Endoscopic image

Endoscopic image - terminal ileum with ulceration and swelling resulting in narrowing of the lumen

Colonic Crohn's disease - as seen at colonoscopy

Photos of Crohn's disease of the colon taken at colonoscopy

Photos of Crohn's disease of the colon taken at colonoscopy

The main common site for Crohn's diseae is the terminal ileum - that is the last part of the small bowel before it joins the large bowel

What is Crohn's disease?

• This is an inflammatory condition of the bowel of unknown cause;
  
  • It affects 1 in 500 - 700 of the population
  • Onset is often in early adult life - 20-40 years but can occur at any age
  • For more information see IBD
• It may affect any part of the gastrointestinal tract including oesophagus, stomach, small bowel and large bowel
• The condition starts as small ulcers in the lining of the gut
  
  • these early ulcers are called "aphthous" ulcers. These have some similarities to mouth ulcers
  • These small ulcers progress to deeper ulcers with fissuring (deeply penetrating areas) - see photo at right
  • The lining of the bowel becomes oedematous (swollen) giving what is described as a "cobblestone" appearance
• Crohn's disease is often patchy - several different areas of the gut are involved;
  
  • The diagnosis is generally made by the appearance at colonoscopy
  • Biopsies can be specific for Crohn's disease (if there are granulomas)
  • Usually the inflammation is non-specific (that is there is helpful additional information that is suggestive rather than diagnostic of Crohn's disease)
  The condition cannot be cured but can be well managed with a combination of medication and surgery (see sections on steroids, salicylates (refer to ulcerative colitis on main menu), azathioprine, monoclonal antibodies (infliximab (Remecaide),  adalimumab (Humira or a biosimilar) and also section on surgery. 

What are the main symptoms?

• There are a great variety of symptoms depending on area of bowel involved;
• The most site of involvement is the ileum - the end of the small bowel - just before it joins the colon;
  
  • There may be lower or mid-abdominal pain (usually cramping or gripping in nature), nausea, diarrhoea, weight loss
  • OR / AND pain and localized tenderness in right lower abdomen
• If the colon is involved there will be more diarrhoea (sometimes mixed with blood and mucus);
  
  • Pain is most likely to be in the left lower part of the abdomen and occur before and during defaecation
• Peri-anal disease presents with anal pain and discharge;
  
  • This may be due to a fissure or fistula.
  • A fissure is a non-healing split in the anus
  • A fistula is a connection or tract between the rectum and the skin immediately adjacent to the anus
• Tiredness is common because of the chronic inflammation as well as anaemia and nutritional deficiencies
• Other possible associated symptoms are arthritis - sometimes only joint pains but also swelling and tenderness , mouth ulcers, and some particular skin rashes. Red eyes with blurring of vision is due to iritis and requires urgent attention

Steroids

Prednisone is the most commonly used steroid in the treatment of inflammatory bowel disease in NZ

Also see the section on Entocort below - a non-absorbed steroid that may be an option for some people

• The term "steroid" can be misleading.
• This refers to a group of compounds that have anti-inflammatory effects.
• There are some structural similarities with body-building (anabolic) steroids but they do not have any "body-building" effects.
• In fact, one of the unwanted effects is a loss of muscle bulk!
• Steroids (fullname is corticosteroids) are actually produced naturally by the body's adrenal glands.
  • Giving steroids as a drug means giving the steroid at a dose more than the body usually makes
  • For Prednisone the equivalent dose to the normal body output is roughly 5mg daily  - more than 5mg is more than the body usually makes.
  • Prednisone has powerful anti-inflammatory effects - therefore it useful many conditions that have inflammation - asthma, arthritis and colitis / IBD.
• The effect of steroids is much greater than that of salicylates (Pentasa or Asacol).
  • The effect is very rapid, usually within 3-4 days but may be delayed for up to 2 weeks.
  • The aim of treatment is to start with a high dose, usually 40mg of prednisone and to continue treatment at that dose until an effect is achieved.
  • The dose is then gradually decreased.
  • The rate of decrease depends on the severity of the underlying condition.
  • Generally if a remission is induced rapidly with a higher dose then the overall duration of the course of medication may be shorter.
  • The drug should be taken as a single dose with breakfast; there is no advantage in splitting the dose (morning and evening).
  • Maintenance treatment (or long-term treatment) should be avoided if possible.
  • Treatment for longer than 2-3 months at doses higher than 20mg runs the risk of significant side-effects (see below).

