BMJ Learning

Crohn's disease: diagnosis and management

د. حسين محمد جمعة
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2010

Key points

The choice of investigation and treatment of Crohn's disease is guided by the site, activity, and behaviour of disease
70% of patients will have surgery at some point in their illness
Smokers are more likely to require surgery for their disease and have a higher risk of relapse after it

Corticosteroids are effective in short term treatment of Crohn's disease but have no long term maintenance effect and are associated with significant side effects including an increased risk of sepsis.
Undertreatment of active Crohn's disease adversely affects pregnancy.
Methotrexate and metronidazole are contraindicated in pregnancy.

Clinical tips

Patients with Crohn's disease should be strongly advised to stop smoking
Constitutional symptoms (malaise, weight loss, and fever) can occasionally be the sole presenting symptoms in Crohn's disease.
Serum C reactive protein (CRP) broadly correlates with disease activity


Colonoscopy with terminal ileal intubation and biopsy is the most reliable diagnostic strategy.
Mesalazine preparations have a minimal effect on the activity of Crohn's disease
Thiopurines (azathioprine and 6-mercaptopurine) are used in steroid-refractory Crohn's disease or started at an early stage in patients with severe symptoms from small bowel Crohn's.
Allopurinol should be avoided in patients receiving a thiopurine.

About 20% of patients cannot tolerate thiopurines and weekly methotrexate is a proved alternative
Infliximab and adalimumab are useful in the management of refractory Crohn's disease and in managing systemic manifestations of the condition

Antibiotics are effective first line treatment for symptomatic perianal disease

Nutritional therapy with a liquid enteral feed can be an effective treatment in Crohn's disease, where tolerated
Extensive colonic Crohn's disease behaves much like ulcerative colitis and the management strategies are broadly similar

What is it?

Crohn's disease is a form of inflammatory bowel disease that can involve any location of the alimentary tract from the mouth to the anus. The inflammation of Crohn's disease is often discontinuous along the longitudinal axis of the gut and may affect all layers of the gut from the mucosa to the serosa.

Classification of Crohn's disease is more complex than in ulcerative colitis due to its numerous possible phenotypes. It is helpful to identify disease location and disease behaviour in order to plan an optimal management strategy.

Crohn's disease most commonly affects the distal ileum and proximal large bowel:

In approximately 50% - ileum and colon are affected
In approximately one third - disease is confined to the small bowel (primarily terminal ileum)
In approximately 20-25% - disease is confined to the colon.
A useful classification for Crohn's disease is illustrated by the Montreal classification of inflammatory bowel disease (Box 1).


Box 1: The Montreal classification of Crohn's disease1

Age at diagnosis

A1 below 16 yearsA2 between 17 years and 40 yearsA3 above 40 years
Location
L1 ilealL2 colonicL3 ileocolonicL4 isolated upper disease*
Disease behaviour
B1 non-stricturing, non-penetratingB2 stricturingB3 penetratingp perianal disease modifier**
* L4 is a modifier that can be added to L1-L3** p can be added to B1-B3 when perianal disease is present

Who gets it?

There is geographic variability of the incidence of Crohn's disease. There is a higher frequency in northern Europe than in more southern latitudes. It is extremely rare in South America and Africa. In westernised countries the incidence of Crohn's disease is around 5-10 per 100 000 per year with a prevalence of 50-100 per 100 000.

There is a peak incidence of Crohn's disease at 15-30 years with a median age of diagnosis of 30 years.
A second peak in the seventh decade is reported. As the site of disease in this group is commonly the sigmoid colon, it is unclear whether this is true Crohn's disease or merely inflammation secondary to diverticular disease.

What causes it?

The cause of inflammatory bowel disease is unclear, but genetically susceptible individuals appear to develop inflammatory bowel disease in response to environmental triggers.

There is a strong genetic contribution in Crohn's disease with 64% concordance in identical twins.
The relative risk of first degree relatives of a patient with Crohn's disease developing inflammatory bowel disease is 14-15 times that of the general population. The site and behaviour of Crohn's disease also seems to have a strong familial basis.


