there are limited controlled data available and the risks of perforation are not insignificant.
• Colonic disease. As for ulcerative colitis, surgery is usually indicated when inflammatory disease is refractory to medical therapy, either in the acute or the chronic active setting. The most common indication for emergency colectomy is failure to settle with medical therapy, but perforation, obstruction, abscess formation, haemorrhage and toxic dilatation may also necessitate urgent surgery. Colectomy with ileostomy formation, leaving a rectal stump, is the preferred emergency technique.
For patients with chronic active disease, a number of other options may be considered, each with advantages and disadvantages.
• Segmental resection may be considered in some patients where disease is localized, but recurrence rates in the remaining colon are high.
• Total colectomy with ileo-rectal anastomosis should be considered where there is rectal sparing (20% of patients with Crohn’s colitis), normal anal sphincters and no perianal disease. Again there is the risk of relapse in the colon that remains, and up to 50% will eventually require a permanent ileostomy. However, the quality of life benefits from the added stoma-free years may be deemed worthwhile in some patients, particularly bearing in mind the risk of male infertility in patients undergoing proctectomy.
• Proctocolectomy with permanent ileostomy carries the lowest risk of relapse (15–25% at 10 years), but healing of the perineum often takes a long time (4–6 months in up to 30% of patients), and up to 10% may have long-term problems with perianal sinuses and persistent cutaneous Crohn’s disease.53
SEVERE PERIANAL AND FISTULATING DISEASE; EXTENSIVE AND COMPLEX CROHN’S DISEASE
These categories frequently require particularly close co-operation between physician and surgeon, and other members of the multidisciplinary team. The same principles as described above for acute and chronic active disease apply, together with the added complexities that come with sepsis and fistulae. Azathioprine and 6-mercaptopurine have been demonstrated to be effective in closing fistulae in trials as well as a meta-analysis, and these should be considered standard therapies in patients in whom fistulae are troublesome.56 A number of other immunosuppressant regimes have also been studied in small numbers of patients, including ciclosporin, but none are yet commonly used in practice.5, 51, 57, 58
Perianal abscesses in Crohn’s disease must be drained early to prevent continuing destructive damage to surrounding structures, particularly the sphincters. Concurrent active Crohn’s disease must also be treated.
Perianal fistulae only require specific treatment if symptomatic and troublesome—usually indicating connection to an abscess cavity. Active Crohn’s disease elsewhere in the gut, most commonly in the colon, must again be treated. Most fistulae respond to metronidazole and/or ciprofloxacin and corticosteroids, with the addition of azathioprine to maintain remission.34, 36, 59 Low fistulae may be best managed by placing a seton suture around the tract to keep it open and allow drainage of pus. Recto-vaginal fistulae may require subsequent repair using techniques such as vaginal advancement flaps once the Crohn’s disease is in remission.
Severe perianal Crohn’s disease is fortunately uncommon. It should be investigated with MRI scanning, trans-anal ultrasound and examination under anaesthesia, the latter allowing drainage of any frank pus and insertion of setons. In addition to azathioprine, antibiotics may be required for periods of several months in severe disease, and it may be necessary to rotate metronidazole and ciprofloxacin to limit the side-effects of neuropathy and development of resistant organisms. Multiple surgical interventions may be required for the drainage of abscesses and seton insertion, doing the minimum necessary on each occasion to allow fistulae to heal. Fistulae resistant to these therapies may require infliximab.60 Although current trial data are derived from relatively simple fistulating disease, there are anecdotal reports of dramatic response in previously refractory and complex fistulae. The difficulty is that many fistulae re-open after initial successful treatment with infliximab (MRI scans suggest that deep tracts rarely heals even if the skin wound closes); the role for repeated infusions of infliximab in this context is currently unknown.
An alternative that should be considered for severe perianal disease, with or without colonic involvement, is that of defunctioning ileostomy. Diversion of the faecal stream usually results in resolution of inflammation, but relapse rates are high (65% at 18 months) when continuity is restored, and often this option simply buys time. The cumulative risk for proctectomy in ano-rectal Crohn’s disease is 17.5% at 20 years.61
Enterocutaneous fistulae are usually a complication of surgery, and may be associated with an abscess which will require drainage. Associated active disease will require treatment, and any down-stream obstruction must be relieved if the fistula is to heal. Parenteral nutrition is likely to be required for at least 4 weeks, and patients with a high output from their fistula (greater than 200 mL per day) will require a proton pump inhibitor and octreotide to reduce the volume of gastric and intestinal secretion. Patients with a short bowel may also require an appropriate regimen of oral isotonic fluids, and possibly intravenous fluid supplements. If nutrition can be restored and sepsis controlled, and the extent of the fistulae adequately determined by appropriate radiological investigation, resection can be considered. Otherwise a defunctioning operation may be required.
