Azathioprine is widely used in Rheumatology for conditions such as vasculitis and Lupus, and by some in Rheumatoid. It certainly has a place in gastroenterology for the management of ulcerative colitis and Crohn's disease, where it is more effective for maintenance of remission than 5-ASA.
However, the use of Azathioprine is beset with problems. Around 10% of subjects have hypersensitivity reactions to this drug, comprising fever, nausea and diarrhoea, fatigue, malaise and myalgia, mandating rapid discontinuation. A further 25-30% have side effects such as hepatotoxicity in the form of transaminitis or myelotoxicity manifesting as neutropenia. As a result, fully 40% of subjects that start azathioprine do not continue with the drug.
Observance of some simple principles can obviate these difficulties. The first of these is widely practiced- measuring TPMT levels before starting azathioprine. In the general population, 89% of subjects are homozygous for high metabolism of azathioprine (high TPMT) , 11% are heterozygous and 0.3% have low levels of TPMT.
It is common practice not to use azathioprine in subjects with lowish TPMT- these are the heterozygotes. This is a missed opportunity as these are the very subjects who are likely to respond the best to the drug. Thus, people with TPMT levels >25 U/ml need no dose adjustment. (Below 25 U/ml, halve the dose, and monitor more frequently). Conversely, those with levels above 65 U/ml, although reassuring on the face of it, are likely to have treatment failure.
Azathioprine is a prodrug of 6-MP. Most of the ingested azathioprine is non-enzymatically cleaved to 6-MP in the liver. Yet, there is a marked non-familiarity with 6-MP amongst Rheumatologists and perhaps to a lesser extent among Gastroenterologists. Several studies show that in subjects with hypersensitivity to azathioprine, nearly 70% tolerate a switch to 6-MP. The dose for 6-MP is half that of azathioprine (1-1.5 mg/kg body weight, rather than 2-2.5 mg/kg). Subjects with flu like reactions, nausea, emesis, myalgias and arthralgias on Azathioprine are likely to be able to switch successfully to 6-MP. OTOH, those with hepatotoxicity and pancreatitis are likely to have the same problems with 6-MP.
The converse does not apply. Thus, subjects who are intolerant to 6-MP should not be switched to azathioprine.
While most practitioners are aware of the importance of measuring TPMT before commencing thiopurines (azathioprine or 6-MP) , there is less awareness of the rather high usefulness of measuring thiopurine metabolites. Two metabolites are measured by most labs- 6-Thioguanine nucleotide (6-TGN) and 6-Methyl mercaptopurine (6-MMPN). The metabolite 6-MMPN is produced en-route to 6-TGN (please see diagram). It is the blood level of 6-TGN that indicates efficacy of azathioprine. Within a blood 6-TGN range of 235-450 pmol/8 x 10^8 RBC (send whole blood in an EDTA tube, just like TPMT), azathioprine is likely to be effective. Below 235, efficacy is likely to be low. This latter could be due to 2 reasons- non compliance, or the fact that not enough azathioprine is being metabolised to the active metabolite 6-TGN. In the latter case , blood 6-MMPN levels will be high (range 0-5700).
The combination of low 6-TGN and high 6-MMPN levels presages treatment failure and hepatotoxicity, and is described as azathioprine resistance. Unlike with non-compliance (where 6-TGN is low and 6-MMPN is normal), increasing the dose of azathioprine where resistance exists is only likely to lead to hepatotoxicity without increasing efficacy.
Keep in mind though that unlike hepatotoxicity, isolated neutropenia is a surrogate marker for the effectiveness of azathioprine. Here, the 6-TGN levels are likely to be high, and may require a reduction in dosage, rather than discontinuation, as with transaminitis. (If hepatotoxicity and neutropenia occur together, discontinue the drug).
There are anecdotal reports that in subjects with high 6-MMPN levels, splitting the dose of azathioprine is likely to improve efficacy and reduce toxicity, while lowering the level of 6-MMPN and maintaining that of 6-TGN. However, this is based on observations from a single study.
It is fair to say that we could be using azathioprine a lot more effectively than we currently do.
Figure. Thiopurine metabolic pathway. Metabolic pathway for AZA and 6MP is shown in the diagram. AZA: Azathioprine; 6-MP: 6-mercaptopurine; 6-TU: Thiouric acid; 6-MMP: 6-methylmercaptopurine; TIMT: Thiopurine methyl-transferase; 6-MMPR: Methyl-mercaptopurine ribonucleotide; TXMP: 6-thioxanthosine monophosphate; 6-TGN: Thioguanine nucleotide; 6-TG: Thioguanine; 6-TGDP: 6-thioguanine diphosphate; 6-TGTP: 6-thioguanine triphosphate; XO: Xanthine oxidase; TPMT: Thiopurine methyltransferase; HPRT: Hypoxanthine phosphoribosyl transferase.
Reference:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208360/
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