Environmental triggers include:
• Not breast feeding
• Higher socioeconomic status
• Drugs: Non-steroidal anti-inflammatory drugs (NSAIDs) have an idiosyncratic effect on inflammatory bowel disease, causing a flare of disease in some patients.
The evidence for avoiding NSAIDs in inflammatory bowel disease is inconsistent. If required, it seems reasonable to advise patients to take a relatively mild NSAID such as ibuprofen for short periods whilst informing them about the possible theoretical increased risk of relapse

Smoking: Crohn's disease is more prevalent among smokers (in contrast to ulcerative colitis) and smokers have more surgery for their disease. Smoking cessation is associated with a 65% reduction in risk of relapse.
Smokers have a 2.5-fold increased risk of relapse after resection compared to non-smokers

Stress has been linked with, and may adversely affect, inflammatory bowel disease

Oral contraceptives: Women taking the oral contraceptive pill are 1.5 times as likely to be diagnosed with Crohn's than those who were not. In patients with an established diagnosis of Crohn's disease, data on the risk of a flare of Crohn's whilst on an oral contraceptive are conflicting, but recent studies have not shown an association beween oral contraceptive pill use and a more severe course of Crohn's disease.

Factors associated with a poor prognosis with an increased likelihood for disabling disease within the first five years after diagnosis include:
• Young age at onset
• Ileocolonic location
• Perianal lesions
• Need for steroids at first flare.

History and examination

Making a diagnosis: history, examination, and investigations in Crohn's disease
The symptoms and signs of Crohn's disease are highly variable according to the location of disease, activity of inflammation, and the behaviour of disease. The differential diagnosis in patients presenting with symptoms for the first time is therefore wide. Symptoms and signs may indicate a likely site of disease (see later) allowing targeted selection of endoscopic and radiologic investigations (Box 2).


Box 2

History

Ask about:
Abdominal pain
Stool frequency, consistency, blood and mucus
Nocturnal diarrhoea
Weight loss, fever
Perianal symptoms
Family history
Travel history
Extra-intestinal manifestations (joints, rashes, eyes)
Antibiotic use
Smoking
Drug history incl. NSAIDs and OCP
Investigations
Full blood count, urea and electrolytes, liver function tests, ESR, C reactive protein
Stool: culture and Clostridium difficile toxin
Consider:
Endoscopy and biopsies:
• Sigmoidoscopy
• Colonoscopy (and terminal ileal intubation)
• Gastroscopy
• Small bowel enteroscopy
• Capsule enteroscopy
Radiology:
• Plain abdominal x ray
• Barium meal
• Small bowel enema
• Barium enema
• MR enteroclysis
• MRI scan perineum
• Transabdominal ultrasound
Examination
Examine for:
Pulse, temperature
Abdominal tenderness/mass/fullness
Perianal and oral inspection


General points
Constitutional symptoms (malaise, weight loss, and fever)
These symptoms may reflect severe disease, but are occasionally the sole presenting symptoms
Pain
Pain is a more frequent and more persistent complaint than in ulcerative colitis
Rectal bleeding
Gross rectal bleeding is uncommon

Diarrhoea

Multiple factors may contribute to diarrhoea in Crohn's disease:
• Bile salt induced diarrhoea/steatorrhoea (due to ileal resection or dysfunction)
• Bacterial overgrowth
• Disordered colonic motility secondary to chronic inflammation
• Altered fluid and electrolyte absorption and secretion
• Exudation of protein and fluid from mucosal wall

Weight loss

Weight loss due to malabsorption (ileal resection or dysfunction) or poor oral intake, for example
Short stature in children
One half of children with untreated Crohn's disease will have short stature


Clinical presentation and disease location
Ileal disease (often with accompanying caecal involvement)
Small bowel obstruction
Fibrotic stricture - colicky, intermittent abdominal pain and/or nausea and vomiting
Fullness/mass in right iliac fossa
Loose stool

Colonic disease

Tenesmus (less frequent than in ulcerative colitis as rectum often not involved)
Diarrhoea
Abdominal pain
Loose stool - may be bloody depending on extent/severity of involved bowel

Perianal disease (precedes intestinal Crohn's disease in 24%)

Skin lesions: Skin tags, maceration, superficial ulcers, abscesses
Anal canal lesions: Fissures, ulcers, and stenosis
Perianal fistulas

Upper gastrointestinal tract lesions (uncommon in absence of disease distal to the duodenum)
Gastroduodenal
Dyspepsia, epigastric pain
Outflow obstruction (oedema/fibrotic stricture) - early satiety, nausea and vomiting
Oesophageal (<2%)
Dysphagia, odynophagia, chest pain, heartburn
Jejunum and ileum
Frank malabsorption and steatorrhoea


Clinical presentation and disease behaviour
1-Stricturing disease
Stricturing disease may be asymptomatic until the luminal calibre is small enough to cause relative obstruction.

