Initiating Azathioprine for Crohn's Disease

Barrett G. Levesque; Edward V. Loftus Jr, MD

Disclosures

Clin Gastroenterol Hepatol. 2012;10(5):460-465. 

In This Article

Management Strategies

Education

It is pragmatic to note to patients that approximately 15% of patients cannot tolerate AZA. These dose-independent adverse reactions include drug fever, pancreatitis, arthralgias, nausea, and rash. Drug fever usually presents within 2 weeks of initiating therapy as a flu-like illness, and requires immediately stopping AZA. The risk of pancreatitis is approximately 3%, typically occurs within the first few weeks of therapy, and requires stopping AZA as well. It is useful to instruct patients to have a low threshold for reporting new symptoms, especially in the first month of therapy. Dose-dependent reactions include leukopenia and hepatotoxicity. Although leukopenia most often occurs within the first month, it may occur at any time during therapy.

Thiopurine therapy in CD carries an increased risk of lymphoma. The Cancers et Surrisque Associe aux Maladies inflammatoires intestinales En France (CESAME) Study Group followed up 19,486 patients with inflammatory bowel disease (60% with CD) for a median follow-up period of 35 months (interquartile range, 29–40 mo). The adjusted hazard ratio for lymphoma in patients treated with thiopurines compared with those treated without thiopurines was 5.28 (95% confidence interval [CI], 2.01–13.9). The adjusted hazard ratio for lymphoma among patients who were never treated with thiopurines was not significantly different from patients for whom thiopurines had been discontinued. Incidence rates of lymphoma in patients continuing thiopurines ranged from 0.37 cases per 1000 person-years in patients younger than age 50 years, 2.58 per 1000 person-years in those aged 50 to 65 years, and 5.4 per 1000 person-years in patients older than age 65 years. There have been rare cases of fatal hepatosplenic T-cell lymphoma in primarily young male patients taking a combination of AZA/6-MP and anti–tumor necrosis factor therapy, or AZA alone, for inflammatory bowel disease (IBD). A small increased risk of nonmelanoma skin cancers has been found in patients on AZA therapy, with an absolute risk increase of 14% among patients taking thiopurines for more than 1 year. Sunscreen and regular skin checks are recommended for patients on AZA therapy. There may be an increased risk of cervical dysplasia among women with IBD on immunosuppressive therapies, especially if they are cigarette smokers, although the results of studies have been conflicting in this regard. Nevertheless, it would be prudent to recommend annual screening for cervical dysplasia if they are on immunosuppressive therapy.

The risks of AZA for CD during pregnancy are weighed against the benefits of medication, and risks of active disease. Active CD during conception and pregnancy has been associated with higher rates of adverse perinatal outcomes. Another study by the Cancers et Surrisque Associe aux Maladies inflammatoires intestinales En France (CESAME) Study Group described the pregnancy outcomes of 204 women with IBD followed up prospectively who were treated with and without thiopurines. The overall rate of congenital malformations in patients receiving medication (3.5%) was not significantly greater than the French general population, although the power of the study may not have been sufficient to detect smaller differences. Overall, it is recommended that risks and benefits of AZA be discussed to enable women to make an informed decision regarding its use during pregnancy. It is reasonable to continue AZA for patients who are tolerating the medication and in remission; however, this decision needs to be made on an individual basis with a discussion of the risks and benefits of therapy.

Vaccinations for influenza virus, Streptococcus pneumoniae, and human papillomavirus, if indicated, are recommended for CD patients considering or taking AZA. Live vaccines in immunosuppressed patients generally are contraindicated. Varicella zoster vaccination has been considered by some physicians in patients taking less than 3 mg/kg body weight daily of AZA, but in our practice we have avoided using this live virus vaccine in any patient on any medication with immunosuppressive properties (except oral budesonide). Reactivation of latent hepatitis B virus is a risk for patients treated with AZA, and hepatitis B surface antigen can be checked before starting AZA for patients with any risk factors for the disease.

Pharmacology

AZA is 55% 6-MP by molecular weight, and the conversion factor of 2.07 is used to convert a dose of 6-MP to a dose of AZA. TPMT, xanthine oxidase, and hypoxanthine phosphoribosyl transferase are the 3 enzyme systems that convert 6-MP to 6-thiouric acid, 6-MMP, and precursors of the active 6-thioguanine nucleotides (6-TGN). 6-TGN are incorporated into nucleic acid and subsequently inhibit synthesis of protein, RNA, and DNA.

Testing for TPMT activity or genotype before initiating AZA will reduce the risk of severe, life-threatening leukopenia in patients exposed to thiopurine who completely lack TPMT activity, and helps guide initial dosing for patients with intermediate and normal activity. Approximately 0.3% of patients are homozygous for the mutant inactive form of TPMT, 11% are heterozygous with intermediate activity, and 89% have normal activity. A recent systematic review found a sensitivity of genotype testing to be 70% to 83% for low to intermediate TPMT activity, with a specificity approaching 100%. Therefore, TPMT activity testing may assess risk of myelotoxicity more accurately than TPMT genotyping. A recommendation for testing TPMT genotype or activity before initiating AZA has been added to the prescribing information for AZA. It also is stated, however, that TPMT testing does not substitute for complete blood count monitoring for patients receiving AZA or 6-MP.

