Azathioprine
Azathioprine, sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, and in kidney transplants to prevent rejection. It is listed by the International Agency for Research on Cancer as a group 1 human carcinogen. It is taken by mouth or injected into a vein.
Common side effects include bone-marrow suppression and vomiting. Bone-marrow suppression is especially common in people with a genetic deficiency of the enzyme thiopurine S-methyltransferase. Other serious risk factors include an increased risk of certain cancers. Use during pregnancy may result in harm to the baby. Azathioprine belongs to the purine analogues subclass of antimetabolites family of medications. It works via 6-thioguanine to disrupt the making of RNA and DNA by cells.
Azathioprine was first made in 1957. It is on the World Health Organization's List of Essential Medicines. In 2018, it was the 358th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.
Medical uses
Azathioprine is used alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation, and to treat an array of autoimmune diseases, including rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Behçet's disease, and other forms of vasculitis, autoimmune hepatitis, atopic dermatitis, myasthenia gravis, neuromyelitis optica, restrictive lung disease, and others. It is also an important therapy and steroid-sparing agent for inflammatory bowel disease and for multiple sclerosis.In the United States, it is approved by the Food and Drug Administration for use in kidney transplantation from human donors, and for rheumatoid arthritis.
Transplantation
Azathioprine is used to prevent rejections of kidney or liver allografts, usually in conjunction with other therapies, including corticosteroids, other immunosuppressants, and local radiation therapy. The administration protocol starts either at the time of transplantation or within the following two days.Rheumatoid arthritis
Being a disease-modifying antirheumatic drug, azathioprine has been used for the management of the signs and symptoms of adult rheumatoid arthritis. Nonsteroidal anti-inflammatory drugs and corticosteroids may be combined or continued with azathioprine, but the combination with other DMARDs is not recommended.Inflammatory bowel disease
Azathioprine has been used in the management of moderate to severe chronically active Crohn's disease, to maintain clinical remission in corticosteroid-dependent patients, and to provide benefit in people with fistulizing Crohn's disease. The onset of action is slow, and several months may be required to achieve a clinical response.Azathioprine treatment is associated with an increased risk of lymphoma, but whether this is due to the drug or a predisposition related to Crohn's disease is unclear. Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects. It may also be used to prevent flares in those with ulcerative colitis.
Others
Azathioprine is sometimes used in systemic lupus erythematosus, requiring a maintenance dose of 15 mg or higher of prednisone in those who experience recurrent flares.It is used as an add-on therapy when steroid therapy is given by mouth for pemphigus and myasthenia gravis, as a "steroid-sparing" agent. Azathioprine is also used to maintain remission in people who have granulomatosis with polyangiitis.
It can be very effective in eczema and atopic dermatitis, though it is not commonly used. The British National Eczema Society lists it as a third-line treatment for severe to moderate cases of these skin diseases.
It was widely used to treat multiple sclerosis until the first half of the 1990s. Concerns about increased risk of malignancy have led to a decreased use, yet it is still used in maintenance treatment for people who frequently relapse. A 2007 Cochrane review found that azathioprine reduced the number of relapses in the first year of treatment and disease progression in the first two to three years and did not find an increase in cancer, and noted the need for direct comparison of azathioprine and interferon beta, conflicting conclusions regarding cancer, and the potential for long-term risks.
A widely used therapy for idiopathic pulmonary fibrosis was azathioprine in combination with prednisone and N-acetylcysteine. A 2012 study showed that this combination produced worse outcomes than a placebo.
Adverse effects
Nausea and vomiting are common adverse effects, especially at the beginning of treatment. Such cases are met with taking azathioprine after meals or transient intravenous administration. Side effects that are probably hypersensitivity reactions include dizziness, diarrhea, fatigue, and rashes. Hair loss is often seen in transplant patients receiving the drug but rarely occurs under other indications. Because azathioprine suppresses the bone marrow, patients can develop anaemia and be more susceptible to infection; regular monitoring of the blood count is recommended during treatment. Acute pancreatitis can also occur, especially in patients with Crohn's disease. Treatment is discontinued in up to 30% of patients due these effects, but therapeutic drug monitoring of the biologically active metabolites, i.e. thiopurine nucleotides, can help to optimize the efficacy and safety. Clinically, most hospitals resort to ion-exchange LC-MS, but the newly developed approach of porous graphitic carbon-based chromatography hyphenated with mass spectrometry appears superior with respect to patient care in this respect.It is listed by the International Agency for Research on Cancer as a group 1 carcinogen.
Pharmacogenetics
The enzyme thiopurine S-methyltransferase is responsible for various activation and deactivation steps in azathioprine's mechanism of action. The first metabolic step that azathioprine undergoes in the body is the conversion to 6-mercaptopurine, which is itself an immunosuppressant prodrug. The TPMT enzyme is responsible, in part, for the methylation of 6-MP into the inactive metabolite 6-methylmercaptopurine – this methylation prevents 6-MP from further conversion into active, cytotoxic thioguanine nucleotide metabolites. Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone-marrow suppression when receiving azathioprine. In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of patients are homozygous for these variants. However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify patients with reduced TPMT enzyme activity, allowing for the adjustment of azathioprine dose or avoidance of the drug entirely. The FDA-approved drug label for azathioprine recommends testing for TPMT activity to identify patients at risk for myelotoxicity. Indeed, testing for TPMT activity is one of the few examples of pharmacogenetics being translated into routine clinical care. Missense SNP in NUDT15 ) has been identified to be a causal factor for AZA-induced leukopenia through a genome-wide association study in East Asians.Cancers
Azathioprine is listed as a human carcinogen in the 12th Report on Carcinogens by the National Toxicology Program of U.S. Department of Health and Human Services, asserting that it is "known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans." Since August 2009, the U.S. FDA has required warnings to be placed on packaging with respect to increased risks of certain cancers.The risks involved seem to be related both to the duration and the dosage used. People who have previously been treated with an alkylating agent may have an excessive risk of cancers if treated with azathioprine. Epidemiological studies by International Agency for Research on Cancer have provided "sufficient" evidence of azathioprine carcinogenicity in humans, although the methodology of past studies and the possible underlying mechanisms are questioned.
The various diseases requiring transplantation may in themselves increase the risks of non-Hodgkin lymphoma, squamous cell carcinomas of the skin, hepatobiliary carcinomas, and mesenchymal tumours to which azathioprine may add additional risks. Those receiving azathioprine for rheumatoid arthritis may have a lower risk than those undergoing transplantation.
Cases of hepatosplenic T-cell lymphoma – a rare type of lymphoma – have been reported in patients treated with azathioprine. The majority occurred in patients with inflammatory bowel disease. Adolescents and young adult males were the majority of cases. They presented with a very aggressive disease course, and with one exception, died of the lymphoma. The FDA has required changes to the labeling to inform users and clinicians of the issue.