2-penetrating disease

Fistulating Crohn's disease:
Perianal fistulas
Communicating fistulas between intestine and other organs or abdominal wall
eg Rectovaginal fistula - foul discharge from vagina, dyspareunia, perianal pain
Colovesical fistula - suprapubic pain, frequency, dysuria, pneumaturia
Enterocutaneous - usually post-surgery

3-Abscess formation

Abscess formation may affect 25% of Crohn's patients at some point. Patients may have spiking temperatures and focal abdominal tenderness.

4-Extra-intestinal manifestations

Extra-intestinal manifestations of Crohn's disease are common. Some of these mirror the activity of the underlying inflammatory bowel disease.
arthralgia of large joints (16-22%),
erythema nodosum,
episcleritis, and oral
aphthous ulceration.


Features which can be unrelated to disease activity and in some cases precede the diagnosis of Crohn's disease include axial arthritis, arthritis of small joints of the hands and feet,
pyoderma gangrenosum,
uveitis, and
nephrolithiasis. 25% of patients with Crohn's disease get symptoms from gall stones. Primary sclerosing cholangitis occurs in 4% but almost always in association with colonic disease.

Investigations in Crohn's disease

to
Establish the diagnosis
Establish the extent of disease
Establish the site and extent of stricturing disease
Establish the activity of disease
Detect extramural complications (eg abscesses and fistulas)
Features of the history and examination will help guide selection of the appropriate investigation(s).

Blood tests in Crohn's disease

CRP broadly correlates with disease activity. Elevated CRP activity in patients in remission identifies those at greatest risk of relapse
Haemoglobin: A number of factors may contribute towards anaemia in Crohn's disease
• Malabsorption (B12 and folate deficiency)
• Bleeding (iron deficiency)
• Anaemia of chronic disease
• Medication (eg azathioprine)


Faecal calprotectin
Faecal calprotectin (a neutrophil derived protein) is becoming more widely used as a tool for monitoring disease activity and treatment response in Crohn's disease. It appears to be a more sensitive marker for disease activity than CRP.

Endoscopic and radiological investigations in Crohn's disease

Endoscopy allows direct inspection of GI tract mucosa, biopsy, and application of therapy (eg dilatation of stenotic strictures). However, not all parts of the GI tract are easily accessible to endoscopy and pathology (eg stricturing disease, inflammatory masses) can impede examination. Radiological techniques allow examination of these areas, but can also provide more detail about extramural complications (fistulas or abscesses).

Endoscopy in Crohn's disease

Colonoscopy and terminal ileal intubation with multiple biopsies is the most reliable diagnostic strategy.
Gastroscopy - this is indicated in the presence of upper GI symptoms.
Small bowel capsule enteroscopy - may be helpful in suspected small bowel Crohn's disease in patients in whom imaging and endoscopy have not demonstrated lesions.

Endoscopy in Crohn's disease

Macroscopic features typical of Crohn's disease include:
• Confluent, deep linear ulcers, aphthoid ulcers
• Skip lesions
• Strictures
• Fistulas
• Rectal sparing.

Histological features typical of Crohn's disease include:

• Transmural inflammation
• Granulomas (nb may occur in other conditions)
• Goblet cells normal (goblet cell depletion is seen in ulcerative colitis).


Imaging
Plain AXR
Plain AXR is indicated if severe Crohn's disease is suspected in order to exclude toxic megacolon or features of bowel obstruction.

Small bowel enteroclysis/small bowel meal and follow through

Small bowel follow through for examination of the terminal ileum has a sensitivity and specificity of 85-95% and 89-94% respectively. Small bowel enteroclysis may also be used for examination of the terminal ileum. In this study, barium is introduced via a nasally placed enteric tube.

Prestenotic dilatation may be seen as a functional effect of a segment of narrowed bowel. When endoscopic examination of the affected bowel is not possible (eg stricturing disease or inaccessible to available endoscopic methods), it can be difficult to distinguish between inflammatory disease and fibrostenotic disease.

CT/MRI

The advantage of cross-sectional imaging over barium studies is in the detection of extramural complications (eg abscess, sacroileitis, gall stones, and renal calculi). In the case of MRI, this may afford detailed information about the patient's Crohn's disease while reducing x ray exposure. Pelvic MRI is useful to define the anatomy of perianal fistulas and assess for local sepsis.

Leukocyte scintigraphy

Leukocyte scintigraphy assesses the presence, extent, and activity of inflammation, but lacks specificity.
Transabdominal ultrasound
Transabdominal ultrasound can be useful for assessing disease activity particularly of the ileum.

