Grades of recommendations (A-D) and levels of evidence (I-IV) are defined at the end of the "Major Recommendations" field.
Azathioprine Indications in Dermatology
The main area of azathioprine use in dermatology is in the treatment of autoimmune dermatoses, in particular bullous pemphigoid (Grade B; level IV), and pemphigus vulgaris (Grade B; level II-iii) where azathioprine is used as a steroid-sparing agent. Accumulating evidence also suggests a role for azathioprine as a single agent in the treatment of severe, recalcitrant atopic dermatitis (Grade A; level I). Double-blind, placebo-controlled trials have shown azathioprine to be of benefit in chronic actinic dermatitis (Grade A; level I) and Behçet's disease (Grade A; level I). It may also be effective as monotherapy in the treatment of severe, recalcitrant psoriasis (Grade C; level IV). Azathioprine is sometimes used in the treatment of other rare dermatological conditions including Wegener's granulomatosis, pyoderma gangrenosum, pityriasis rubra pilaris, lupus erythematosus and lichen planus, but evidence to support its usage in these conditions is anecdotal (Grade C; level IV).
Azathioprine Contraindications
Azathioprine is contraindicated in patients with known hypersensitivity to the drug (Grade A; level III). Evidence of teratogenicity with azathioprine in humans is equivocal, but adequate contraceptive precautions are advised when either partner is taking azathioprine. Azathioprine is also contraindicated in pregnancy (except where benefit may outweigh risk such as in allograft recipients) (Grade A; level II-ii). 6-Mercaptopurine (6-MP) has been identified in colostrum and in the breast milk of women receiving azathioprine treatment. Women on azathioprine should therefore be advised to bottle feed their babies. It is strongly recommended that azathioprine should not be used in patients whose thiopurine methyltransferase (TPMT) status is unknown (Grade A; level II-ii). Very low or absent TPMT activity is a contraindication to the usage of azathioprine because of the high risk of life-threatening pancytopenia (Grade A; level II-ii). Concurrent treatment with allopurinol results in an important drug interaction which may cause significant myelosuppression, and should therefore be avoided (Grade A; level III).
There are concerns that azathioprine treatment increases the risk of developing a malignancy. Accumulating evidence suggests that this risk is smaller than was originally feared. Nevertheless, patients should be advised of this risk, and it is recommended that azathioprine treatment should not usually be initiated or continued in patients with known malignancy (Grade A; level III).
Pretreatment Thiopurine Methyltransferase Assessment
Although there are currently no published prospective studies for dermatological conditions which demonstrate improved prognosis, TPMT screening prior to azathioprine treatment is considered by some clinicians to be essential (Grade A; level II-ii).
- Pretreatment thiopurine methyltransferase (TPMT) measurement should be performed in all patients prescribed azathioprine for treatment of dermatological conditions
Azathioprine Dosage
The recommended dosage of azathioprine for dermatological indications is 1 to 3 mg kg-1 daily, adjusted within these limits according to response. If no improvement occurs in the patient's condition within 3 months, consideration should be given to withdrawing azathioprine. Care should be taken when prescribing azathioprine in the elderly: it is recommended that the dosage used is at the lower end of the range. There are currently no data to support prescribing azathioprine in doses outside the above range. However, modified dosage regimens based on TPMT activity have been published for both adults and children (Grade C; level III), and are the logical progression of this pharmacogenetic assessment.
Azathioprine should not be used in patients with very low / absent TPMT activity (deficient), as the danger of severe and prolonged myelosuppression is significant (Grade A; level II-ii). Patients with inflammatory bowel disease and low TPMT activity have been shown to be at increased risk of azathioprine toxicity. Thus, for patients with low TPMT activity, alternative systemic therapies should be considered (Grade A; level II-ii). If a trial of azathioprine is deemed appropriate in this situation, a low-dosage regimen should be used (0.5 to 1 mg kg-1 daily) and extra care taken with haematological surveillance (Grade B; level III).
