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)
  

• Azathioprine is currently used in up to 50% of people with IBD at some stage during the treatment
• 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.
  • One option is to have a "drug holiday" for 6-12 months if you have had treatment for more than 5 years and the condition is in complete remission.  There is still a risk of relapse and azathioprine will need to be restarted at the first sign of recurrent symptoms
    
• There has been an increasing use of azathioprine in the treatment of ulcerative colitis.
  • There is an argument that drugs with any significant risks should not be used the treatment of ulcerative colitis because the results of surgery are good leading to a cure of disease.
  • However the contrary argument is that the results of azathioprine are excellent without the need for major surgery.
  • Most gastroenterologists will now suggest treatment with azathioprine before considering surgery
    
  • See section on surgery in ulcerative colitis

Drug interactions

• Azathioprine blood levels may be affected by other drugs.
  • The most significant interaction is with allopurinol (used for gout) – this could significantly increase the levels of azathioprine and lead to serious problems.
  • Minor effects on blood levels have been observed with frusemide and ACE inhibitors (Inhibace, Accupril).
• Once remission is achieved it is usually possible to stop the 5-ASA drug (Pentasa, Asacol).
  • Occasionally there is a relapse if the 5-ASA is stopped suggesting that the combination was better
    
  • The other reason for considering continuation of Pentasa or Asacol even when there is excellent control with azathioprine is the effect of these drugs on reducing the risk of colon cancer.

The "dampening of the immune system" can be achieved safely.

• This involves careful monitoring.
• Taking care to find the appropriate dose.
• In reality there is very little risk of infections.
• There is no increased risk of common infections like colds, flu, sinus problems, skin infection, etc.
• The main problem with azathioprine is an “allergic” type reaction.
  • The risk is about 1:10.
  • This can present as a headache, nausea, joint aches, backache, abdominal pain, flu-like symptoms or a skin rash.
  • The onset of these symptoms can be within 2-3 days or make take 1-2 months.
  • The medication needs to be stopped and the symptoms will subside over 2-3 days.
• Nausea alone is probably not an allergic reaction.
  • Nausea may gradually improve over time.
  • Sometimes taking the medication at night can help.
  • A lower dose may be tolerated OK.
  • Sometimes the alternative drug called 6-mercaptopurine causes less nausea
    
• The side-effect with the most potential for problems is a rapid fall in the white blood cell count.
  • These are the cells that fight infection.
  • The fall has to be very severe before there is any risk of serious infection.
  • Because of this possibility, there needs to be close monitoring of the white blood cells during the first few months.
• A rare but serious side-effect is pancreatitis.
  • If you experience severe pain in the upper abdomen it is important to contact your doctor immediately.
• Changes in liver enzyme tests occur in about 5% of people.
  • This occurs after 2-4 months.
  • There are usually no symptoms and this problem is only picked up on blood tests.
  • The changes completely resolve after stopping the medication.
  • Usually another similar drug called 6-mercaptopurine is tried - see below.

Monitoring with blood tests - getting the dose right

• I generally recommend the first blood test 2 weeks after starting treatment, then continuing with monthly tests for 3-4 months.
  • over the longer term, 3-4 monthly tests are usually adequate.
  • Any dose increase will require tests on a monthly basis for 2-3 months.
  • It may take 6-12 months before the appropriate dose if reached.
  • It is considered safer to slowly build up to the right dose.
• The other test that needs to be checked particularly during the first 6 months is the liver enzyme tests.
  • If there are elevations in the liver enzymes then the drug will need to be stopped.
• A gradual fall in the white cell count can occur over several months or years.
  • For this reason it is recommended that blood tests are performed every three months.
• There is significant individual variation in the metabolism of azathioprine.
  • The correct dose can vary from 1 – 5 tablets daily (50mg to 250mg).
  • The dose requirement is partly determined by the activity of an enzyme called TPMT. There is an assay for this enzyme. Some gastroenterologists will routinely test TPMT enzyme activity before starting treatment.
  • This assay is available in NZ (Christchurch) - about 1 in 300 people have very little TPMT activity and are at risk of severe problems with toxicity because of a rapid fall in white cell count.
  • The correct dose is indicated by some blood tests changes, by the response of the disease, by the ability to get off Prednisone without recurrence of symptoms and by blood levels - 6TGN assay.
  • A blood test giving the level of the drug (measures 6-TGN) - one of the main metabolites of both azathioprine and 6-mercatopurine) - has become available.
  • Measuring blood levels may be useful to confirm that the correct dose is being used. If the blood level is low then the drug can be increased with some confidence.
    