Management of Crohn's disease

Treatment options in the management of Crohn's disease are guided by:
• Site of disease
• Activity of disease
• Behaviour of disease (fistulating, stricturing, or inflammatory).
Approximately 80% of patients with Crohn's disease will have surgery during their lifetimeand close dialogue between the gastroenterologist, surgeon, and patient is required to decide on appropriate timing and type of surgery.


Drugs used in Crohn's disease
Aminosalicylates
5-ASA is rapidly absorbed from the jejunum and a variety of delivery systems are used to deliver the drug to the colonic mucosa. Oral preparations and topical preparations (as suppositories or enemas) are available.

Efficacy

Although initial studies demonstrated the efficacy of mesalazine preparations in controlling active Crohn's disease, more recent data suggest that mesalazine preparations have limited efficacy. A meta-analysis of data described a small improvement in the Crohn's Disease Activity Index (CDAI) in patients receiving oral Pentasa (a dose of 4 g/day) compared to placebo. However, the clinical significance of this small change has been debated. Mesalazine appears clinically no more effective than placebo in management of active disease.

Two meta-analyses of randomised controlled trials investigating the role of mesalazine in the maintenance of remission in Crohn's disease have come to contradictory conclusions.
A recent expert consensus does not recommend 5-ASA treatment for the maintenance of medically induced remission in Crohn's disease.

Corticosteroids

Corticosteroids can be used to induce remission in relapses of Crohn's disease. They have no role in maintenance therapy. Corticosteroids may be applied topically (suppositories, liquid or foam enemas), orally (as prednisolone or budesonide) or intravenously (as hydrocortisone). The decision to use corticosteroids has to be balanced against the adverse effects associated with their use.

Adverse effects

Fifty per cent of patients report adverse effects with corticosteroid use. Early effects include acne, moon face, oedema, sleep disturbance, dyspepsia, and disturbed sleep. Patients should be advised to avoid abrupt withdrawal of steroids due to the risk of Addisonian crisis. With prolonged or repeated use, patients may develop osteoporosis, myopathy, and cataracts. Supplementation with vitamin D and calcium has been advocated for all patients receiving corticosteroids with the intention of reducing loss of bone mineral density.

On withdrawal of corticosteroids, a syndrome of arthralgia, malaise, and myalgia can occur which may be difficult to distinguish from constitutional symptoms of Crohn's.
Modified release budesonide is used in ileal and right sided colonic Crohn's disease. It has fewer systemic side effects than prednisolone due to its high first pass metabolism.

Of particular concern is the observed increased risk of sepsis. Postoperative sepsis is increased in patients pretreated with corticosteroids. Non-operated patients receiving systemic corticosteroid therapy have an increased risk for intra-abdominal or pelvic abscess. Corticosteroid therapy has also been shown to be associated with significant mortality so alternatives are increasingly sought.


Efficacy
In mildly active ileocaecal Crohn's disease, budesonide achieves remission in 51-60% over 8-10 weeks, but at its conventional starting dose of 9 mg/day, it is less effective than prednisolone (OR 0.69, 95% CI 0.51 to 0.95). Prednisolone when given at a dose of 0.5-0.75 mg/kg/day and tapered to zero over 17 weeks achieves remission in 60% of patients but rapid reduction in dosage is associated with early relapse of disease.

Corticosteroids are therefore effective at inducing remission, but alternative therapy to prevent relapse should be considered early. If given, corticosteroids should be prescribed with a strategy of complete withdrawal. Tapering the dose of corticosteroid identifies patients who:
Rapidly relapse
Do not respond
Need adjunctive treatment
Need inpatient treatment.

Dosage

No standard regimen of dosage is universally employed, but reduction in reasonably large increments (eg prednisolone 40 mg-30 mg-20 mg-15 mg-10 mg-5 mg-0) at one to two week intervals should be undertaken once symptoms have remitted.

Thiopurines

The thiopurines (azathioprine and its metabolite 6-mercaptopurine (6-MP)) have been used for more than 30 years as immunomodulatory therapy in patients with inflammatory bowel disease.
The timing of introduction of immunomodulatory therapy should take into account previous treatment, current symptoms, adverse effects of other therapeutic options, and patient preference:

The timing of introduction

Failure of first line agents to induce remission
Two or more corticosteroid courses in one calendar year
Relapse of disease with corticosteroid dose <15 mg
Use at an early stage in patients suffering severe symptoms from active disease
Relapse within three months of stopping corticosteroids
Postoperative prophylaxis of complex (fistulating or extensive) Crohn's disease.


