Gastroenterology training and education

Discuss the indications for Aza and 6MP?

• Steroid dependent or refractory IBD
• Fistulating and perianal CD
• Maintenance treatment- effective for maintaining remission for many years in up to 95 percent of patients with Crohn’s disease whose remission was initially achieved with these drugs.

Discuss the pharmacology of thiopurines?

• Azathioprine is a pro drug which undergoes conversion to 6-MP.  The conversion is done non-enzymatically by glutathione present in red blood cells and other tissues.
• 6-MP is then metabolized in the liver and gut by one of three enzymes; 6-thiopurine methyl transferase (TPMT), Xanthine oxidase, and Hypoxanthine-guanine-phosphoribosyl transferase (HGPRT).  HGPRT converts 6-MP to active metabolite 6-thioguanine (6-TG) nucleotides whereas the other two enzymes metabolises 6-MP to inactive metabolites.

Discuss the mechanism of action of thiopurines?
The precise mechanism is unknown. It appears likely that their thioguanine nucleotide metabolites modify the immune response by inhibiting DNA synthesis in T-lymphocytes. Interference with neutrophil function may also be important.

Discuss the dosage for thiopurines?

• Azathioprine- maximum dose of 2.5mg/kg body weight
• 6-MP- maximum dose 1.5 mg/kg body weight
• These drugs (AZA or 6-MP) are generally started at 50 mg. If the medication is well tolerated after one month, then the dose of 6-MP is increased to 75 mg and AZA is increased to 100 mg, depending on the patient’s weight. After three months of therapy, the dose of 6-MP and AZA may be further increased to 100 mg and 150 mg, respectively, if no obvious therapeutic response is seen, provided that the patient is tolerating the therapy and the WBC is > 4 X 10(3)/L.
• A minimum effective dose for inducing remission is unknown. Further, whether leukopenia is needed to induce a response is controversial.
• Allopurinol blocks the metabolism of 6-MP by inhibiting xanthine oxidase and so in these patients, it is often adequate to use half doses of AZA or 6-MP.

Discuss the efficacy of thiopurines in maintaining remission?
A Cochrane review concluded that

• The Peto odds ratio (OR) for maintenance of remission with azathioprine was 2.32 (95% CI 1.55 to 3.49) with a NNT of 6.
• The Peto OR for maintenance of remission with 6-mercaptopurine was 3.32 (95% CI 1.40 to 7.87) with a NNT of 4.
• Higher doses of azathioprine improved response.
• A steroid sparing effect with azathioprine was noted, with a Peto OR of 5.22 (95% CI 1.06 to 25.68) and NNT of 3 for quiescent disease.
• A benefit on induction of remission has also been suggested but the magnitude of benefit is unclear, particularly since several months of treatment are required before maximal efficacy is observed.

Discuss the time to response for thiopurines?
These are slow acting drugs and take 3-6 months to exert their effect. Thus these drugs are not indicated for monotherapy in acute relapses of inflammatory bowel disease.

Discuss the use of azathioprine versus 6-MP?
There is greater published evidence with azathioprine, however they can be used for similar indications and are equally effective.  A proportion of patients intolerant of azathioprine (predominant GI side effects) can tolerate 6-MP. Azathioprine is generally preferred in UK.

How long the thiopurines should be continued??
It is generally recommended that therapy with AZA/6-MP who has achieved remission should be continued indefinitely, as long as the treatment is well tolerated. Some experts recommend stopping thiopurines after 4 years in view of the risk of malignancy with continued use of thiopurines.

Discuss the side effects of thiopurines?

• Common side effects- nausea, vomiting and malaise. Dyspeptic symptoms can be minimized by taking the drug with meals.
• Dose dependent such as bone marrow depression and liver dysfunction
• Dose independent including pancreatitis , allergic reactions such as drug fever or rash, and pneumonitis
• Infectious- patients should be watched carefully for opportunistic infections especially those on concomitant steroids
• Neoplastic – A meta-analysis estimated that the risk of lymphoma in patients with IBD treated with azathioprine or 6-MP was increased fourfold compared with the general population.

Discuss the monitoring needed during thiopurine treatment?

• A complete blood count with differential should be obtained weekly for the first month and then 3 monthly for as long as the patient is receiving therapy.If the white cell count decreases below 4x 10(9)/L or the platelet count decreases below 120 x 10(9)/L, the dose should be reduced until these parameters normalize, while if the white blood cell count decreases below 3 x 10(9)/L or the platelet count decreases below 80 x 10(9)/L the drug should be discontinued until these parameters normalize.
• Liver function tests should be obtained every three months A dose-dependent elevation in serum aminotransferases can occur. Mild hepatitis is usually reversed by lowering the drug dose by up to 50%.  Besides mild hepatitis, both 6-MP and AZA can cause severe cholestatic jaundice, which may progress despite discontinuing therapy. Thus, treatment should be stopped in patients who develop significant unexplained hyperbilirubinemia while on therapy.

Discuss the argument for testing for TPMT before initiating treatment with thiopurines?

• Toxicity of AZA or 6-MP is largely related to the activity of TPMT. Deficiency of TPMT leads to preferential metabolisation of 6-MP and AZA to thioguanine nucleotides responsible for much of the drug toxicity.
• Low TPMT activity has been observed in up to 11 percent (heterozygous) of the population, with 0.3 percent (homozygous) having negligible activity.
• Either TPMT genotype or TPMT enzyme activity can be measured. TPMT enzyme activity is often measured in clinical practice in UK
• Low TPMT enzyme activity may lead to increased risk of myelosuppression.  However, the majority of patients who develop myelosuppression while taking AZA do not have detectable TPMT gene mutations. Thus a normal TPMT screening test does not preclude bone marrow and/or liver toxicity.  Thus, even when TPMT testing is performed, regular FBC and liver function tests must still be obtained.
• Experts vary in their use of TPMT. However, in current clinical practice TPMT levels are often measured before initiating treatment. Those with absent TPMT enzyme activity should not receive AZA or 6-MP. Patients with normal TPMT enzyme activity can be treated either by beginning with a low dose and increasing incrementally to the target dose or by beginning with the target dose at the outset.
• In non responding patients 6-TG levels may be obtained to check compliance.

Discuss the safety of thiopurines in pregnancy and lactation?

• Both azathiopurine and 6MP are considered are safe in pregnancy.
• Reports of teratogenicity with these drugs have occurred in foetuses in which exposure was from either the mother or father. Males on 6-MP should probably stop the agent three months before conception to lessen the risks of spontaneous abortion and foetal abnormalities.
• Azathioprine and 6-MP are detectable at low levels in breast milk. Mothers taking these drugs should avoid breast feeding, although no good data are available regarding risks to the nursing infant.