Spontaneous enterocutaneous and intra-abdominal fistulae usually arise from a diseased ileo-caecal segment. The latter may connect to the small bowel or colon, or less commonly to the bladder or vagina. Early surgery with an en bloc resection and repair of any secondary defects is indicated. The role of infliximab in this situation is not currently known.
Extensive and complex Crohn’s disease may incorporate any of the features described in the course of this review. A multidisciplinary approach becomes more important as the complexity increases, and the supervising physician must be vigilant for disease-related problems such as short-bowel syndrome, nutrient deficiencies, osteoporosis and the development of gastrointestinal malignancy. Nutritional support and therapy become increasingly important in disease refractory to pharmacological therapy, and where surgical options are limited by extensive disease and a short small bowel.
MAINTENANCE OF REMISSION
In patients who have suffered with severe Crohn’s disease, maintenance of remission is clearly a desirable objective. Unlike ulcerative colitis, the trial data supporting a role for 5-aminosalicylic acid derivatives in the maintenance of Crohn’s disease remission are at best questionable, and meta-analyses have shown no clear advantage.62 Even for maintenance of post-operative remission, where early trials showed significant benefit, the more recent, largest, and possibly most rigorously structured study did not support their use.63–65 A meta analysis suggests little overall benefit, with the number needed to treat to prevent one relapse being 25.66 In the context of severe disease this might be worthwhile, but the studies were not designed specifically to look at this question.
Although long-term corticosteroids at supraphysiological doses (greater than 7 mg prednisolone per day) do have some effect in reducing relapse rates in those who initially respond, this approach is generally undesirable due to the well-known sequelae of steroid therapy, such as hypertension, diabetes and osteoporosis.1 In spite of the problems, there are some patients who remain steroid dependent, and it is this group in particular who should be monitored and treated for ensuing side-effects.67 Budesonide is associated with fewer side-effects than conventional corticosteroids due to high first pass metabolism in the liver. It does delay relapse for a few months, but trial data suggested that it was no different to placebo at 1 year.12
Azathioprine and 6-mercaptopurine are used to treat refractory Crohn’s disease and effectively maintain remission.38, 40 Higher doses are more effective, with meta-analysis suggesting a number needed to treat of seven, and little evidence supporting low doses (1 mg per kg body weight or less).68 Some centres also use these drugs for post-operative prophylaxis, particularly where there is endoscopic evidence of relapse following surgery (seen in up to 72% of patients at 1 year). Data do now also appear to support the use of methotrexate to maintain remission, at least in patients whose disease was initially controlled by methotrexate.42
Following the lessons of rheumatoid arthritis, it may be that combination therapy from outset, for example, using methotrexate, 5-ASA and steroid, will produce better long-term remission for severe disease than a stepwise introduction of therapy.69
Probably the clearest and most important message to impart to all patients with Crohn’s disease, particularly those with severe disease, is the need to stop smoking. There are a wealth of data demonstrating that smokers suffer much higher rates of relapse and at least double their risk of requiring surgery compared to non-smokers, and there are now good data showing that those who stop smoking rapidly adopt the risk profile of non-smokers.70–73
The recent therapeutic application of a monoclonal antibody in the form of infliximab, and the recognition that thio purine methyl transferase (TPMT) mutations have an important effect on azathioprine metabolism may herald immediate future directions and developments for the treatment of severe Crohn’s disease. A second anti-TNF antibody has already undergone clinical trials and other molecular therapies will inevitably follow as our understanding of Crohn’s disease pathogenesis improves.74 Recombinant IL-10, antibodies to the adhesion molecule α4β7 and inter-cellular adhesion molecule (ICAM) antisense oligonucleotides are just three examples of substances recently studied in clinical trials, and many more are in development, targeted at various steps of the inflammatory cascade.75, 76
Not all therapies will necessarily be new. One of the big hopes for the genetic analysis of inflammatory bowel disease in the short term is that it will allow the rational sub-classification of Crohn’s disease. Using genetically defined homogeneous patient groups, it should be possible to carry out pharmacogenetic trials of existing therapies and identify in which patients they work, in which they don’t, and why. Better targeting of these existing therapies should follow. There is already the suggestion that particular TNF haplotypes might predict the response to anti-TNF antibodies, and with the proliferating knowledge regarding polymorphisms within genes related to drug activity and metabolism, a host of pharmacogenetic studies are waiting to be carried out.
Ultimately the current armamentarium of drugs and therapies available for use in severe Crohn’s disease will be viewed as dangerous, unpleasant and unnecessary. Their relatively low efficacy, unpredictability and poor side-effect profile will be recognized for what they are by future generations of gastroenterologists. The need is for rational new therapies to prevent the development of severe disease and hopefully target the cause of Crohn’s disease, rather than achieve blanket immunosuppression or the blocking of single components within complex immune and inflammatory cascades. Such rational therapies are, however, many years away, and will have to wait for an improved understanding of the genetic and environmental basis of Crohn’s disease.