Dose
The target dosing regimen for the thiopurines is 2-2.5 mg/kg/day for azathioprine and 1-1.5 mg/kg/day for 6-mercaptopurine. The dose is reduced if blood monitoring reveals likely toxicity (reduced white cell count or platelets, or deranged liver enzymes). Macrocytosis is an expected effect of therapy and does not warrant cessation, however, if there are any concerns about this or any other aspect of thiopurine therapy, expert advice should always be sought.

Adverse effects

These include:
Flu-like symptoms (myalgia, headache, and diarrhoea). Occur after 2-3 weeks and cease when the drug is withdrawn
GI side effects (28%) (nausea and vomiting)
Leukopenia (5%). Can develop suddenly and unpredictably
Hepatitis (0.3%)
Pancreatitis (3.3%).

Most of these adverse effects necessitate stopping the drug, however, expert advice should always be sought in this event.
Despite the adverse reactions detailed above azathioprine appears to be an acceptably safe drug for long term use providing monitoring occurs for bone marrow toxicity and liver toxicity.

In a 30 year review of the use of azathioprine in 622 patients with inflammatory bowel disease, 28% stopped azathioprine because of side effects (predominantly nausea and vomiting). No mortality from neutropenic related sepsis occurred.
With the exception of patients having hypersensitivity reactions to azathioprine, 6-MP may be introduced in patients intolerant of azathioprine.

Metabolism of azathioprine - toxicity

Allopurinol (a xanthine oxidase inhibitor) should generally be avoided in patients receiving azathioprine. The breakdown of azathioprine is inhibited resulting in an increased risk of myelosuppression. However, in patients in whom there is a poor response to azathioprine, some centres are able to measure azathioprine metabolites, identifying patients who may benefit from coprescription of allopurinol with a reduced dose of azathioprine.

Thiopurine methyl transferase (TPMT) is another enzyme that metabolises azathioprine. Genetic polymorphisms of this enzyme occur and one per 300 individuals is severely deficient in TPMT. As these patients are more liable to toxic effects of the drug, it is becoming more common practice to check blood TPMT levels prior to commencing therapy. A lower starting dose of azathioprine may be selected in affected patients.


Cancer risk and thiopurines
Although azathioprine and mercaptopurine are associated with an increased risk of lymphoma, the absolute risk is very low (one extra lymphoma is seen for every 300-1400 years of treatment). The risk is greater with older patients. It has been calculated that the number needed to treat (NNT) to cause one additional lymphoma per year was 4357 persons aged 20-29 years and 355 persons aged 70-79 years.

Monitoring

Monitoring schedules for azathioprine are broadly similar in different centres. The British National Formulary recommends weekly FBC assessment for four weeks followed by three monthly blood tests. More frequent blood testing should be adopted when there is a change in dose for whatever reason.

Efficacy and duration of treatment with thiopurine

Azathioprine and 6-mercaptopurine are effective at inducing remission in active Crohn's disease (OR 2.36; 95% CI 1.57 to 3.53). The efficacy of azathioprine in inflammatory bowel disease appears to be sustained for at least five years and increasing the duration of treatment will keep patients in remission for longer.
Azathioprine and 6-mercaptopurine are sometimes effective in closing and maintaining closure of perianal fistulas.

Pregnancy and lactation

Azathioprine and 6-mercaptopurine do not appear to affect pregnancy outcomes in patients with inflammatory bowel disease and discontinuation prior to or during pregnancy is not indicated. Small amounts of azathioprine and mercaptopurine are secreted in breast milk. However, no evidence of harm to children of mothers taking azathioprine has been demonstrated.

Methotrexate

Methotrexate is effective in inducing remission and preventing relapse in Crohn's disease. It is used in patients who are intolerant to Azathioprine/6-MP or have disease that is refractory to thiopurine treatment.
Dose and efficacy
Induction of remission: 25 mg/week IM for 16 weeks
Maintenance of remission: 15 mg/week IM

The above regimen achieves induction of remission in 39% of patients. Of these, 65% have a sustained response.46 A lower dose or oral administration appears to be ineffective at inducing remission. Oral dosing for maintenance therapy is preferred by many patients.
Oral bioavailability of methotrexate is highly variable in Crohn's disease and patients having oral dosing for maintenance therapy should be monitored closely for disease activity.