Dosing

AZA metabolism has several clinical implications. There is an inverse relationship between TPMT enzyme activity and 6-TGN concentration. For patients with normal genotype or activity level, it is reasonable to start with a dose of 2 to 2.5 mg/kg body weight daily of AZA (1.0 –1.25 mg/kg/d of 6-MP). Thiopurines at any dose are contraindicated in patients with absent or homozygous-deficient TPMT activity. Starting with low doses will not prevent life-threatening myelosuppression in these patients. For patients with heterozygous genotype or intermediate activity level, the starting dose is reduced by half, but may be increased in time to the full dose in many patients. Starting with low doses (eg, 50 mg/d) of AZA to reduce toxicity, and then increasing this dose over several weeks, will not prevent, but will only delay, dose-dependent toxicity (such as bone marrow suppression) and will not prevent dose-independent reactions (eg, drug fever, pancreatitis, arthralgia, rash). In a patient with a history of drug fever or pancreatitis, it is not recommended to change from AZA to 6-MP or 6-MP to AZA. However, several studies have suggested that 6-MP may be tolerated in up to 60% of patients who develop afebrile flu-like illness, nausea, vomiting, or rash while on AZA. A therapeutic response may take 2 to 4 months for most patients.

Efficacy

In the ideal setting, AZA therapy serves as a steroid-sparing agent that maintains clinical remission and attains mucosal healing. The data supporting these goals have been mixed in clinical trials. In the National Cooperative Crohn's Disease Study, Summers et al did not find a statistically significant difference between AZA (2.5 mg/kg/d) and placebo in rates of relapse over 1 to 2 years. A systematic review by Khan et al in 2011 showed no significant effect in inducing remission of AZA/6-MP vs placebo with a wide CI (relative risk [RR], 0.87; 95% CI, 71–1.06), and a trend but no significant prevention of relapse, again with a wide CI (RR, 0.64; 95% CI, 0.34–1.23). In this review, 3 AZA withdrawal trials showed a significant benefit for patients maintained by AZA in clinical remission (RR, 0.39; 95% CI, 0.21–0.74). In comparison, a 2010 Cochrane meta-analysis of the efficacy of AZA or 6-MP for inducing remission in CD showed a significant advantage of AZA over placebo, with a number needed to treat of about 5 to observe benefit in 1 patient. Overall, treatment with AZA may confer a 10% to 25% risk reduction for relapse compared with placebo. In a prospective randomized trial of AZA vs infliximab vs combination therapy, mucosal healing rates at week 26 were significantly lower with AZA therapy than infliximab or combination therapy at 16.5%, 30.1%, and 44%, respectively.

In patients without other contraindications who are unable to wean corticosteroids or achieve remission, adding a biologic agent to AZA increases the likelihood of clinical and endoscopic remission. The efficacy of combination therapy compared with AZA alone has been shown to be superior both in patients naive to AZA and in whom AZA has failed in the past.

Monitoring and Optimization

Myelosuppression is a dose-dependent adverse reaction that may occur at any time during AZA therapy. Frequent monitoring of complete blood count (CBC), as well as liver transaminase level for hepatotoxicity, is recommended. A genetic analysis of patients with myelosuppression on AZA therapy showed that only 27% carried mutant alleles, and therefore normal TPMT testing does not exclude the possibility of future leukopenia. A large retrospective cohort study showed that most severe neutropenia and thrombocytopenia occurs during the first 8 weeks of therapy; however, myelosuppression has been found even a decade after starting therapy, which supports intercurrent illness as an alternative etiology of leukopenia. Leukopenia (defined as below the normal limit for the testing laboratory) warrants stopping the medication and restarting at a lower dose once leukopenia has resolved. Even mild increases in liver transaminase levels are concerning, and if other etiologies are excluded, warrant discontinuing the medication owing to rare but present risks of nodular hyperplasia and fibrosis.

Assays for 6-TGN and 6-MMP are commercially available. Levels of 6-TGN greater than 235 to 250 pmol/8 × 108 erythrocytes and 6-MMP levels greater than 5700 pmol/8 × 108 erythrocytes have been found to correlate with therapeutic response and hepatotoxicity, respectively. Data on the utility of measuring metabolites are mixed. Nonresponders may have low or high 6-TGN levels and there are few safety data for doses greater than 2.5 mg/kg/d of AZA in CD. A meta-analysis examining the utility of 6-TGN levels in IBD showed that median levels were 66 pmol/8 × 108 red blood cells higher among responders than nonresponders, but there was significant heterogeneity. Patients with levels above and below a threshold of 230 to 260 pmol/8 × 108 erythrocytes had remission rates of 62% and 36%, respectively. Patients with and without hepatoxicity may have high 6-MMP levels; however, an increase in the alanine aminotransferase level in a patient on AZA without other liver disease warrants decreasing the AZA dose. AZA metabolite assessment is probably most useful in assessing patients with no or incomplete response, when nonadherence is suspected, and in finding a therapeutic dose in patients who are TPMT heterozygotes.

Allopurinol competes with xanthine oxidase, shunts metabolism away from 6-MMP production, and increases levels of 6-TGN. The addition of allopurinol may correct an unfavorable ratio of 6-TGN to 6-MMP by reducing 6-MMP concentrations and increasing 6-TGN concentrations. The addition of allopurinol to AZA, and subsequent substantial dose reduction of AZA, has been suggested in patients with hepatoxicity, arthralgias, or nausea to correct an unfavorable ratio of 6-TGN to 6-MMP. This is controversial and has been associated with high rates of opportunistic infections, despite small prospective studies showing safety of long-term use. If this is to be undertaken, we suggest an allopurinol dose of 100 mg/d, a reduction in the thiopurine dose to 25% of the original dose, and frequent CBC monitoring thereafter. Monitoring of 6-TGN metabolites should be performed after 1 to 3 months of therapy. Therapy with 6-TGN has been shown to be associated with early hepatic nodular hyperplasia disease of the liver and is not recommended in our clinical practice.

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