• Ulcerative Colitis
• Pentasa / Asacol
• Proctitis
• Steroids
• Surgery
• Azathioprine

Mild ulcerative colon - the pattern of blood vessels cannot be seen - there is a granular appearance to the lining of the colon


Severe ulcerative colitis - deeper ulceration and loss of mucosa

What is ulcerative colitis?

• This is an inflammatory disease of unknown cause that is limited to the large bowel (colon).
  
• It begins in the rectum and spreads back up the colon.
  
• The mucosa(lining of the bowel) is inflamed (reddened with a granular surface – like a rash).
  
• Despite the name actual ulcers do not occur except during severe acute attacks.

What are the main symptoms?

• The main symptom is diarrhoea (often with blood and mucus).
  • As well as frequent bowel motions there is usually urgency and a feeling of incomplete emptying.
  • There may be some discomfort in the left lower abdomen.
  
  
• The disease is characterised by remission and relapses. The extent of disease is variable.
  • ¼ have total colitis (pancolitis).
  • ½ have limited colitis (only rectum and part of colon involved).
  • ¼ have involvement of the rectum only(proctitis).
    • When only the rectum is involved there may not be loose motions and the main symptoms are bleeding and urgency.
  
  
• Colonoscopy is very helpful to determine extent and severity of disease.
  
• Most patients (90%) go into remission after first episode but have continue to have a relapsing course.
  
• There is a risk of the disease progressing to involve more of the colon.
  • The risk of progression is about 30% for rectal involvement (proctitis).
  • There may be a decrease in this risk with more aggressive treatment.
  • Early treatment of relapses is important. This is often better with "self-management". That usually means knowing when to start steroids rather having to consult a doctor first.

Symptoms other than diarrhoea.

• There can be other symptoms that do not involve the bowel.
  • Arthritis.
    • Affects mainly knees, ankles, elbows and wrists.
    • Tends to relapse and remit with the activity of the colitis.
    • Less commonly there is sacro-ileitis which gives persistent backache and morning back stiffness.
  • Iritis is a condition that gives a painful red eye with blurring of vision – urgent treatment is required.
  • Rarely there can be serious effects on the liver that gradually progress over time.

Treatment - medications

• This is a brief summary - more details are given in sections on each medication
• A mild relapse is managed with increased dose of oral salicylates(a 5-ASA preparation such as Pentasa, Asacol or Dipentum.
  
• A more severe attack will require oral steroids (Prednisone)
  
• Oral 5-ASA compounds (salicylates) are usually continued as long term maintenance treatment.
  • They reduce the risk of relapse by 50% (usual doses are Pentasa or Asacol four tablets per day).
    
• Immunomodulators such as azathioprine are being used more commonly to maintain remission usually for periods up to 5-10 years (see section on azathioprine).

Salicylates - this term includes Salazopyrin, Asacol, Pentasa and Dipentum

• This is a group of drugs that have some structural similarities to aspirin.
  • The correct term is 5-amino-salicylates (5-ASA).
  • They have a mild anti-inflammatory effect on the bowel.;
  • The first drug was salazopyrin (sulphasalazine).
    • This was initially developed for the treatment of rheumatoid arthritis.
    • By chance this was found to have an effect on ulcerative colitis.
    • This drug is a combination of a 5-ASA compound and a "sulphur" drug.
    • The main problem has been delivering the drug to the right part of the bowel.
      • 5-ASA is destroyed by stomach acid.
      • Salazopyrin gets round this problem but joining the 5-ASA molecule with the sulphur drug.
      • The bond between these two compound is split by bacteria in the colon.
      • Therefore Salazopyrin only works in the colon.
    • The "sulphur part" is absorbed and can cause side-effects.
      • In particular this can be responsible for a rash, nausea and changes in the blood count.
      • There is also a reversible decrease in sperm count (possible some decrease in male fertility).
        
• There are now three new formulations of this old drug.
  • They avoid the need for the "sulphur" part of the part and therefore have less side-effects.
  • Pentasa is a slow release formulation using enteric coated microspheres.
    • This gives a graduated release of drug throughout the small bowel and large bowel.
    • This makes this drug suitable for small bowel Crohn's disease.
    • The tablet size is large and the tablet dissolves into "gritty" granules if there is delay or difficulty with swallowing the tablets.
    • They can be dissolved in water before ingestion but the granules will tend to settle in the bottom of the glass - needs to be stirred before swallowing.
  • Asacol is also slow release but is based on a pH-sensitive coating.
    • This is effective but can be variable in effect because of differing pH profiles in peoples digestive system.
    • If there is diarrhoea with rapid transit through the gut then these tablets can be recognized unchanged in the bowel motions.
    • The tablet size is smaller than Pentasa.
    • It is suitable for small bowel Crohn's disease - mainly ileal disease (near the end of the small bowel).
  • Dipentum is a formulation where two 5-ASA molecules are joined together.
    • There is a special bond that is broken by bacteria - similar concept to salazopyrin but without the "sulphur" part.
    • This is very effective way of delivering drug to the colon - the highest concentrations are in the left side of the colon.
    • This makes this drug suitable if there is colitis of more limited extent (say just the rectum and sigmoid colon).
    • Dipentum has no activity in the small bowel.
    • The disadvantage of this medication is diarrhoea in up to 15%.
    • This is obviously not desirable as diarrhoea is the main symptom to treat! The effect is reduced by taking with food and by gradual dose increase.
    • It is important to note that for a given dose you are getting double the delivery of drug.
    • Some people with proctitis (inflammation confined to the rectum) actually also have constipation - "a colon of two halves". Dipentum can be a good choice in this setting.


