Pharmacology

Azathioprine is chemically 6-[(1-Methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine, a steroid-sparing purine analog. It is a derivative of 6-mercaptopurine, and many of its biological effects are like those of the parent compound.

Pharmacodynamics. Azathioprine converts to its active metabolites, 6-mercaptopurine and thioguanine, by the action of hypoxanthine-guanine phosphoribosyltransferase and thiopurine methyltransferase to inhibit purine synthesis. Its metabolites are incorporated into the replicating DNA to halt its division and may also mediate most of its immunosuppressive and toxic effects.

Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. Like other immunosuppressants, it suppresses the proliferation of T and B lymphocytes. By suppressing the immune system, it reduces the inflammation that accompanies immune reactions. It is used as an immunosuppressive in the treatment of multiple sclerosis and reduces new inflammatory lesions and relapse rates.

Pharmacokinetics. Azathioprine is well absorbed after oral administration and has a half-life of 5 hours. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low (less than 1 mcg/mL). Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable. Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides as major metabolites.

Pharmacogenetics/pharmacogenomics. Thiopurine methyltransferase (TPMT) genotyping can help to identify patients with low or absent TPMT activity who are at increased risk for severe, life threatening myelosuppression from azathioprine.

Clinical trials

The first clinical trial of azathioprine in multiple sclerosis was reported in 1969 (22). Since then, 21 clinical trials of azathioprine for multiple sclerosis have been published, but only 7 of these were controlled and involved patients with either exacerbating or chronic progressive multiple sclerosis.

A systematic review of clinical trials of azathioprine for multiple sclerosis showed a statistically significant benefit of azathioprine therapy at follow-up for 3 years (05). Azathioprine was a fair alternative to interferon beta although no head-to-head comparison between the 2 drugs had been made. Benefits as well as risks of azathioprine need to be considered.

The placebo-controlled Avonex-Steroids-Azathioprine study evaluated efficacy of interferon beta-1a alone and combined with low-dose azathioprine alone or low-dose azathioprine and low-dose corticosteroids as initial therapy (09). At 2-year follow-up, combination treatment did not show superiority over interferon beta-1a monotherapy in patients with early active relapsing-remitting multiple sclerosis. The 5-year extension of this study to examine the short- and long-term value of the appearance of new active lesions in predicting extent of cortical and subcortical deep gray matter atrophy has been completed, but the results are not yet published (ClinicalTrials.gov identifier: NCT01628315).

Effects of immunosuppressive and immunomodulatory drugs for multiple sclerosis on disability progression over 4 years was examined in an open, uncontrolled, nonrandomized, retrospective study (24). No statistical difference was found in the long-term progression of disability among patients treated with corticosteroids, azathioprine, interferon beta-1b, interferon beta-1a, glatiramer acetate, and mitoxantrone.

In a clinical trial, azathioprine was shown to reduce the expanded disability status scale and the annual relapse rate in Chinese patients with neuromyelitis optica spectrum disorders (15). Within the safe upper limits, a higher concentration of 6-thioguanine nucleotides in erythrocytes was associated with better efficacy of azathioprine.

Indications

Azathioprine has been approved as an adjunct for the prevention of rejection in renal transplantation. It is also approved for the management of active rheumatoid arthritis to reduce signs and symptoms.

Off-label uses

Azathioprine is used in the treatment of multiple sclerosis, where several clinical trials have shown decreases in relapses but no slowing in progression of the disease. There are limited data on the safety of azathioprine in multiple sclerosis.

Azathioprine is 1 of the agents recommended for prevention of further attacks of neuromyelitis optica. Results of a study based on review of medical records and telephone survey of patients with neuromyelitis optica indicate that azathioprine is well-tolerated and efficacy may be optimized by early initiation of treatment, adequate dosing, and monitoring of hematologic parameters (06). A retrospective review of patients with neuromyelitis optica spectrum disorders based on medical records concluded that azathioprine could prolong the duration of remission after treatment, especially given within 2 weeks after attack (16). Combination of azathioprine with glucocorticoids was more effective than glucocorticoids alone in the remission. In a long-term follow-up of patients with neuromyelitis optica, continued azathioprine use from early disease onset was strongly associated with maintenance of neurologic function, and there was no disability accumulation in two-thirds of patients (02).

Immunosuppression is used in the treatment for myasthenia gravis and azathioprine was the first choice (21). Use of azathioprine for this indication is limited by lack of randomized evidence, the need for prolonged administration, and adverse effects. Azathioprine may be considered for treatment of myasthenia gravis if symptoms are not adequately controlled with anticholinesterase drugs. Results of a single-blind trial to compare the steroid-sparing effect of azathioprine and methotrexate show that both have equal efficacy, but the latter is less expensive (10). A patient with limb-girdle myasthenia gravis, in whom symptomatic treatment with pyridostigmine was ineffective, improved by addition of azathioprine (23).

Glucocorticoid therapy combined with azathioprine has been reported to be an effective treatment for recurrent autoimmune hypophysitis (25). Azathioprine has also been used as an alternative to corticosteroids for the treatment of hypophysitis due to IgG4-related disease (04).

