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Publisher:: Oxford University Press

Print Publication Date:: May 2010

Print ISBN-13:: 9780199204854

Published to Oxford Medicine:: May 2010

DOI:: 10.1093/med/9780199204854.001.1

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Crohn’s disease

Chapter:: Crohn’s disease
Author(s):: Miles Parkes

DOI:

10.1093/med/9780199204854.003.1511_update_002

Update:

Updated information regarding Crohn’s disease pathogenesis, optimization of thiopurine therapy and initiation and cessation of anti-TNF therapy. In particular, evidence for the benefit of combination anti-TNF therapy with thiopurine (from the SONIC study) and criteria for stopping anti-TNF therapy (from the STORI study).

A relevant case history from Oxford Case Histories in Gastroenterology and Hepatology has been added to this chapter.

Updated on 28 November 2012. The previous version of this content can be found here.

Crohn’s disease Case History—A 22 yr old woman presenting with a two-year history of diarrhoea, intermittent abdominal pain and weight loss.

Essentials

Crohn’s disease is a common form of chronic inflammatory bowel disease. Typically involving the terminal ileum, colon, and perineum, it causes patchy transmural inflammation characterized microscopically by granulomata. Common complications include fibrotic strictures, fistulas, and abscesses.

The trigger is unknown but an unregulated mucosal immune response to commensal bacteria drives the chronic inflammation. Variants in several genes involved in innate immunity are strongly associated, with NOD2, interleukin-23, and autophagy pathways all recently implicated. Smoking also increases the risk.

With a pattern of episodic flares, Crohn’s disease has significant morbidity but low mortality. Treatment of acute inflammatory disease is usually with corticosteroids or therapeutic diets; for steroid-dependence or frequent relapse immunosuppression with azathioprine, 6-mercaptopurine or methotrexate is indicated. Anti-tumour necrosis factor (anti-TNFα) antibody therapy can induce rapid remission of aggressive or resistant disease and maintain remission in such cases.

Despite increased use of immunosuppressants 80% of patients require surgery in the long term, most commonly for ileal stricturing. Timely, conservative surgery is the key, minimizing the length of small-bowel resected and using laparoscopic approaches where possible. For colonic disease requiring surgery, segmental colectomy or subtotal colectomy with ileorectal anastomosis are preferred, but significant rectal or perianal involvement may require proctocolectomy and ileostomy.

Perianal Crohn’s disease is treated medically with antibiotics, azathioprine, and anti-TNF antibody therapy; and surgically with abscess drainage and placement of seton sutures through fistulas where possible, rather than more radical options.

Introduction and history

Crohn’s disease is a form of chronic, relapsing inflammatory bowel disease characterized by discontinuous segments of transmural inflammation. It can affect any part of the gastrointestinal tract but most commonly involves the terminal ileum, colon, and perineum. The eponymous term ‘Crohn’s disease’ derives from the index description of chronic ileal inflammation in young people in 1932 by Crohn, Ginzburg, and Oppenheimer. However, many much earlier reports describe what would now be called Crohn’s disease. Colonic Crohn’s disease was formally differentiated from ulcerative colitis by Lockhart-Mummery and Morson in 1960, although recent genetic studies suggest, perhaps unsurprisingly, that they are closely related.

Aetiology

Precise pathogenic mechanisms are unknown, but Crohn’s disease evidently results from a complex interplay of genetic and environmental factors producing an excessive, unregulated inflammatory response to luminal microflora in susceptible individuals. The trigger has not been identified.

Susceptibility to the initial trigger may result from a defective mucosal barrier: either increased intestinal permeability, allowing luminal antigens to access the mucosal immune system, or aberrant innate immunity, which would increase risk of microbial invasion. Evidence from genetic studies increasingly implicates the latter in Crohn’s disease, the former perhaps being more relevant in ulcerative colitis. Early failure to control microbial ingress may lead to activation of alternative, adaptive immune pathways mediated by CD4+ T cells. In Crohn’s disease these are predominantly Th1 and Th17 cells, secreting signature cytokines interferon (IFN)-γ/interleukin (IL)-2 and IL-17 respectively, with TNFα, IL-10, and IL-23 also being critical mediators.

Environmental factors

The clearest environmental association is with smoking, which more than doubles the risk of developing Crohn’s disease while being protective against ulcerative colitis. The mechanism is unclear. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the oral contraceptive pill are also associated, the former perhaps by increasing intestinal permeability—well recognized to precede flares of Crohn’s disease. Interestingly, 10% of healthy first-degree relatives of Crohn’s disease patients have increased intestinal permeability, suggesting a heritable basis.

Many patients are concerned about dietary precipitants for Crohn’s disease. Excess refined sugar and lack of fibre have been noted in retrospective studies, but may reflect dietary accommodation to early symptoms. Response to therapeutic diets also suggests food antigens are important but no single foodstuff is consistently associated.

Microbiological determinants represent obvious potential triggers, and self-limiting infections such as yersinia do precede Crohn’s disease in some instances. More contentiously, specific chronic infections might cause the persisting inflammation. Advocates of Mycobacteria paratuberculosis, which causes the granulomatous intestinal inflammation of Johne’s disease in cattle, highlight its common presence in pasteurized milk and detection of its DNA in Crohn’s ulceration. Furthermore, recent genetic studies have highlighted substantial overlap between Crohn’s disease susceptibility genes and those for leprosy and mendelian susceptibility to mycobacterial disease (MSMD). However, epidemiological evidence shows no clustering of Crohn’s disease in livestock farmers, and antituberculous therapy is not effective in Crohn’s disease. The contribution of mycobacteria to disease aetiology thus remains speculative.

A role for commensal bacteria appears more secure, particularly in perpetuating intestinal inflammation after the initial trigger. Clinical evidence comes from attenuation of Crohn’s disease inflammation following diversion of the faecal stream with ileostomy; while experimentally, intestinal inflammation in animal models of inflammatory bowel disease is markedly reduced in ‘germ-free’ conditions. Some commensals are particularly implicated, including bacteroides and adherent invasive Escherichia coli, while others confer protection, including Faecalibacterium prausnitzii and ‘probiotic’ strains of lactobacilli and bifidobacter.