• Diarrhoea is also a possible side-effect with Asacol and Pentasa.
  • Less common - perhaps 5%.
  • Therefore it is often worth stopping the drug for a while to try to work out if this is a problem.
    
• There is often some trial and error required to find the formulation that suits.
  • As well there are some theoretical reasons to suggest one may be better in given circumstances.
  • The newer formulations are an advance but are not necessarily any more effective.
  • If you are already using salazopyrin and are not experiencing any problems then there is no need to change.
    
• There is an advantage of salazopyrin if you also have joint pains.
  • This drug is still an important part of treatment of many types of arthritis.
  • Arthritis is common with IBD - therefore the older drug can be useful for treating both arthritis and colitis.
    
• The newer formulations have less problems with indigestion, nausea and headaches.
  • Higher doses can be used because of less risk of side-effects.
  • This is no problem with male fertility (sperm counts).
  • There is a much reduced risk of rash or changes in the blood count (anaemia or low white blood count).
    
• Serious side-effects are very uncommon.
  • They include unusual inflammatory conditions - pericarditis, "pleurisy".
  • There is a rare side-effect called interstitial nephritis.
    • This can be a serious form of kidney disease and is reversible if the drug is stopped in time.
  • I recommend a yearly blood test including renal function to find this problem early.

• The 5-ASA drugs have only a modest ant-inflammatory effect.
  • Much less than the effect of steroids.
  • Only mild to moderate disease will be brought into remission by these drugs alone.
    
• The great advantage is that there are minimal side-effects.
  • Therefore they are suitable for long-term use.
  • Compared to steroids where there are increasing risks of side-effects with increasing duration of use.
    
• he effect may be different for ulcerative colitis and Crohn's disease.
  • Ulcerative colitis
    • The 5-ASA drugs have an important role in the maintenance of remission. There is strong evidence for a reduction in risk of relapse by 50%. This means continuing to take the medication while you are well.
    • The results are better if the drug if taken regularly. This means taking drug even when the disease seems to be completely settled.
    • When the colitis is first diagnosed it is often unclear how much of a problem there will be with relapses. If there are infrequent mild relapses then intermittent treatment may be the best option.
    • However the majority of people with colitis (more than proctitis) eventually opt for maintenance treatment - this means long-term.
    • For proctitis treatment - see FAQs).
    • The other significant advantage of maintenance treatment is a reduction in the risk of colon cancer by 50% (see section on colon cancer and IBD).
  • Crohn's disease
    • Crohn's disease that just involves the responds in much the same way as for ulcerative colitis - perhaps a little less effective than for ulcerative colitis.
    • Small bowel Crohn's disease can now be treated with the newer formulations. There is definite evidence for good effect in short-term treatment.
    • The evidence for effect in maintenance treatment - prevention of relapse - is less convincing but most gastroenterologists would recommend continuing with long-term treatment.
    • Another special role for 5-ASA drugs is the prevention of relapse after surgical treatment of Crohn's disease - particularly resection of ileum (small bowel).
      • There are some good studies that show that starting (or continuing) treatment after the operation decreases the relapse rate (as determined by colonoscopy) 3 years later.
      • The effect is not that dramatic and does require taking 6-8 tablets per day of Pentasa or Asacol (according to the studies) - 4 tablets per day is unlikely to be effective. This issue is discussed in the FAQs section.

• Proctitis is chronic inflammation (of the ulcerative colitis type) confined to the rectum.
  • That is only the last few inches of the bowel are involved.
  • Diarrhoea is generally not the problem.
  • The main symptoms are bleeding, frequency and urgency of bowel motions and a feeling of incomplete emptying.
  
