• Crohn's Disease
• Steroids
• Monoclonal antibody
• Immunomodulators

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


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


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

What is Crohn's disease?

• This is an inflammatory condition of unknown cause;
  
  • It affects 1 in 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;
  
  • Oesophagus, stomach, small bowel and large bowel
• The condition starts as small ulcers;
  
  • Called "aphthous" ulcers
  • These are similar 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)

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 localised 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

• Steroids (fullname 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.
  • 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.
    • 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

• 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.
    • In particular, 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).

• 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).

• 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
    • May aggravate a previously mild problem (called impaired glucose tolerance).
  • Stretch marks on the abdomen.
  • Eye problems - rare.
    • Glaucoma (increased pressure in the eye).
    • Cataracts.
  • Aggravation of indigestion, ulcer disease and maybe reflux.
  • Headaches - if persistent could be related to steroids.
  • Thinning of bones (osteoporosis).
    • Fractures related to bone thinning.
    • 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".
    • The aim of this treatment should be more than just reduction in dose of steroids - but the goal of getting off the steroids completely.
  
  
• The time for a change is a matter of judgment.
  • As a guide I think that being on steroids for more than 3 months in the year on a regular basis is unacceptable as a long-term plan for treatment.

Normal colon (appearance at colonoscopy)


Severe Crohn's disease of the colon

Remecaide and Humira  (infliximab and adalimumab)

• These drugs are antibodies that have been developed to remove one specific molecule responsible 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)

• After one infusion about 70% of people with Crohn’s disease have had a good response.
  • 1/3 have complete resolution of all symptoms.
  • This effect is observed within 2 weeks.
    
• 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).

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 a fortnightly subcutneous injection (easy to learn how to self-administer)
    


• maintenance treatment with Humira is now fully funded for selected patients.


• The availability of infliximab depends on the local arrangements within each DHB.

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 and then is usually able to be completed without problems.


• There has been a lot of concern about the possibility of infections.
  • TNF is an important part of the body’s defence against some infections.
  • In practice the risk of significant infections is about 2%.
  • There are recommendations to have a CXR and skin for TB - particularly if there is any even of previous exposure to tuberculosis.


• 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.
  • Infliximab and adalimumab have been widely used in the USA for several years.
    

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 azathioprine used and how does it 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 underdosing 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.