Genetic determinants

Although environmental influences are clearly important, it is genetic studies that have made most progress in recent years. The effect sizes for most confirmed susceptibility genes are modest but they highlight critical molecular pathways predisposing to Crohn’s disease. The major theme emerging is the importance of the early host immune response to bacterial ingress—particularly innate immunity.

NOD2, the first Crohn’s disease gene identified, encodes an intracellular receptor for bacterial muramyl dipeptide and (by poorly understood mechanisms) modulates toll-like receptor signaling and activation of NF-κB, a transcription factor for several proinflammatory mediators. For NOD2 heterozygotes the risk of Crohn’s disease is doubled compared to wild type, while homozygotes have 17-fold increased risk. Interestingly there is significant heterogeneity, both for disease (NOD2 variants are specifically associated with ileal Crohn’s disease) and ethnicity (no NOD2 mutations are found in Japanese patients).

Signals identified by genome-wide association scans in Crohn’s disease converge on two other key immune pathways. One is the activation of naive CD4+ T cells by IL-23. Confirmed association with variants in genes for the IL-23 receptor and IL-12B (which encodes a subunit common to IL-12 and IL-23) among other components of this pathway strongly corroborates functional experiments in mouse models, which also implicate IL-23 in chronic intestinal inflammation.

Another key component is autophagy. Replicated association at two separate genes, ATG16L1 and IRGM, first highlighted autophagy, and NOD2 mutations are now known to disrupt this previously unsuspected pathway. Autophagy is the mechanism by which cells engulf, compartmentalize, and digest cytoplasmic debris and intracellular bacteria. Its disruption permits prolonged survival of several intracellular microorganisms—perhaps important for the intracellular bacteria postulated to play a role in Crohn’s disease pathogenesis, including adherent invasive E. coli and M. paratuberculosis.

In which cell the primary genetic abnormalities impact remains unknown (prime candidates being intestinal macrophages, dendritic cells, T cells, and epithelial cells) but already the idea that Crohn’s disease results from an ‘overactive’ immune system appears simplistic. Increasing laboratory and clinical evidence suggests that at least some elements of the immune response are defective. Whether intestinal inflammation is driven by failure to eliminate intracellular infection, inappropriate activation of adaptive immune pathways, failure of immune regulation, or some other mechanism entirely must await further investigation.

Pathology

Crohn’s disease can affect any part of the gastrointestinal tract but most commonly causes ileocaecal (40%), exclusively ileal (30%), or exclusively colonic (25%) inflammation with or without perianal involvement (25%). Diffuse small-bowel, upper gut, or oral Crohn’s disease are less frequent. Colonic disease often spares the rectum. These patterns typically remain stable in any given patient over time. Ulcers are usually present, with appearances varying from small aphthous lesions overlying lymphoid aggregates to scattered punched-out, serpiginous, longitudinal or pleomorphic ulcers (see Fig. 15.11.2). Inflammation is patchy, giving rise to ‘skip lesions’, and transmural—manifest as deep ulceration and cobblestoning endoscopically, and fat wrapping at surgery. The bowel wall is usually thickened, often producing luminal stenosis, and the mesentry oedematous with regional lymph node enlargement.

Fig. 15.11.2

Colonoscopic appearance of linear and pleomorphic ulceration of Crohn’s disease.

Histologically Crohn’s disease is characterized by a patchy chronic transmural inflammatory infiltrate, maximal in the submucosa and lamina propria. This consists of lymphocytes, characteristically organized as lymphoid aggregates, macrophages and plasma cells. Acutely, neutrophils infiltrate around crypts producing cryptitis. Fissuring ulcers can penetrate deeply, sometimes to the serosal surface to produce fistulas, and noncaseating epithelioid granulomata formed from macrophages and giant cells may be found at any level—present in up to 60% of cases (Fig. 15.11.1). Typically in the colon there is preservation of goblet cell numbers and crypt architecture compared to ulcerative colitis.

Fig. 15.11.1

Crohn’s disease affecting large bowel, showing fissuring ulceration (narrow arrow) and transmural inflammation with a ‘Crohn’s rosary’—lymphoid aggregates studded along the outer border of the muscularis propria (broad arrow).

(Courtesy of Dr Vicki Save, Addenbrooke’s Hospital, Cambridge.)

Epidemiology

Crohn’s disease can affect people of any age but peak incidence occurs in early adulthood, with a smaller peak in the seventh decade. There is a marginal predominance in women and 15% of patients have an affected relative. Crude annual incidence in Western countries ranges from 1.8 to 10 per 100 000, with a north–south gradient (higher in the north) across Europe and North America. Incidence is highest in Ashkenazi Jews and low but increasing in Japan (0.25 per 100 000).

Longitudinal studies from the United States of America and Denmark showed that Crohn’s disease incidence increased significantly (2.7-and 6-fold respectively) between 1960 and 1980 but has since stabilized. This contrasts with the currently increasing incidence in paediatric populations and non-Western societies, perhaps reflecting adoption of ‘Western’ lifestyles. Increased awareness and improved diagnostics have undoubtedly also contributed.

Estimates of Crohn’s disease prevalence also vary significantly, in part according to ascertainment method. Thus population- and primary-care-based surveys in the United Kingdom put the prevalence as high as 140 to 210 per 100 000, while studies in secondary/tertiary care are lower at 70 to 100 per 100 000. Either figure indicates that the burden of disease is substantial in terms of both morbidity and cost. Best estimates of direct health care costs suggest an average figure of £3300/patient-year for Crohn’s disease (2004 data), but with large variation and much higher costs with severe disease or complications requiring hospitalization.

Clinical features

Crohn’s disease A 22 yr old woman presenting with a two-year history of diarrhoea, intermittent abdominal pain and weight loss.