  
• The treatment should concentrate on medication given through the anus.
  • There are a variety of formulations available.
  • The easiest (and most acceptable) method of delivering drug to the affected area is by suppositories (e.g. Asacol suppositories).
    • This results in good delivery of 5-ASA to the rectum and perhaps further up to the sigmoid colon.
  • Colifoam enemas are also convenient to use(foam in a pressurized container).
    • Many people with proctitis alternate between these two types of medication or, by trial and error, find that one is better for them.
    • Colifoam is a steroid (like Prednisone) but the absorption is minimal and steroid side-effects are virtually unknown.
    • There is no problem with long-term use.
  • Liquid enemas (Pentasa and Asacol enemas) are more difficult to use.
    • They may be the most effective form of treatment and are able to treat inflammation extending further up the colon.
    • However most people are only able to manage more than short-term treatment.
  
  
• Taking tablets as well as per "rectal treatment" does have an additive benefit.
  • Usually this means a 5-ASA tablet like Asacol or Pentasa
  • Another 5-ASA tablet called Dipentum has some theoretical advantages (and some supporting trial data) for proctitis or distal colitis.
    • This medication needs to be introduced slowly and should be taken with meals to lessen the chance of causing diarrhoea.
  • Oral Prednisone and /or azathioprine are rarely required for proctitis.

Prednisone is the most commonly used steroid in NZ.

•  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 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 (the adrenal gland) usually makes.
  • Prednisone has powerful anti-inflammatory effects - therefore it useful many conditions that have inflammation - asthma, arthritis and colitis / IBD.
    
  • For Prednisone the equivalent dose to the normal body output is roughly 5mg daily.
• 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) and 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 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.
    • 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).

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 - may aggravate a previously mild problem (called impaired glucose tolerance).
  • Stretch marks on the abdomen.
  • Eye problems - 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).
    • 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.
• 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.

Colectomy (surgical removal of the colon) results in a cure of the disease.

• This operation may be performed as an emergency procedure, or may be recommended as a planned procedure because of failure of medical treatment.
• Forming an ileal pouch is a common operation for ulcerative colitis.
  • The surgical term is IPAA - ileal pouch - anal anastomosis.
  • This means there is no “bag” (an ileostomy).
  • A pouch or reservoir is fashioned out of small bowel.
    • About 30-40cms of small bowel is required - out of 300cms in total.
    • The small bowel is turned back on itself and stapled down the middle to create a pouch or reservoir (J pouch).
    • The pouch is joined directly on to the anus (anal canal) - about 2-3cms from the entrance.
  • Because there is no colon then it is usual to pass 5-6 bowel motions per day.
    • This is because the main task of the colon is to absorb fluid and minerals (sodium).
  • Getting up once at night is common - a few people will have leakage and need to use a pad.
  • There are two or three stages to the operation.
    • The first is the colectomy - removal of the inflamed colon. If there has been steroid treatment for a few months before the operation or general deterioration in health status then this is all that can be done with this stage.
    • If general health status is good with no problems expected with wound healing then, during the initial operation, a pouch made from small bowel can be fashioned and connected to the anal sphincters.
    • The final stage is closure of the ileostomy - this is done once there has been complete recovery and a "healthy" pouch has been confirmed.
    • It can still be several months before there is good function in the pouch.
    • From this is can be seen that the operation is a time-consuming multi-stage process and not a quick fix!
      
• Surgery is a cure for the colitis because the disease only affects the colon.
  • This is statement needs to be qualified in two ways;
    • There is a type of inflammation that can affect the ileal pouch (pouch made from the small bowel) - called "pouchitis".
    • Some non-bowel features of the condition can continue - i.e arthritis, liver disease.
  • No further medication will be required for the colitis.
    • However it is common to use "bowel slowing medication" to reduce the number of bowel motions per day to an acceptable level.
  • Bowel frequency may be as much as before the operation BUT;
    • There is not the urgency.
    • There is a general improvement in wellbeing because the inflammation has gone.
    • Bowel frequency can be decreased using medication such as loperamide or codeine.
  • There may still be a need for some long-term attention to diet.
    • The sort of diet that is sometimes recommended is similar to the exclusion diet (as discussed in irritable bowel section).
      
• A technically successful pouch operation cannot be guaranteed for everybody.
  • The operation is not commonly performed over age of 65 years.
  • If the anal sphincters are weak (damaged) then the operation is not advised.
  • A successful initial result is not possible for all for technical reasons (perhaps 2-3% failure rate).
  • Approximately 10% will eventually convert back to an ileostomy (bag) because of problems with pouch function (10 years follow-up information).
  • Remember that a temporary bag is required for all for 3-6 months after the initial operation.
  • An ileostomy is a very acceptable option long-term option.
    • Quality of life surveys suggest that there is equivalence of quality of life compared to a successful pouch operation.
    • There has been a major improvement in bags/appliances and there is excellent help through ostomy (stomal therapy) nurses and osteomate societies (e.g www.ostomyinternational.org).
    • Contents from the small bowel empty into the bag 5-6 times per day.
    • This is a thick odourless liquid that is easily emptied from the bottom of the bag - messy bag changes are not required.

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.

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.