In patients with high TPMT activity (see Appendix 2 in the original guideline document for laboratory ranges), the azathioprine dose should be at the higher end of the range of 1 to 3 mg kg-1 daily. It is probably safe to treat these patients from the outset with dosages of azathioprine towards the top end of this dosage range provided the usual measures are taken to monitor for myelosuppression. However, azathioprine intolerance unrelated to TPMT activity is not uncommon, and a lower initial dose of azathioprine is advocated by some authors for the first month of therapy, even in patients with high TPMT activity. In patients with inflammatory bowel disease, high TPMT activity predicts treatment failure with azathioprine. Thus, in dermatology patients with high TPMT activity, azathioprine dosage should be at the top of the recommended dose range of 1 to 3 mg kg-1 daily. In patients who fail to respond to 3 months of this dosage regimen, and in whom no adverse effects occur, dosage above the 1 to 3 mg kg-1 daily range might be considered for a trial period (Grade C; level III). However, if this approach is adopted, care should be taken in monitoring for myelosuppression and possible hepatotoxicity.
- If no therapeutic response is observed within 3 months of starting azathioprine, treatment should usually be withdrawn.
- In patients with very low/absent TPMT activity (deficient), azathioprine is contraindicated.
- In patients with low TPMT activity, azathioprine should either not be prescribed or, if used, the dose should be low (0.5 to 1 mg kg-1 daily) with careful monitoring for myelosuppression.
- In patients with normal or high TPMT activity, azathioprine dosage should commence at the top of the 1 to 3 mg kg-1 daily dosage range. In patients who fail to respond, and in whom no adverse effects occur, dosage above the 1 to 3 mg kg-1 daily range might be considered for a trial period.
Monitoring for Azathioprine-Induced Toxicity
It is advised that dermatologists carry out weekly blood tests (full blood counts [FBCs] and liver function tests [LFTs]) until maintenance dose is achieved, followed by regular monitoring reducing to a minimum of once every 3 months for the duration of therapy (Grade A; level I).
For higher dosages and for patients with hepatic or renal impairment, initial blood count monitoring more frequently than once weekly is advised. Return to weekly FBCs and LFTs should also follow an increase in dosage in azathioprine in patients already established on this treatment. It is also advised that patients on azathioprine be instructed to report immediately any evidence of infection, unexpected bruising or bleeding or jaundice. In patients with low TPMT activity (3 to 8 nmol h-1 mL-1 red blood cells), monitoring for FBC and LFTs should be more frequent than outlined above due to the increased risk of toxicity. Acute pancreatitis is a rare but well-recognized side-effect of azathioprine treatment. In azathioprine-treated patients with acute abdominal pain and/or severe vomiting, acute pancreatitis should be considered and serum amylase measured.
Monitoring for azathioprine toxicity should include:
- Weekly monitoring of full blood count (FBC) and liver function tests (LFTs) for the first 4 weeks of therapy, or until the maintenance dose is achieved; reducing to a minimum of once every 3 months for the duration of therapy.
- More frequent monitoring of FBC and LFTs is advised in patients with hepatic or renal impairment, in the elderly and in those treated with high doses of azathioprine.
- Increase in dosage of azathioprine should be accompanied by return to weekly FBC and LFTs for 4 weeks, reducing to a minimum of once monthly or every 2 months for the duration of therapy.
Azathioprine-Induced Susceptibility to Infection
- Azathioprine in combination with prednisolone is associated with an increased risk of infection, which may be fatal in the elderly. Dermatologists are advised to use the minimum necessary doses of immunosuppressive therapies to control immunobullous diseases in the elderly (Grade A; level II-ii).
- Live vaccines are contraindicated for patients receiving azathioprine (Grade A; level III).
- Killed vaccines may elicit a diminished immune response in patients receiving azathioprine (Grade B; level II-ii)
Azathioprine-Related Malignancy
- Dermatologists should make patients aware of the possible increased risk of malignancy related to long-term azathioprine therapy (Grade B; level IV).
- Skin photoprotection should be advised when relevant (Grade B; level IV).
Patient Information and Informed Consent
- Before azathioprine is prescribed, the clinician should provide the patient with an azathioprine patient information sheet, and discuss the anticipated benefits and possible side-effects.
Definitions:
Levels of Evidence
I: Evidence obtained from at least one properly designed, randomized controlled trial
II-i: Evidence obtained from well-designed controlled trials without randomization
II-ii: Evidence obtained from well-designed cohort or case–control analytical studies, preferably from more than one centre or research group
II-iii: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence
III: Opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committees
IV: Evidence inadequate due to problems of methodology (e.g., sample size, or length of follow-up, or conflicts of interest)
Grade of Recommendations
- There is good evidence to support the use of the procedure
- There is fair evidence to support the use of the procedure
- There is poor evidence to support the use of the procedure
- There is fair evidence to support the rejection of the use of the procedure
- There is good evidence to support the rejection of the use of the procedure