The clinical presentation of Crohn’s disease varies from ‘classical’ to diagnostically challenging and nonspecific. With severe disease patients may have systemic upset, with fever, tachycardia, and anaemia. More often, however, a modestly raised C-reactive protein (CRP) and vague or irritable-bowel-like symptoms may be the only clues mandating further investigation. Many patients report remitting and relapsing symptoms for years before the diagnosis is made. A family history of inflammatory bowel disease and smoking history should be sought.

For patients with established disease the Harvey–Bradshaw index provides a simple objective assessment of activity, while the Crohn’s disease activity index requires symptom diaries plus laboratory data, limiting it to clinical trials. The Inflammatory Bowel Disease Questionnaire (IBDQ) is the best validated quality of life tool.

Symptoms

Symptoms are significantly determined by site of intestinal inflammation and typically include lower abdominal pain, diarrhoea, anorexia, and weight loss. Tiredness, malaise, sweats, and extraintestinal manifestations can be prominent.

Abdominal pain reflects gut wall ulceration and mesenteric oedema, and often localizes to the right iliac fossa with ileocaecal disease. It may be colicky, exacerbated by eating and associated with other obstructive features such as vomiting or bloating, or constant, reflecting the presence of deep ulceration. The absence of tenderness suggests a fibrotic stricture—usually the small bowel. Abdominal pain due to coincident gallstones or renal stones, both associated with Crohn’s disease, can cause confusion.

Weight loss is common with active Crohn’s disease, particularly involving the small bowel, so patients should be weighed at each clinic visit. Contributory factors include food avoidance due to abdominal pain or mouth ulceration, intestinal protein loss, catabolism induced by inflammation or sepsis, and malabsorption reflecting the combination of diffuse small-bowel disease, resection, and bacterial overgrowth.

Diarrhoea occurs in 80% of patients. Bowel frequency correlates with inflammatory activity, particularly in the colon, with bacterial overgrowth and ileal resection potentially contributing. Bleeding per rectum is less common than in ulcerative colitis, as is urgency—unless the rectum is involved or the anal sphincter damaged. An important point: many Crohn’s disease patients consider three to four semi-solid bowel evacuations per day to be ‘normal’ and it is the change from baseline, including nocturnal frequency, which is important in assessing disease activity.

Perianal symptoms are often mild, even with apparently severe involvement: pain usually indicates an abscess; fistula discharge is common; and anal stricture may produce constipation or tenesmus.

Signs

Many patients with even severely active Crohn’s disease appear deceptively well. A minority are anaemic or malnourished. A persisting tachycardia may point to dehydration, severe inflammation, or sepsis. The oral cavity should be inspected for ulceration and glossitis, and nails for clubbing.

The commonest abnormal examination finding is right iliac fossa tenderness, often with associated fullness or a mass due to thickened and matted bowel loops. Equivalent findings may be found over any affected bowel segment.

Anorectal examination may reveal various signs from violaceous fleshy or ‘woody’ skin tags to anal fissure, ulcer, abscess, and fistulas. Anal stenosis may be detected.

Signs related to specific complications may be evident—e.g. fever and tachycardia with intraabdominal collection, distension and high-pitched bowel sounds with obstruction, and so on.

Extraintestinal manifestations

Extraintestinal manifestations of Crohn’s disease commonly affect the mouth, joints, skin, and eyes and less commonly the liver and lungs. These are more frequent with colonic involvement and may precede intestinal symptoms.

Aphthous mouth ulcers are usually associated with active intestinal inflammation. These should be distinguished from haematinic deficiency (glossitis, angular cheilitis), oral candida, and particularly oropharyngeal Crohn’s disease—which usually causes fissuring and thickening of the lips but can present with deep sulcal ulceration and buccal cobblestoning. There is overlap with orofacial granulomatosis where 60% have asymptomatic intestinal lesions of Crohn’s disease. Both oral Crohn’s disease and orofacial granulomatosis can be successfully treated with a low-benzoate, low-cinnamon diet or topical steroids.

Joint involvement is seen in up to 30% of Crohn’s disease patients. It ranges from arthralgia to inflammatory arthritis and includes ankylosing spondylitis. The inflammatory arthritis can be an asymmetric large-joint arthropathy with pain and effusions prominent with active intestinal inflammation, or a symmetrical small-joint arthropathy. Each has distinct genetic associations. Where possible NSAIDs should be avoided as they increase gut permeability and can trigger a Crohn’s disease flare.

Eczema and psoriasis often flare with active Crohn’s disease, but the most common specific dermatological manifestation is erythema nodosum. Usually found at initial presentation, it settles with resolution of bowel inflammation rarely to recur.

Ocular inflammation usually presents as uveitis, episcleritis, or conjunctivitis. Crohn’s disease patients developing red eye, eye pain, and/or visual disturbance should receive emergency ophthalmic assessment. Persistently abnormal, particularly cholestatic liver function tests should prompt investigation including magnetic resonance cholangiography for primary sclerosing cholangitis.

Differential diagnosis

The differential diagnosis of Crohn’s disease depends on its specific presentation.

Ileitis in young patients closely mimics appendicitis, while chronic symptoms are often diagnosed as irritable bowel syndrome. In older patients colonic, particularly caecal, carcinoma must be considered. Clinicians often rely on a raised CRP or faecal calprotectin to identify patients with irritable-bowel-like symptoms needing further investigation. However, strong clinical suspicion (e.g. family history of Crohn’s disease) may warrant further investigation despite normal screening tests.

With demonstrated intestinal inflammation, distinguishing inflammatory bowel disease from infection is the commonest challenge. Occasionally the diagnosis of Crohn’s disease cannot be confirmed until the second flare. In known Crohn’s disease patients, when abdominal symptoms recur the challenge is distinguishing active inflammation from other causes. Most of the latter are discussed below (see ‘Complications’) but it is noteworthy that a history of inflammatory bowel disease increases susceptibility to infectious enterocolitis, and that irritable bowel syndrome is as common in individuals with Crohn’s disease as in the general population. Failure to appreciate these points can cause both diagnostic confusion and inappropriate treatment choices such as over-use of corticosteroids.