Adverse effects
Adverse effects of methotrexate are predominantly gastrointestinal and withdrawal of treatment occurs in 10-18% of patients. Gastrointestinal side effects are reduced by the administration of folic acid.

A number of different regimens of folic acid prescription are used. Folic acid may be given as a single weekly dose of 5 mg or 10 mg two or three days apart from methotrexate administration. Some centres advocate a "folate sandwich" with folic acid for three days prior and for three days after the dose of methotrexate.

Side effects

Vomiting, diarrhoea, nausea, and stomatitis
Hepatotoxicity
Hypersensitivity pneumonitis
Bone marrow toxicity.
Methotraxate is contraindicated in pregnancy.

Monitoring

A reasonable monitoring strategy would be:
Liver function tests and full blood count every two weeks for two months followed by two monthly blood tests
CXR, blood gases, and lung function testing if unexplained shortness of breath or persistent cough.

Infliximab and adalimumab

Adalimumab and infliximab are anti-TNF monoclonal antibodies with potent anti-inflammatory effects. Tumour necrosis factor-alpha (TNF-alpha) plays an important role in the inflammatory process in inflammatory bowel disease.
Adalimumab and infliximab have similar efficacy and adverse effect profiles, but differ in their dosing regimens and the fact that adalimumab can be self administered by the patient.


The National Institute for Health and Clinical Excellence (NICE) has recommended adalimumab or infliximab in patients with severe, active Crohn's whose disease has not responded to conventional therapy (including immunosuppressive and/or corticosteroid treatments), or who are intolerant of or have contraindications to conventional therapy.

Infliximab and adalimumab are useful in the following situations:

• Refractory luminal Crohn's disease
• Steroid dependent Crohn's disease
• Refractory fistulising Crohn's disease
• Systemic manifestations of Crohn's disease
• Ankylosing spondylitis and sacroileitis
• Pyoderma gangrenosum
• Crohn's uveitis
• Metastatic Crohn's disease.

Adverse effects

Problems related to the development of antibodies to the anti-TNF agent (counteracted by concomitant administration of azathioprine or methotrexate):
Acute infusion reaction
Delayed infusion reaction (serum sickness-like reaction)
Loss of response to treatment

Other adverse effects

Infection
A slight increase in opportunistic infections is seen in patients who are also taking immunosuppressant agents.
Reactivation of TB
Patients are screened with a chest x ray ± tuberculin skin testing prior to treatment.
Abscesses must be drained and treated before anti-TNF treatment.


Malignancy
Although no increased rate of malignancy has been observed with anti-TNF treatment in Crohn's disease an increased risk has been reported in rheumatoid arthritis and it can be inferred from its mechanism of action that it should be avoided in malignancy.

Efficacy

Luminal Crohn's disease
44% of patients with initial response to infliximab are in remission at 30 weeks when given maintenance doses of infliximab compared to 21% in the placebo group. Induction treatment with adalimumab (160 mg/80 mg) induced remission in 36% of patients at four weeks compared to 12% in those receiving placebo (P<0.05).

Fistulising Crohn's disease

36% of treated patients had complete response to infliximab treatment compared to 19% in the placebo group in the ACCENT II study.
Pyoderma gangrenosum
In a placebo-controlled trial, 46% of treated patients responded to infliximab versus 6% in the placebo group (P=0.025).

The best response is achieved:

• If the CRP is elevated
• In pure colonic disease
• In non-stricturing disease.
Maintenance treatment with an anti-TNF agent is associated with:
Reduced rate of complications
Reduced rate of hospitalisation
Reduced rate of surgery.


There is evolving evidence that anti-TNF agents alter the clinical course of Crohn's disease and recent research has focused on the use of anti-TNF agents at an early point in the disease.
Dose
Infliximab induction: 5 mg/kg IV at 0, 2, and 6 weeks
Maintenance: 5 mg/kg IV 8 weekly
Adalimumab induction: 80 mg then 40 mg (s/c) 2 weeks later
or 160 mg then 80 mg 2 weeks later
Maintenance: 40 mg (s/c) every other week.
The optimal duration of treatment is not clear. NICE recommends reviewing the appropriateness of continuing anti-TNF treatment at one year.

Pregnancy and lactation

Infliximab and adalimumab appear to be safe in pregnancy with no increased risk in fetal malformations observed. Consideration may be given to stopping infliximab in the third trimester as infliximab can cross the placenta during this period. Infliximab is probably compatible with breast feeding, but there is limited evidence on whether infliximab passes into breast milk and the long term implications of this are unknown. In light of this, it is probably better to advise stopping breast feeding while on infliximab.