Side effects of steroids (early and medium-term)

Early side-effects

• Most people experience no problems from steroids in the first 1-2 months.
  • In fact it is common to feel great - some elevation of mood, improved appetite.
  • Higher doses (20-40mg per dose) can cause problems with sleeping.
  • Mental changes can occur rarely. Possible symptoms include agitation, irritability, "feeling wired". Rarely there can be confusional state with aggressive behaviour.
  • Higher blood sugars for diabetics can be a problem.
• Overall short term treatment (4-6 weeks) is tolerated very well (with minimal risk).
  
  

Medium term effects (1-3 months)

• Fluid retention
  • Contributing to up to 4kg weight gain.
  • This is mostly reversible weight gain.
• Facial fullness / mooning
  • Only a "cosmetic" issue - and reversible.
  • But can be a significant negative impact of treatment.
• Increase in appetite.
  • This leads to weight gain that may be difficult to get off after stopping medication.
• Skin changes.
  • Mainly increased acne (if already at risk).

Longer term effects (more than 3 months)

• These effects may be evident after 3 months.
• This is a long and troubling list of side-effects but many people can tolerate longer treatment without problems.
  • Thinning of skin.
  • Easy bruising.
  • Loss of muscle bulk, particularly quads leading to difficulty with stairs, getting out of a chair.
  • High blood pressure.
  • Diabetes. Steroids may aggravate a previously mild problem (called impaired glucose tolerance).
  • Stretch marks on the abdomen.
  • Eye problems - rare. Includes glaucoma (increased pressure in the eye) and cataracts.
  • Aggravation of indigestion, ulcer disease and maybe reflux.
  • Headaches - if persistent could be related to steroids.
  • Thinning of bones (osteoporosis) possibly leading to fractures.  This is most likely to occur in the spine, hip or wrists.  This is not usually a problem until after 1-2 years of treatment but the risk will depend on other factors.  These risk factors include age, post-menopausal state, early menopause, family history of osteoporosis and most importantly the dose and duration of treatment.
  • Special issue for children - suppression of growth.
• It is obviously desirable to avoid these longer term problems.
  • Most of these changes will reverse when the steroids are stopped.
  • To achieve this goal there may need to be an alternative plan. This usually means changing to azathioprine (dampening down the immune system). This type of treatment is often described as "steroid-sparing".
  • Increasingly there is a move to earlier introduction of biologics - in NZ the only available treatments are infliximab (Remicaide or biosimilar) and adalimumab (Humira).  One major aim avoid is to avoid long term steroid treatment
  • The aim of this treatment should be more than just reduction in dose of steroids - but the goal of getting off the steroids completely.
  • Entocort - seee below - can used on occasions as an aid to treatment to help reduce the final amount from 5mg to stopping completely
• The time for a change is a matter of judgment.
  • As a guide I think that being on steroids for more than 2 months in the year on a regular basis is unacceptable as a long-term plan for treatment.
  • Steroids remain very powerful medications to reduce inflammation and should be used when needed. Hopefully the usage will gradually decrease as other options become available.

Steroid dependency

This means being unable to come the Prednisone because of early relapse of symptoms

This may simply show that the disease is very active and other treatments need to be given to replace the effect of Prednisone

However it can also imply severe suppression of the adrenal gland which is no longer making cortisol because of long term Prednisone

One option, rarely used but effective, is to use Entocort (below) to aid the reduction of Prednisone below 5mg  - Entocort is given 2-3 daily and Prednisone is reduced by 1mg per month.  Once off prednisone then the Entocort can be gradually withdrawn.