Yersinia enterocolitica and M. tuberculosis can mimic Crohn’s disease, sharing an ileocaecal predilection and causing acute and chronic inflammation respectively. However, the cause of most cases of acute ileitis is never determined and only a minority develop Crohn’s disease. Campylobacter, shigella, and salmonella cause an acute colitis usually with fever and sometimes with a reactive arthritis and Clostridium difficile is increasingly found outside conventional risk groups. E. coli can cause colitis, the 0157 serotype triggering haemolytic uraemic syndrome. Rarer causes of enterocolitis include amoebae, schistosomiasis, and cytomegalovirus, emphasizing the need for careful microbiological and histopathological assessment. Rectal and perianal ulceration can be caused by sexually transmitted infections such as gonorrhoea, syphilis, and lymphogranuloma venerium.

Noninfectious mimics of Crohn’s disease include drugs, ischaemia, Behçet’s disease, lymphoma, small-bowel carcinoma, solitary rectal ulcer, and radiotherapy. NSAIDs can produce intestinal inflammation and rarely ‘diaphragm’ strictures, and Fleet phospho-soda colonoscopy bowel preparation commonly causes rectal aphthoid ulceration with focal active colitis on histopathology. Nicorandil can produce oral and deep perianal ulceration, and mycophenolate mofetil occasionally causes right colonic ulceration. Ischaemic colitis can mimic Crohn’s disease with segmental involvement and solitary rectal ulcers can be large and pleiomorphic but histopathology discriminates. Diverticulitis can mimic Crohn’s disease clinically and histopathologically: colonoscopic biopsies from a diverticular segment must be labelled as such.

For colonic inflammation the major differential diagnosis for Crohn’s disease is ulcerative colitis. Differentiation is possible for about 95% of cases (Table 15.11.1), leaving 5% as indeterminate or, more accurately, unclassified due to equivocal appearances. Ulcerative colitis can mimic Crohn’s disease with a prominent caecal patch of inflammation well recognized in distal ulcerative colitis, or where inflammation becomes patchy on treatment.

Table 15.11.1 Features distinguishing Crohn’s disease from ulcerative colitis

	Crohn’s disease	Ulcerative colitis
Clinical features
Bloody diarrhoea	Uncommon	Common
Perianal disease	Common	Uncommon
Abdominal mass	Common	Rare
Endoscopy/radiology
Rectal inflammation	Uncommon	Defining feature
Distribution	Patchy	Continuous
Ulceration	Pleomorphic, deep	Superficial, fine
Strictures/fistulas	Characteristic	Rare
Histology
Depth	Transmural	Superficial
Infiltrate	Lymphocytes, macrophages, plasma cells	Neutrophils, plasma cells, eosinophils
Granulomas	Characteristic	Confined to ruptured crypts

Clinical investigation

With any significant acute enterocolitis excluding infection is critical. Three stool samples should be sent for microscopy, culture and C. difficile toxin assay. Serological tests for yersinia and polymerase chain reaction for cytomegalovirus should also be requested where appropriate.

For chronic symptoms a few baseline tests provide important diagnostic indicators. Faecal calprotectin, although not widely available, is highly sensitive for intestinal inflammation. On blood tests an even modestly elevated CRP or ESR is consistent with active Crohn’s disease, sometimes accompanied by elevated platelet and neutrophil counts and a low serum albumin. The latter reflects cytokine-mediated down-regulation of hepatic synthesis and intestinal protein loss. Anaemia is common, and multifactorial in origin; ferritin, vitamin B₁₂, and folate should be checked. Liver and renal function tests and coeliac serology are advisable. Anti-Saccharomyces cerevisiae antibody assays are positive in 50 to 75% of cases but add little beyond conventional investigation and are not widely used. Plain abdominal radiography helps assessment of severe diarrhoea or possible obstruction, although increasingly CT is the investigation of choice for the latter.

Where baseline tests indicate possible Crohn’s disease, choice of next investigation depends on clinical context. Ileocolonoscopy with biopsies is highly sensitive for Crohn’s disease presenting with diarrhoea. Appearances vary, but Crohn’s disease hallmarks are segmental inflammation with pleomorphic ulceration and cobblestoning, most commonly ileocaecal (Fig. 15.11.2). Endoscopists should biopsy the rectum and intervening normal colon where inflammation is patchy to aid histopathological interpretation.

Where abdominal pain predominates, the choice usually lies between CT enterography and barium small bowel radiology (enteroclysis having higher sensitivity for subtle mucosal change than follow-through)—with abdominal ultrasound scanning or MR enteroclysis alternatives in some centres (see Chapter 15.3.3), and capsule enteroscopy presenting another sensitive modality for subtle small-bowel lesions. The goal is to identify small-bowel ulceration, oedema and luminal stenosis (Fig. 15.11.3). Cross-sectional modalities also show wall thickening and inflammatory change in the mesentry, while dynamic studies (ultrasound, enteroclysis) are particularly helpful in assessing obstruction.

Fig. 15.11.3

A long ileal stricture shown on barium small-bowel radiology.

(Courtesy of Dr Nicholas Carroll, Addenbrooke’s Hospital, Cambridge.)

Special tests

◆ MRI perineum—detailed anatomical assessment of complex perianal fistulas
◆ Sinograms—to delineate enterocutaneous fistulas
◆ ⁹⁹Tc HMPAO-labelled white cell scans—detect and localize intestinal inflammation
◆ Capsule endoscopy—highly sensitive for subtle small-bowel ulceration; avoid in stricturing disease

Criteria for diagnosis

No single feature is sufficient or necessary to diagnose Crohn’s disease. Instead, diagnosis is based on cumulative clinical, laboratory, radiological, endoscopic, and histopathological evidence. This is usually straightforward, but where uncertainty exists the multidisciplinary team should carefully review the evidence.