The combination of low-dose azathioprine with prednisone and interferon beta did not improve the long-term outcomes in patients with multiple sclerosis (12).

A Cochrane review of randomized trials of immunosuppressants for multiple sclerosis concluded that the benefit-risk balance of azathioprine is uncertain, although it may be effective in decreasing relapses and progression of disability over 24 to 36 months compared with placebo in patients with relapsing-remitting multiple sclerosis (07).

Contraindications

Goals and duration of treatment

The aim of therapy with azathioprine is to reduce the relapses and slow the progression of multiple sclerosis. Azathioprine requires 6 to 8 weeks for action and the maximal in vivo immunosuppressive effect of azathioprine requires 3 to 6 months of daily use. Therefore, azathioprine is frequently combined with more rapidly acting corticosteroids. The effects of immunosuppressant treatment lasting less than a few years are difficult to assess on the lengthy course of multiple sclerosis, which can span several decades. In a long-term study with medium duration of 3.7 years to study the effect of disease-modifying therapies on aquaporin-4-IgG positive neuromyelitis optica spectrum disorder, azathioprine and mycophenolate mofetil reduced the risk of relapses and disability progression (13).

Dosing

Starting dose is usually 50 mg tablet once daily orally; a single tablet can be broken into 2 and taken twice a day. Dose may be titrated starting with 1.5 mg/Kg and increased to 3 mg/Kg daily depending on the white blood count and tolerability.

Special considerations

Patients on azathioprine therapy should have complete blood counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary.

Pediatric. Safety and efficacy of azathioprine in pediatric patients have not been established in clinical trials. However, there is a case report of a 10-year-old boy with multiple sclerosis who was seropositive for antibodies against myelin oligodendrocyte glycoprotein-IgG (MOG-IgG) and showed clinical and MRI stability with MOG-IgG seroconversion over a 5-year period of treatment with azathioprine plus oral methylprednisolone without major side effects (27).

Geriatric. Azathioprine has been used in elderly patients, but caution is required in those with renal or hepatic impairment.

Pregnancy. Increasing evidence from prospective cohort studies suggests that azathioprine is safe for the fetus during pregnancy (18). A review of the medical records of women with systemic lupus erythematosus who were exposed to azathioprine during pregnancy showed that it was not associated with poor fetal outcome, such as congenital malformations (Saavedra et al 2015).

However, azathioprine can increase the risk of spontaneous miscarriage, low birth-weight, and preterm delivery and should not be given during pregnancy without carefully weighing risks versus benefits. Azathioprine is secreted in breast milk as its metabolite 6-mercaptopurine in low concentrations, and its use is generally not recommended in nursing mothers.

Anesthesia. Azathioprine is an antagonist of competitive neuromuscular blockers. No other precautions have been recommended for anesthesia in patients who have received azathioprine, but surgical procedures under anesthesia may carry a risk of bleeding complications due to thrombocytopenia caused by azathioprine.

Interactions

The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia. Azathioprine may inhibit the anticoagulant effect of warfarin.

Allopurinol use concomitant with azathioprine can cause severe myelosuppression.

Adverse effects

Gastrointestinal disturbances and leukopenia are the most frequent adverse events of azathioprine therapy; these adverse effects occur in more than 10% of the patients with multiple sclerosis. Infections, allergy, anemia, thrombocytopenia, and pancytopenia are also common—occurring in 1% to 10% of cases. Pellagra is a rare adverse effect in patients receiving oral azathioprine for neuromyelitis optica (26). Azathioprine-associated hepatotoxicity and myelosuppression are common in myasthenia gravis with a prevalence of 15.2% and 9.1%, respectively (11). Melanocytic nevi can appear during immunosuppressive therapy of autoimmune diseases, and this complication has been reported during azathioprine therapy in myasthenia gravis (01). Switching the treatment to mycophenolic acid is recommended to prevent further development of nevi. There is a possible risk of increased malignancy with long-term use, eg, 10 years of continuous use or with a lifetime dose of 600 grams. Use of azathioprine in patients with non-thymoma myasthenia gravis may be associated with a slightly increased risk of cancer (19). Thiopurine S-methyl-transferase (TPMT) genotype has been associated with azathioprine-related adverse events in patients with myasthenia gravis but there is no statistically significant difference among wild-type and other TPMT genotypes for minor adverse events (17). This study supports the view that TPMT genotyping alone is not enough to adequately personalize azathioprine therapy in myasthenia gravis patients.

Adverse effects involving the central nervous system may occur following use of azathioprine for non-neurologic indications. A case of progressive multifocal leukoencephalopathy has been reported during treatment of pulmonary sarcoid disease using azathioprine and steroids (08). Rather than experiencing further neurologic deterioration that is often fatal, this patient made a slow recovery following termination of immunosuppression.

A study has shown that the risk of malignancy in multiple sclerosis patients after azathioprine is similar to that of the general population and does not change with other disease-modifying agents as sequential treatments (14).

Management. Most of the adverse effects of azathioprine are easily managed by dosage adjustment or discontinuation of the drug.