Entocort

• Entocort is steroid that is not absorbed (budesonide) - actually there is low level absorption
• Therefore the anti-inflammatory effects are limited to the bowel and the side-effects (as listed above) are largely avoided
• The medication is in a slow release formulation specifically designed for Crohn's disease of the small bowel but significant medication is also released into the colon
• Three capsules of Entocort (3 x 3mg capsules) is approx. equivalent to Prednisone 40mg daily (usually given as 2x 20mg tablets)
• Clinical trials have shown some loss of efficacy with continued use for 3-6 months - therefore shorter courses are the best options.
• Absorption (systemic) is approximately 10% of the dose (but may vary between individuals)  - therefore at 3 caps daily  - the equivalent Prednisone dose is 4mg daily.  At this dose a mild degree of adrenal suppression will be seen with longterm use and occasionally mild steroid effects  - fluid retention, facial mooning, easy brusing - particularly in elderly patients
• In New Zealand the prescribing of Entocort is limited to 6 months and requires a special authority.  A further 6 months may be prescribed on extension of application.
• Entocort has a proven beneficial effect on microscopic colitis (also called lymphocytic colitis and collagenous colitis). 
• this a condition that is different from ulcerative colitis or Crohn's disease but it is an "inflammatory" problem at the microscopic level
• like the IBD conditions - the cause is not known
• this condition tends to "wax and wane" therefore intermittent treatment is given depending on symptoms.  The condition is usually self-limiting - i.e resolves over time - the average duration is 3 years but there is a wide range
• The usual dose is 2 caps for 1-2 months then 1 caps for 1-3 months.  Repeat courses may be required as this condition may have several replases before settling completely for most people within 3 years

Normal colon (appearance at colonoscopy)

Severe Crohn's disease of the colon

Remecaide and Humira  (infliximab and adalimumab) - anti-TNF monoclonals

• These drugs are antibodies that have been developed to remove one specific molecule that is important for causing inflammation – that is TNF or tumour necrosis factor.
  • This antibody binds specifically to TNF and renders it inactive.  The result is a rapid decrease in the inflammation in the bowel.
  • TNF is a major contributor to inflammation in the bowel but is also involved in other diseases, in particular in arthritis.
  • Infliximab and adalimumab are very effective treatment in Crohn's disease (also used in rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis)
  • Infliximab is given by intravenous infusion.
  • Adalimumab is given by subcutaneous injection

• Both these agents have proven ability to settle inflammation in Crohn's disease (and to a lesser extent in ulcerative colitis)
• After treatment for 2-3 months about 70% of people with Crohn’s disease have had a good response (significant decrease in symptoms but still some activity of disease)
• About 1/3 will have complete remission  - that is, no symptoms and complete healing of the lining of the bowel
• The impressive part about the response to infliximab and adalimumab is the healing of the ulceration seen on colonoscopy.
  • Often the response to steroids and salicylates seems reasonable but when the colon or small bowel is examined there is still significant ulceration (active disease).
  • Without mucosal healing there is still the chance of complications such as scarring and fistula (see Crohn's disease section).

• The results for ulcerative colitis are less impressive but infliximab does have a role in acute colitis (in-hospital treatment).
• There is resonable data on long term treatment for ulcerative colitis with both infliximab and adalimumab. Infliximab is available in NZ - mainly for patients who have responded to acute / emergency treatment  -  i.e the option of continuing treatment that has worked.
• Adalimumab is funded for UC in other countries - may be funded in NZ soon.

What about the longer term response?

• Sustained response is possible with repeated treatments.
  • For infliximab this is an infusion every 2 months - there is a small “drop-off” in effect over time.
  • For adalimumab (Humira) this is given as a fortnightly subcutaneous injection - that is just under the skin using a small needle - like giving insulin for diabetics
  • It is easy to learn how to self-administer with automated pens that take the anxiety out of self-injection
  • It is likely that the effect is maintained over several years but longer term data is required.  Some people may need a dose increase but this is not funded in New Zealand at present

• maintenance treatment with Humira is now fully funded in NZ for selected patients with Crohn's disease (also funded for some patient with ankylosing spondylitis - a condition associated with Crohn's disease)
  
  
• both infliximab and adalimumab are very useful treatments for fistula - abnormal connections  - ie. draining holes - most commonly around the anus but can also occur with connections from the bowel to the vagina, bladder and abdominal wall.  This problem is sometimes referred to as "fistulizing disease".  This is a major challenge and involves a combination of medical treatments and surgery. 