Treatment

Overview

Treatment of Crohn’s disease must be tailored to the individual. Patients need a consistent medical approach underpinned by information and support, e.g. from specialist nurses and national patient organizations (see ‘Useful websites’). Nutritional deficits must be corrected, with medical therapy for active disease and timely surgery for refractory inflammation or complications. Treatment should be escalated according to disease severity and clinical progress. Mucosal healing is the goal and probably reduces risk of complications. Those with severe disease should be admitted to hospital for intravenous corticosteroids, fluids and electrolytes, and close monitoring. Most improve within 5 to 7 days. Site of disease affects treatment choice, as does the patient’s previous experience and views regarding tolerability and risks vs benefits. Prospectively evaluated prognostic biomarkers are currently lacking, but Crohn’s disease often behaves more aggressively in those with early age of onset, diffuse disease or deep ulceration, marked perianal involvement, early requirement for steroids, and prominent extraintestinal manifestations. In such patients, and those with recurrent relapse, maintenance immunosuppressive or biological therapy must be considered early. The clinician must synthesize all these strands in formulating an appropriate, individualized treatment plan.

Smoking

All Crohn’s disease patients who smoke should be advised to stop. This halves risk of relapse.

Diet and nutrition

Dietetic assessment and advice is critical, particularly in patients who have lost weight. The large majority should be fed or supplemented enterally. Parenteral nutrition is reserved for those with intestinal failure due to obstruction, high output fistula, or short bowel syndrome.

For Crohn’s disease affecting the upper gastointestinal tract and small bowel, therapeutic diets can—by poorly understood effects on mucosal immunity and gut flora—suppress inflammation. Amino acid (‘elemental’), peptide, and protein-based liquid feeds are equally effective, being nutritionally replete and used exclusive of all other foods for 2 to 4 weeks. Disease remission occurs in 40 to 80% of patients able to tolerate them.

Advantages of therapeutic diets include rapid nutritional restitution and avoidance of corticosteroids—limiting their adverse impact on growth (in children), osteoporosis, and superadded sepsis. Limitations mainly relate to palatability and frequency of early relapse. Specialist dietetic supervision, offering choice of flavour or preparation, and building gradually towards calculated nutritional requirements greatly increases adherence. Nasogastric or gastrostomy tube feeding are occasionally required. Successful transition to eating should start with a basic low fat, low fibre exclusion diet with phased reintroduction of normal foods over several weeks to identify specific dietary intolerances. This in itself can produce prolonged remission, although addition of immunomodulatory therapy may be required.

Patients with a stricture should have a low-residue diet to avoid bolus obstruction (avoiding sweetcorn, apple skins, etc.); and lactose intolerance is common in Crohn’s disease requiring a lactose-free diet with calcium supplementation. Oral Crohn’s disease often responds to a low-benzoate, low-cinnamon diet.

Medical therapy

5-Aminosalicylates

Early randomized controlled trials of sulphasalazine in active Crohn’s disease showed nonsignificant advantage over placebo, but subgroup analysis suggested possible benefit in colonic Crohn’s disease. Mesalazine also lacks efficacy in Crohn’s disease. Of six methodologically rigorous trials, some indicated modest benefit but this was not significant on metaanalysis. There is a strong case for dropping mesalazine from the treatment algorithm of mild to moderately active Crohn’s disease.

Mesalazine should also be abandoned as maintenance therapy following medically induced remission, because of its demonstrated lack of efficacy. After many years on treatment many patients may be resistant to the idea of stopping (indeed, may report symptom recurrence). A pragmatic approach is to try a slow wean.

After surgical resection maintenance mesalazine may confer some benefit, although the effect size is small (number needed to treat (NNT) = 11 to prevent one relapse at 12 months) and appears restricted to exclusively small-bowel disease. Given the cost and inconvenience it should be reserved for selected cases, and only after more effective measures such smoking cessation.

Antibiotics

Antibiotics can successfully treat perianal abscesses, discharging fistulas, and small-bowel bacterial overgrowth complicating Crohn’s disease. Metronidazole with or without ciprofloxacin is best and may be required for several weeks. Some clinicians recommend antibiotics for active Crohn’s colitis but supporting trials evidence is modest. A randomized controlled trial of antimycobacterial therapy for Crohn’s disease showed no benefit over placebo.

Corticosteroids

For most gastroenterologists, corticosteroids constitute the therapeutic mainstay for active Crohn’s disease. They induce symptomatic remission or satisfactory clinical response in 80% of patients with active disease. Typically given as a course of oral treatment reducing over 6 to 8 weeks, the conventional starting dose is prednisolone 40 mg/day. Smaller starting doses appear less effective. Severe disease mandates hospital admission for intravenous therapy with hydrocortisone (100 mg four times daily) or methyl prednisone (40 mg twice daily).

Corticosteroid side effects can be mitigated by using oral budesonide, formulated for ileocaecal release. High first-pass hepatic metabolism ensures low systemic availability. The efficacy of budesonide approaches that of prednisolone. Where the latter is required, e.g. for more severe and extensive disease, calcium and vitamin D with or without oral bisphosphonate should be co-prescribed to limit osteoporosis.

Long-term corticosteroid therapy is ineffective and should be avoided in Crohn’s disease. For the 35 to 40% of patients relapsing frequently off steroids (e.g. at least two relapses a year) or unable to wean without relapse, immunosuppressive or biological therapies are mandated.

Immunosuppressants

Azathioprine and 6-mercaptopurine are the most commonly used immunosuppressants, with methotrexate second-line and alternatives such as tacrolimus and thalidomide used less frequently. Where remission is maintained the vogue is towards increased duration of therapy—driven by evidence of increased risk of relapse on stopping even after many years in remission.