Antibiotics

Metronidazole and ciprofloxacin are effective at treating perianal disease, and are effective first line treatments. They have also been demonstrated to show some efficacy in active luminal disease. Postoperative recurrence is reduced with metronidazole therapy.
Dose
Metronidazole 400 mg tds PO
Ciprofloxacin 500 mg bd PO

Adverse effects

Prolonged use of ciprofloxacin (>6 months) is associated with spontaneous Achilles tendon rupture. Metronidazole is associated with a dose dependent irreversible peripheral neuropathy. Both antibiotics are best given for no longer than three months and should be withdrawn if there is any evidence of adverse side effects.


Nutrition
Total enteral nutrition (administered orally or via nasogastric tube) or oral nutritional supplements have been reported to induce remission in 53-80% of patients with active Crohn's disease. Feeds that are lower in long chain triglycerides may carry the most benefit. However, studies have failed to demonstrate a difference in remission rates when comparing elemental and standard polymeric formulas. The mechanism of action is unclear, but reduction in the intestinal microbiota may be an important component of its action.

Enteral feeding may be appropriate for use in patients with Crohn's disease in the following situations:
As an adjunct to other therapies in patients with refractory disease
Patients with significant side effects from corticosteroid, immunosuppressants, or infliximab
As an alternative to corticosteroids or immunosuppressive therapy in patients keen to explore other therapies first.

The disadvantages of enteral nutrition include:

• Early relapse rate after cessation of therapy
• Compliance in an adult population
• Less effective than corticosteroids on an intention to treat basis
• Relative high cost.

Induction and maintenance of remission in Crohn's disease

The management of active Crohn's disease and the maintenance of its remission are guided by the site and severity of disease and by patient choice. There should be a low threshold for suspecting septic complications which require antibiotics and formal drainage of any collections. Surgical therapy may be required for severe disease that has failed to respond to medical treatment.

Complications of abscess or stricturing disease may also require surgical intervention. Endoscopic dilatation of short strictures, particularly anastomotic strictures, can be used in selected patients but carries about 5% risk of perforation.

Active ileocolonic disease and colonic disease: specific points

Mild disease
No treatment may be a choice in this scenario


Severe disease
Corticosteroids (prednisolone, budesonide, or IV hydrocortisone, but for no longer than three months)
Antibiotics (metronidazole and ciprofloxacin in selected patients)
Nutritional therapy - as an adjunct to therapy
In hospitalised patients: prophylactic low molecular weight heparin
Azathioprine/methotrexate - (see above)
Infliximab - If immunomodulatory agents fail to control disease

Surgery

Some experts advocate surgery in preference to infliximab in active ileocolonic disease in this situation if medical therapy has been ineffective within 2-6 weeks particularly if there is a short segment of stricturing terminal ileal disease
Approximately 50% of patients remain symptom free for five years after right hemicolectomy for Crohn's disease

Extensive colonic Crohn's behaves much like ulcerative colitis and such patients are at risk of developing toxic megacolon.

Extensive small bowel disease:

specific points
Azathioprine/methotrexate - Early introduction of immunomodulating agents may be appropriate due to the large burden of disease and to avoid corticosteroid side effects
Nutritional therapy - There are severe nutritional consequences of extensive small bowel disease and nutritional support is an essential part of its management
Surgery - Extensive small bowel resection risks short bowel syndrome and careful discussion between the surgeon, physician, and patient is required

Oesophageal and gastroduodenal disease: specific points

PPIs are a useful adjunct to Crohn's specific therapies
Perianal disease
The prevalence of perianal fistulas varies according to the site of intestinal disease:
12% patients with isolated ileal disease
92% of patients with rectal Crohn's.


Management depends on identifying:
The anatomy of the fistulous tract(s)
Presence of local sepsis.
MRI or examination under anaesthetic are the most sensitive modalities for diagnosing and characterising perianal disease. In expert hands, endoanal ultrasound may be useful. Rectosigmoid inflammation is assessed by sigmoidoscopy. A combined medical and surgical approach is often required in symptomatic perianal disease.