• The availability of infliximab depends on the local arrangements within each region of New Zealand but recent changes in funding should have made this treatment more available throughout the country.
• Many countries are using biosimilars for infliximab. This is cheaper option and have proven to be successful with no problem switching over to the new drug

Dose changes

• It has been difficult to increase the dose of adalimumab or infliximab in NZ because of restrictions with funding
• Best practice in other countries involves taking a blood immediately before the next dose to check trough levels.  This is more effective with infliximab but blood levels for adlalimumab can also be checked. Low blood levels should lead to a dose increase
• It is hoped that swicthing to a biosimilar for adlalimumab in NZ will lead to the ability to increase to weekly dosing. 
• This will re-establish control again in a significant proportion of patients
• Some patients lose control not because of low blood levels but due to high antibody levels to the drug.  This can also be checked and will become common practice.

What about side-effects?

• There is a small risk of infusion reactions .
  • Allergic type reactions - at the time of giving the treatment.  This is usually just some flushing or dizziness.
  • The infusion is stopped for a short time (infliximab) and then is usually able to be completed without problems.
  • There may be some redness and swelling around the injection site for Humira injections.  The starting dose is 4 injections which does increase the chance of some discomfort at the injection site with the first use

• There has been a lot of concern about the possibility of infections.
  • TNF is an important part of the body’s normal defence against some infections.
  • In practice the risk of significant infections is about 1-2%. You should consult your specialist if any unusual syptoms develop or if you have an unexplained fever than is persisting
  • There are recommendations to have a CXR and blood tests to check for TB prior to starting treatment - particularly if there is any even of previous exposure to tuberculosis.
  • There should be a range of blood tests looking for exposure to infections  - including Hepatitis B and C, herper zoster.

• There have been reports of an increased number of cases of lymphoma after infliximab treatment.
  • This issue is still unclear but longer term follow-up is very reassuring.  There may be no risk or the risk is very small.  All the potential risks need to be carefully discussed with your specialist and weighed up against the gains that are achieved - which vary for each person
  • Infliximab and adalimumab have been widely used for over 10 years.  Therefore there is growing experience with these treatments and the ability to limit any negative effects is increasing

Other moncolonal antibodies

• There are several new drugs becomiong available for Crohn's disease
• Vedolizumab abd ustekinumab are under active consideration for NZ (already available in Australia)
• These drugs have similar success rates as infliximab or adalimumab but offer an option those that did not responsd to these first two options
• They are also an option if there is gradual loss of effect of anti-TNF drugs
• In general swiching within the same class of drug will not work because of antibody formation - this can now be tested
• It is important to maintain the action of anti-TNF drugs as long as possible.  This is best done using combination treatment with azathiprine or methotrexate

More severe inflammation of the colon

This diagram shows Crohn's disease of the termial ileum - the last part of the small bowel before the junction with the colon. There is narrowng of the bowel (the lumen) which will lead to cramping abdominal pain

Why is does immune suppression work?

• Inflammatory bowel disease is an inflammatory condition of unknown cause.
• However it is known that there are overactive immune cells in the gut that are causing some of the damage to the lining of the gut.
• Mostly it seems that these immune cells are over-reacting to the normal environment, particularly to the bacteria that are normally present in the lumen of the gut.
• Dampening down the immune system is a highly effective way of treating ulcerative colitis or Crohn's disease (IBD).

This can be achieved with two treatments – azathioprine and methotrexate.

• Azathioprine is currently used in up to 50% of people with IBD at some stage during the treatment. Methotrexate is used less commonly but is also effective.

What is the expected effect?

• Azathioprine leads to complete relief of symptoms in over 80% of patients who are able to tolerate the medication.
  
• The effect can take some time – up to 6-9 months although some benefit is usually seen after 3 months.
  
• The main benefit is getting off the steroids (Prednisone).  Steroids have side-effects if taken over a long period of time (see tab on steroids).

What is the recommended duration of use for azathioprine?