Azathioprine and 6-mercaptopurine

The thiopurines azathioprine (2–2.5 mg/kg) and 6-mercaptopurine (1.5 mg/kg) are steroid-sparing and effective in maintaining remission in Crohn’s disease (NNT = 3). They inhibit purine synthesis via 6-thioguanine triphosphate to prevent leucocyte proliferation. Azathioprine or mercaptopurine take up to 16 weeks to work and should be considered early for aggressive disease, severe perianal disease, steroid-dependence or patients requiring two or more courses of corticosteroids per year. Treatment should continue for at least 4 years when effective and well tolerated—and often longer.

Some 10 to 20% of patients will be intolerant of thiopurines due to myalgias, nausea, rash, mild hepatitis, or cytopenias, and occasionally pancreatitis (2%). Risk of lymphoma appears slightly increased but it remains extremely rare. Patients should be warned of possible profound neutropenia and need regular monitoring of blood count and liver function, particularly following commencement or dose increase. Minor elevations of liver enzymes, lymphopenia, and macrocytosis are not significant.

Variation in the thiopurine methyltransferase (TPMT) gene affects efficacy and safety of thiopurines. 1 in 300 Europeans have negligible enzyme activity and risk severe neutropenia—preventable by measuring TPMT activity or genotype before starting therapy. However subsequent blood test monitoring is still required. TPMT heterozygotes are predisposed to thiopurine side effects, and may respond to lower doses.

Crohn’s disease Where toxicity develops, switching from one thiopurine to the other often helps, despite their chemical similarity. For patients seemingly unresponsive or intolerant, doses should be pushed to the limit of the dosing range or tolerability for 16 weeks before trying alternatives. Monitoring of thiopurine metabolites 6TGN (the active moiety) and 6MMP (a by-product which can induce hepatotoxicity) can help to optimize therapy—for example, checking compliance, increasing doses where 6TGN levels fall below the target range, or adding allopurinol and reducing initial thiopurine doses by 75% in individuals who develop abnormal LFTs due to preferential ‘shunting’ towards 6MMP.

Methotrexate

Methotrexate is also effective for inducing and maintaining steroid-free remission in Crohn’s disease. The index randomized controlled trial used an induction dose of 25 mg/week and 15 mg/week maintenance given intramuscularly. Most centres now use oral methotrexate at these doses—supported by retrospective evidence of efficacy. Blood test monitoring is again advised. Methotrexate is teratogenic and should be avoided in women of child-bearing potential.

Other immunosuppressants

Randomized trial evidence is lacking for other immunosuppressants. From available data tacrolimus appears promising for refractory inflammatory disease and closing fistulas, and thalidomide may have a short-term role but is limited by toxicity. Oral ciclosporin is not effective.

Biological therapies

Infliximab and adalimumbad are effective treatments for severe, refractory Crohn’s disease whether acute or chronic. Both are monoclonal antibody therapies targeting TNFα, neutralizing circulating TNFα, mediating antibody-dependent cellular cytotoxicity, and inducing T-cell apoptosis. The ACCENT 1 study showed 60% of patients with active luminal Crohn’s disease experienced rapid improvement of symptoms following one intravenous infusion of infliximab (5 mg/kg). Subsequent data demonstrated benefit in closing fistulas, healing ulcerated mucosa, and maintaining steroid-free remission in 30 to 50% of patients responding to initial induction and then given 8 weekly infusions of infliximab. Improved quality of life and reduced hospitalization significantly offset the high treatment costs. The newer, subcutaneously administered anti-TNF antibody therapies such as adalimumab and certolizumab appear equally effective, at least with regard to luminal disease.

Anti-TNF therapies are generally well tolerated but major side effects include life-threatening infection (sepsis must be excluded and abscesses drained before treatment), reactivation of tuberculosis (mandating screening), infusion reactions including anaphylaxis, and increased risk of lymphoma. The SONIC study showed the combination of infliximab and azathioprine to be significantly more effective than either alone at inducing and maintaining remission, and anti-TNF therapies should thus routinely be combined with immunomodulator therapies. For steroid-refractory or -dependent Crohn’s disease where thiopurines have not been tried, doses not maximized, or insufficient time allowed, infliximab may provide a therapeutic ‘bridge’ to an optimized thiopurine regime. Infliximab may then be withdrawn. Where Crohn’s disease flares in spite of an optimized thiopurine regime, or patients are intolerant of immunosuppressants, regular anti-TNF antibody therapy may be required long term. Questions relate to treatment duration. The STORI study suggested that 50% of individuals in ‘deep remission’ with normal inflammation markers and mucosal healing at endoscopy remain well a median of 2 years after stopping infliximab but continuing immunomodulator therapy. Nearly all of those who relapsed safely and effectively recaptured remission starting back on infliximab.

Anti-TNF antibody therapies appear less effective in smokers, patients with small-bowel disease, and those without raised CRP. Concerns regarding infliximab efficacy dwindling over time have been reduced by the arrival of the alternatives adalimumab and certolizumab.

Other therapies

Several novel therapies are currently being evaluated. These include antibodies targeted at adhesion molecules (natalizumab demonstrated efficacy but causes demyelination; vedolizumab is more specific and safer) and proinflammatory cytokines, antisense intercellular adhesion molecule-1, inhibitors of chemotactic factors, and a variety of small molecules. Given recent data highlighting the central role of IL-23 and autophagy in Crohn’s disease, these represent exciting potential therapeutic targets.

Surgery

Despite the substantially increased use of immunosuppression since 1980, surgery is still required in 80% of patients with Crohn’s disease long term. The two main indications are refractory inflammation and complications of disease (the latter are discussed in the next section). Close collaboration between experienced supervising physicians and surgeons, and open discussion with the patient regarding treatment options, facilitates joined-up clinical management.

Surgery for refractory Crohn’s disease should be timely and conservative. Increasingly, laparoscopic approaches are used. Timeliness means patients not enduring medical therapies when it is clear they are not working, nor being propelled toward surgery before it is warranted (e.g. for radiologically severe but minimally symptomatic strictures). Patients should be involved in discussions regarding long-term efficacy and safety of second-line medical therapies vs risks, benefits, and expected outcomes of surgery.