  • If the blood level is high then there may be an increased risk of a low white blood cell count or other side-effects.

Are there any alternatives to azathioprine?

• 6-mercaptopurine.

  • This drug has some structural similarities to azathioprine and can be tried if side-effects develop with azathioprine.
  • This has a 50% chance of being tolerated without side-effects.
  • The switch is often made if there is nausea or problems with abnormal liver tests.
  • The risk of pancreatitis and allergic reactions is probably the same with both medications. If there has been a significant episode of abdominal pain following the use of azathioprine (suspected pancreatitis), then it is probably unwise to risk taking 6-mercaptoprine
    
  • The dose is usually half of the azathioprine dose - 50mg (one tablet) 6-mercaptopurine = 100mg (2 tablets) of azathioprine.  However the correct dose will still take some time to determine as there is a lot of variabiilty between people in absorption and metabolism of these medications 
  • If you are unable to tolerate azathioprine or 6-mercaptopurine then the choices become more difficult. Surgery may be the right option or perhaps methotrexate.

• Methotrexate

• Sometimes another type of medication called methotrexate is used to suppress the immune system (mainly used in severe Crohn’s disease were surgery may not be a good option).
  
• A few facts about methotrexate
  • This also works by suppressing the immune system.
  • The drug has been used in cancer treatment and is very commonly used for treatment of rheumatoid arthritis.
  • Methotrexate is given either orally or by subcutaneous injection (similar to a diabetic).
  • Weekly dosing. 
  • Oral treatment is easier but has less reliable absorption compared to injection. 
  • The most effective dose is 25mg per week; the starting dose may be lower (10-15mg per week). 
  • Folic acid 5mg is usually given on days 2-5 after methotrexate is given.
  • Methotrexate has proven ability to bring Crohn's disease into remission but side effects limit the usefulness of the drug.
    
  • About 50% of people come off the drug after 3 months because of side-effects. The main problem is nausea. Mouth ulcers are common.
  • Careful monitoring of blood tests is required - liver tests, red cell and white cell counts. Persistent cough of breathlessness should prompt immediate medical attention
  • In some countries methotrexate is chosen ahead of azathioprine. In NZ the usage of methotrexate in Crohn's disease is limited but growing in acceptance
  • Information about treatment of ulcerative colitis using methotrexate is sparse. Many specialists feel that the drug has little place for the treatment of ulcerative colitis and consider that surgery is usually the right option (if all other options have been explored).
  • These decisions are very individual - a lot depends on attitudes to surgery and exposure to potential risk with any new medication that is tried
    

Possible long term effects

• The only other theoretical concern with long durations of treatment with azathioprine is the risk of malignancy.
  • The risk of cancer was first raised after long-term reviews of renal transplant patients treated with azathioprine.
  • In this setting there is an increased risk of skin tumours after 10-15 of treatment and an increased risk of lymphoma (cancer of the lymph glands) noted after 15 years of continuous treatment.
• There may a small increased risk of lymphoma for patients with inflammatory bowel disease treated with azathioprine.
  
  • This risk of lymphoma is probably the only significant issue here.  There is definitely no increased risk of colon cancer or any other cancer.  However, it is sensible to exercise caution by using available cancer prevention strategies - that is liberal use of sunscreen, regular cervical smears and mammograms.
  • Smaller single centre studies did not show any problems but a meta-analysis (combination of all studies) has shown an increased risk of lymphoma
    
  • Lymphoma is actually a very rare cancer.  It becomes a matter of comparing (weighing up) the often dramatically improved quality of life against the slightly increased risk of a very rare type of cancer.
  • This issue requires discussion with your doctor. Part of the balancing of risks is considering the risks of continuing Prednisone (steroid) treatment and the risks of surgery with the risks of azathioprine treatment. If azathioprine is discontinued because of the perceived long-term risks then a relapse is likely in the next year and some other treatment (with associated risks) will need to be given.