• Azathioprine has been used for Crohn’s disease and ulcerative colitis since the late 1960’s.
  • Treatment was initially continued for many years (5-10 years).
  • In the late 70’s several studies questioned whether the medication worked at all and the treatment become less popular.
  • It is now clear that these studies were not continued for long enough to see an effect (less than 6 months treatment was given).
• In the late 80’s the medication was used more commonly but only for 2 years then the drug was discontinued even when there was an excellent response.
  • A review of this practice showed that relapse of the disease was common within one year after stopping the medication.
• There has been a gradually increasing confidence with using azathioprine in recent years and an acceptance of the powerful therapeutic effect (once the correct dose is achieved).
  • The average dose has increased as we have become better at using the drug in an optimum way.
  • Monitoring of 6-TG levels (blood levels of the active metabolite) has shown us that we have been under-dosing many people in the past.
• There is now an acceptance that 5 years duration would be a minimum duration of treatment but probably 10-15 years or more is a reasonable safe limit.
  • Treatment beyond this limit may be considered after careful discussion with your specialist.
  • Many gastroenterologists would now advocate long-term treatment with azathioprine.  i.e the risks and negative consequences of coming off treatment significantly outweigh possible issues with long-term treatment
    

Click here for more details on azathioprine and methotrexate

This diagram shows the surgery required for Crohn's disease of the terminali leum

A portion of bowel can be removed and joined together without significant effects on bowel function

Surgery for Crohn's disease

Surgery is required if medical treatment fails to control the symptoms.

• The most common problem is "blockage pain" - this is typically cramping pain after meals (1-2 hours after the meal) and may be associated with a feeling of distension and nausea.
• This is due to narrowing of the bowel at some point - a common site is at, or close to, the junction between small and large bowel (called the terminal ileum)
  
• Narrowing can be caused by swelling of the bowel from inflammation and this will often improve with medication aiming to reduce the inflammation and swelling.  However over time, particularly if the disease is not well controlled, scarring of the different layers of the bowel can occur leading to a fixed narrowing (fibrosis) that does not respond to medication.  
• In this situation removing the narrowed segment is the best option (a surgical resection). Sometimes this can be avoided by refashioning the bowel to create a wider lumen (central space) without removing any bowel and occasionally for short areas of narrowing (stricture) a balloon dilatation may provide relief of symptoms
  

Surgery can be a very effective means of relieving symptoms.    

• The operation may be able to be performed by laparoscopic (keyhole) approach - leaving only a small incision
• The bowel is usually joined together immediately and normal eating can start within a few days.
• If there is complicated disease, particularly if infection is present, then a temporary ileostomy may be required (this requires a bag covering a stoma (or opening) on the wall of the abdomen to collect bowel contents).  This is removed and normal continuity restored after 2-3 months once the join (anastomosis) has fully healed

Why try to prevent surgery?

• Crohn's disease is not cured by removing diseased parts of the bowel. The disease may come back in previously healthy segments of bowel - typically at the join of previous surgery.
• This recurrence of disease may takes many years.  The rate of recurrence is difficult to predict  - another operation may never be required or there could be a need for an operation an another 2-3 years.
• Surgery needs to be performed if troublesome symptoms but careful consideration needs to be given to ways of preventing or least  delaying another operation

How to prevent another operation?

• The most effective medication is azathioprine.  This will commonly be started soon after an operation. 
• If the disease seems to been relatively slow "grumbling" disease i.e symptoms for 10 years (perhaps with no or minimal medication before an operation was required) then a more low key approach may be justified.  In this situation I use a salicylate (Pentasa or Asacol).  The dose required to prevent a recurrence is relatively high (8 tablets per day) and needs to be continued long-term
• This is some evidence that a course of the antibiotic Metronidazole for 3 months - starting immediately after the operation - can delay a recurrence.    If this is true then this seems to be an easy treatment to consider  - i.e a short course of treatment for longer term gains
• There is good evidence that the anti-TNF drugs (Remecaide and Humira) can prevent recurrence after an operation.  This is not funded at present for this indication but would be a good option if the disease has been severe and there have been two previous operations

There is good information that smoking increases the risk of the disease coming back.  Stopping smoking is crucial. No point taking strong medication if smoking is undoing any benefit !!!

When will a "bag" be required?

• This is becoming a less common situation with improved medical treatment.  Sometimes a temporary bag (covering and collecting bowel contents from a stoma or ileostomy) is required if surgery has been complicated or if there is infection in the abdomen.
• Rarely for disease of the colon that is not controlled or for severe disease around the rectum and anus with fistula then the colon needs to be removed and the end of the small bowel attached to the abdominal wall (ileostomy).
• This is obviously a disappointing situation but experience suggests that people are pleased with the outcome and the resulting control of the disease.  The major advantage of a bag is complete confidence with regards to continence