Conservative surgery minimizes risk of long-term harm, particularly short-bowel syndrome. Thus strictureplasties (incising longitudinally and suturing vertically) effectively open short strictures and are favoured over small-bowel resections where possible, while for resections only macroscopically involved bowel is removed. For colonic disease panproctocolectomy carries the lowest risk of relapse but at the cost of permanent ileostomy. Segmental colectomy or sub-total colectomy with ileorectal anastomosis are usually preferred where possible. Surgery for perianal sepsis and fistulas usually involves drainage and placement of seton sutures, together with medical management, rather than more aggressive interventions which carry high risk of nonhealing wounds or faecal incontinence.

Optimization for surgery includes dietitian-supervised correction of any malnutrition. Oral supplements are preferred but parenteral nutrition may be required. Corticosteroids should be minimized to limit adverse impact on wound healing—but evidence indicates continued azathioprine/mercaptopurine therapy perioperatively reduces complications, including sepsis. For severe coloanal Crohn’s disease a defunctioning ileostomy should be considered. Technically straightforward, diverting the faecal stream usually settles coloanal inflammation, relieving symptoms and permitting subsequent elective panproctocolectomy on a clinically fit patient. Whether some patients might avoid colectomy and be maintained in remission on stoma reversal if started on thiopurine or biological therapy is unclear.

Approximately one-half of patients requiring surgery for small-bowel Crohn’s disease require a repeat operation within 10 years, especially smokers. For patients deemed at high risk of early postoperative relapse, e.g. those requiring resections in quick succession or with residual diffuse disease, azathioprine should be considered. Increasingly clinicians recommend colonoscopy for all patients 6 months post-ileal resection, with institution of azathioprine in those with perianastomotic ulceration. This is a sensible strategy but its long-term benefit has yet to be established in prospective trials.

Complications and their management

The complications of Crohn’s disease confer significant morbidity and some mortality.

Acute complications of Crohn’s disease

◆ Venous thromboembolism is common and potentially life-threatening, requiring vigilance and low-molecular-weight heparin during all hospital admissions.
◆ Intestinal obstruction manifesting as colicky pain, vomiting, distension, and absolute constipation presents acutely or subacutely and is due variably to food bolus, active inflammation (with mural oedema), adhesions, and fibrotic stenosis. Strictures usually affect the terminal ileum but can occur anywhere from oesophagus to anal canal. Inflammatory markers and abdominal CT constitute key investigations. Episodes usually resolve with conservative management: nil by mouth, intravenous fluids, corticosteroids, and nasogastric tube for pronounced vomiting. Recurrent episodes refractory to low-residue diet (exclusion of mushrooms, sweetcorn, vegetable skins, etc.) and increased immunosuppression (if evidence of inflammation) require endoscopic dilatation or surgical resection/strictureplasty.
◆ Intestinal perforation, caused by deep fissuring ulcers characteristic of Crohn’s disease, presents acutely as peritonitis but symptoms may be considerably masked by corticosteroid therapy. Following diagnostic confirmation, usually on CT, urgent surgical resection is mandated. Fortunately, free perforation is rare as fibrotic serosal reaction and fat wrapping contain most leaks.
◆ Toxic megacolon is rare in Crohn’s disease, but those with acute severe colitis and systemic upset (fever, tachycardia, etc.) require close monitoring and serial abdominal radiographs. Where transverse colonic diameter is more than 6 cm at presentation and this persists despite 24 to 48 h maximal medical therapy, or develops during such treatment, colectomy is mandated to prevent perforation.
◆ Severe bleeding is rare. After resuscitation, therapeutic options include endoscopic haemostasis (adrenaline injection and clipping), angiographic occlusion, or surgical resection.