Antibiotics - First line treatment (ciprofloxacin and/or metronidazole) for symptomatic perianal disease
Infliximab - Early use of infliximab is effective in the management of perianal fistulas once sepsis has been treated
Azathioprine/6-MP - Second line therapy in simple perianal fistulas. It may be used as first line treatment in more complex disease

Surgery - Drainage with a non-cutting seton is recommended. A seton is a suture that is passed through the internal fistula opening into the fistula track and out through the external opening and tied into a loop. It maintains drainage and prevents abscess recurrence and may be left in situ long term. An abscess complicating complex disease requires drainage. A diverting ostomy may be an option in patients with severe, symptomatic perianal Crohn's disease

Surgery in Crohn's disease

Approximately 80% of patients with Crohn's disease will have surgery during their lifetime.25 Patients developing intestinal failure from extensive resection tend to have had several operations within a short period because of sepsis or other complications. Nutritional status is best optimised before surgery. Abscesses require formal drainage in addition to antibiotic treatment.

Ileocaecal Crohn's disease with obstructive symptoms - if surgery is used as primary treatment, there is a 50% chance of no further operation.
Stricturoplasty - Limited to strictures <10cm. There is a risk that strictures may harbour cancer.
Colonic disease - segmental resection is preferable if disease is localised.
Steroid treatment (20 mg prednisolone/day or equivalent dose) for greater than six weeks is a risk factor for postoperative complications.

Postoperative recurrence

Factors which have been shown to reduce postoperative recurrence:
• Not smoking
• Metronidazole (20 mg/kg/day) for three months after surgery for ileocolonic disease
• Mesalazine (>2 g/day) after small bowel resection
• Azathioprine may be used.


Pregnancy and Crohn's disease
Pregnancy does not affect the course of inflammatory bowel disease, however, undertreatment of active inflammatory bowel disease may adversely affect pregnancy.
Metronidazole and methotrexate are contraindicated in pregnancy. Vaginal delivery should be avoided in the presence of active perianal disease.

Contraception and Crohn's disease

When choosing appropriate contraception it should be noted that oral contraceptives are absorbed by the small bowel and efficacy may be reduced in patients with small bowel disease. If an oral contraceptive agent is used, a preparation with a low oestrogen content may be helpful given the increased risk of venous thromboembolic events in patients with active Crohn's disease.

Cancer risk and Crohn's disease

In ulcerative colitis, there is a five to tenfold increased risk of developing colon cancer compared to age matched controls. The risk of cancer in Crohn's disease is as great as the risk for an equivalent extent and duration of ulcerative colitis. More recent studies have shown no increased risk of colorectal cancer65 which may be due to treatment with mesalazine preparations and the use of surgery in patients found to have dysplasia at colonoscopy.

The risk of small bowel adenocarcinoma, although rare, is increased more than

60-fold in Crohn's disease.
Current guidelines recommend that patients with colonic Crohn's disease are offered entry into a surveillance programme in which they have episodic surveillance colonoscopy with biopsies to detect dysplasia.

Ultimately 70% of patients people have surgery for their Crohn's disease during the course of their lifetime. Such discussions should include reassurance that it should be possible to reduce the chance of this with adequate and timely treatment.

Allopurinol is a xanthine oxidase inhibitor and will increase the risk of azathioprine toxicity.

The indications for infliximab therapy include:

• Refractory luminal Crohn's disease
• Steroid dependent Crohn's disease
• Refractory fistulising Crohn's disease.
• Systemic manifestations of Crohn's disease:
• Ankylosing spondylitis and sacroileitis
• Pyoderma gangrenosum
• Crohn's uveitis
• Metastatic Crohn's disease.


The optimal duration of infliximab treatment is not clear. At present, the requirement for continued infliximab treatment is reviewed at one year. A better response is observed if the CRP is elevated. Patients with isolated colonic disease respond best. those who respond to initial treatment, 44% are still in remission at 30 weeks.

Corticosteroids have not been shown to reduce the risk of postoperative recurrence. They increase the risk of postoperative sepsis. Metronidazole (20 mg/kg/day) for three months after surgery for ileocolonic disease reduces the risk of postoperative recurrence.

Young age at onset is associated with a worse disease course.

Isolated colonic disease is not associated with a disabling disease course.
Ileocolonic disease location is associated with a worse disease course.
Perianal lesions are associated with a worse disease course.
The need for steroids for first flare of disease

is associated with a worse disease course.

Azathioprine or methotrexate may be used as first line treatment in complex perianal disease or as second line treatment in simple fistulas.
Corticosteroids are not first line agents in perianal disease

The risk of her child having inflammatory bowel disease is 15 times greater than the general population.
Low dose steroid therapy is not effective at maintenance of remission in Crohn's disease.





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