Subacute/chronic complications

◆ Intraabdominal or pelvic abscesses can result from localized perforation or internal fistulation. Symptoms include abdominal pain and marked weight loss but can be surprisingly nonspecific and frequently mistaken for active luminal inflammation. Markedly elevated inflammatory markers and low albumin indicate sepsis and mandate abdominal CT. Treatment options, decided by multidisciplinary review and depending on the patient’s clinical status, include antibiotics (metronidazole and ciprofloxacin) with radiological drainage and elemental diet or corticosteroids to suppress Crohn’s inflammation. Surgical drainage/resection is usually best deferred while sepsis is thus controlled. Parenteral nutrition and intensive care may be required in severe cases.
◆ Perianal abscesses and fistulas present with pain, swelling, and discharge. This can be cyclical. Fistulas may be simple (single intra- or trans-sphincteric track) or complex (including extension above levators, ‘horseshoeing’ contralaterally, or secondary tracks). Management includes defining the anatomy (by examination under anaesthesia ± MRI perineum), drainage of abscesses, control of infection with metronidazole ± ciprofloxacin and suppression of disease activity. Insertion of seton sutures keeps fistula tracks open, preventing repeated blockage and abscess formation. For recurrent perianal Crohn’s disease, azathioprine or infliximab reduces inflammation and fistula activity. Severe, refractory disease may require defunctioning ileostomy or panproctocolectomy.
◆ Symptomatic anal strictures should be dilated under anaesthetic, with benefit prolonged by using a dilator at home.
◆ Internal fistulas. Rectovaginal fistulas cause faeculent vaginal discharge; colovesical fistulas cause pneumaturia / recurrent urinary infections; and enterocolic fistulas present with diarrhoea, ‘malabsorption’, and weight loss. Enterocutaneous fistulas are postoperative complications, mostly closing spontaneously by 6 weeks unless communicating with inflamed or obstructed bowel. Resectional surgery for fistulas should be preceded by control of sepsis and inflammatory disease, optimization of nutrition and delineation of fistula anatomy by appropriate imaging.
◆ Short-bowel syndrome following extensive resection is likely if there is less than 120 cm of small bowel ending in ileostomy or 80 cm with colon in situ (colonic bacteria ‘scavenge’ calories by fermentation, producing volatile fatty acids which are absorbed).
- ◆ Other patterns of malabsorption in Crohn’s disease include:
- ◆Vitamin B₁₂ deficiency—following ileal resection B₁₂ levels should be monitored yearly and replaced parenterally where deficient.
- ◆ Choleretic diarrhoea—ileal resection prevents resorption of bile acids in the enterohepatic circulation. In the colon they can stimulate marked watery diarrhoea. Treat with cholestyramine.
- ◆ Bacterial overgrowth of the small bowel results from stasis produced by scarring and stricturing. Symptoms include diarrhoea, nausea, bloating and flatulence. Treat with antibiotics (e.g. metronidazole, doxycycline, coamoxiclav); often prolonged or rotating courses required.
- ◆ Iron deficiency. Oral iron preparations frequently poorly tolerated or ineffective—intravenous iron sucrose/iron dextran often required.
- ◆ Zinc, magnesium, and selenium deficiency should be ascertained and treated.
◆ Growth failure is a major risk in adolescents, particularly with disease activity around puberty. Height and weight must be monitored on growth charts. Acute relapse should be managed with dietary therapy (elemental/polymeric) where possible. The priority is rapid induction of remission to restore growth, and infliximab or surgery may be required to achieve this. Long-term corticosteroids must be avoided: azathioprine or infliximab are frequently used to maintain remission.
◆ Osteoporosis occurs in approximately 12% of Crohn’s disease patients, with increased fracture risk. Corticosteroid therapy, low body mass, poor dietary intake of calcium, smoking, hypogonadism, and uncontrolled inflammation all contribute. Regular bone densitometry is indicated, with calcium/vitamin D supplements and bisphosphonates given as required.
◆ Gallstones and renal stones are more common, and symptoms may be confused with active Crohn’s disease. Conventional management is indicated.
◆ Colon cancer is increased in Crohn’s disease. As with ulcerative colitis, risk correlates with disease extent, activity and duration. In one study neoplasia was detected in 16% of patients over 20 years. Regular surveillance colonoscopy is warranted after 10 years extensive Crohn’s colitis, with biopsy series including any mucosal irregularities. Risk of small bowel carcinoma increases 40-fold compared to the general population, usually within chronic strictures, but remains very rare.

Prognosis

To a patient newly diagnosed with Crohn’s disease the lack of a cure and uncertain future is understandably concerning. However, an aggressive or refractory course is unusual, and although morbidity during flares is substantial these are mostly short-lived and usually interspersed with long periods of remission with near-normal quality of life. Although prognostic markers are lacking, population-based data from Denmark indicate 55% of patients to be in remission and 15% with mild disease only 1 year after diagnosis. Some 10 to 30% of patients relapse each year, less if immunomodulatory drugs are used.

Up to 80% of Crohn’s disease patients require surgery long-term, a figure unchanged over 30 years despite substantially increased azathioprine use. For ileal/small-bowel Crohn’s disease, surgery is required on average 8 years after diagnosis. Some 30 to 40% of patients experience symptomatic relapse by 5 years postoperatively, with 30% requiring further surgery within 10 years. Smoking more than doubles this risk. Surgery is required less frequently for exclusively colonic disease. Risk of relapse following panproctocolectomy is low in such individuals.

Despite the imperfections of current therapies Crohn’s disease does not dramatically increase mortality. In a large United Kingdom-based cohort study, Crohn’s disease was associated with an overall hazard ratio of 1.73. The effect was greatest in 20- to 39-year-olds, reflecting the large impact of a small number of deaths in this age bracket, usually due to acute complications such as sepsis, pulmonary embolism, bowel perforation, and postoperative complications.

Heredity, fertility, and pregnancy

Each child of a Crohn’s disease-affected individual has a 2 to 4% risk of developing Crohn’s disease, rising to approximately 30% where both parents are affected. Fertility is reduced in women with Crohn’s disease, and miscarriage rate is higher particularly with active disease during pregnancy. Most Crohn’s disease therapies are safe in pregnancy but risks and benefits should be carefully discussed with patients. Acute flares should be treated with corticosteroids or dietary therapy (elemental or polymeric); and maintenance treatment with azathioprine or infliximab (the latter until the third trimester) should usually be continued. Only minimal amounts of thiopurine appear in breast milk. Methotrexate is contraindicated in pregnancy.

Areas of controversy

◆ The precise role of commensal gut flora (and the possible contribution of one or a small number of pathogens) in triggering and sustaining the intestinal inflammation of Crohn’s disease
◆ Use of systemic corticosteroids for Crohn’s disease in view of side effects and possibly the increased risk of fistulas
◆ For patients in remission on azathioprine, 6-mercaptopurine, methotrexate, or anti-TNF antibody therapy, how long to continue these treatments and when risks of long-term immunosuppression outweigh benefits of controlling active Crohn’s disease
◆ Whether anti-TNF antibody therapy provides more effective and safer control of Crohn’s disease than thiopurines long term
◆ Whether surgical resection (especially laparoscopic) is preferable to long-term immunosuppression for corticosteroid-refractory terminal ileal Crohn’s disease
◆ For protection against osteoporosis, optimal use and timing of calcium supplementation and/or bisphosphonates with respect to corticosteroids

Likely future developments

◆ Increasing use of specialist nurses and patient self-management
◆ Use of the internet rather than the physician as primary information source
◆ More widespread use of biological therapies
◆ Use of genetic and biomarker data to delineate heterogeneity within the Crohn’s disease population; value for prognosis, stratification for drug trials, and possibly ‘personalized’ therapy
◆ Progress in characterizing environmental trigger(s) facilitated by genetic knowledge
◆ Increased knowledge regarding pathogenic mechanisms feeding development of rational new therapies and possibly vaccines for those identified as genetically at risk

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