6-MP and Azathioprine (Imuran)
Mercaptopurine, also known as 6-mercaptopurine or most commonly called 6-MP, is a generic medication used for the treatment for Crohn’s diseasewhich is sold under the brand name Purinethol. Azathioprine (brand name Imuran) is a prodrug of 6-MP which is converted to 6-MP by the liver. (Aprodrug is an inactive medication that is converted to an active medication by the body. Prodrugs are sometimes used because they have a unique delivery system or are metabolized differently than the active medication, which may increase the amount of medication absorbed. The differences between 6-MP and Azathioprine are discussed below.)
6-MP and Azathioprine are immunosuppressant medications, which reduce or change immune system activity, optimally resulting in less inflammation in the GI tract and alleviating the symptoms of Crohn’s disease. In addition to Crohn’s disease, 6-MP is primarily used to treat acute lymphatic leukemia, and also utilized in cases of arthritis induced psoriasis and ulcerative colitis. Azathioprine is used to prevent organ transplant rejection, and for many immune related diseases such as rheumatoid arthritis, lupus and multiple sclerosis, in addition to IBD.
History of 6-MP and Azathioprine
6-MP was first discovered in 1951 by the team of Gertrude B. Elion and George H. Hitchings at the pharmaceutical company Burroughs Wellcome, which later merged to become GlaxoSmithKline. Azathioprine was discovered in 1957 by the same team. The FDA approved 6-MP for use in leukemia in 1953 and Azathioprine was approved to prevent organ transplant rejection in 1968. Elion and Hitchings later shared the 1988 Nobel prize in Medicine, in part for their work in developing these medications. The use of 6-MP in Crohn’s disease began in the late 1960’s, but neither medication has been officially approved by the FDA for the treatment of Crohn’s disease.
Treatment of Crohn’s Disease with 6-MP and Azathioprine
Treatment of Crohn’s disease with 6-MP or Azathioprine is often used to wean patients who are steroid dependant and maintain remission. They are classified as maintenance therapies. 6-MP is usually taken orally, either as a tablet or a liquid suspension. The average absorption rate is 50% when taken orally. The daily adult dosage for Crohn’s disease is between 1.0 to 1.5 mg/kg of body weight.
Azathioprine is also a tablet which is taken orally for Crohn’s disease, but is administered intravenously for other diseases. The daily adult dosage in Crohn’s is between 1.5-4mg/kg of body weight. Both medications have very specific dosage and timing instructions that must be followed for the optimum benefit. Taken once or twice daily, it can take several weeks to 6 months before seeing the full benefit of these medications, so 6-MP and Azathioprine are not used to treat acute flares. Rarely, certain people do not contain the enzyme necessary to break down 6-MP and Azathioprine in the body (called TPMT). A blood test should be obtained prior to starting treatment to rule out this possibility.
6-MP and Azathioprine improve symptoms and help retain remission in about two-thirds of patients. There are numerous studies looking at the effectiveness of both of these medications. One 1985 study showed that 6-MP was effective for healing fistulas in Crohn’s disease patients, though the mean response time was 3.1 months. A 2004 study looked at the effectiveness of 6-MP in the absence of concurrent steroid therapy, and found that there was some measure of improvement in nearly all of the 24 patients, however relapse occurred once the medication was discontinued. This 30 year review of Azathioprine treatment in over 2000 patients showed that the medication had overall remission rates of 45% for Crohn’s disease and 58% for ulcerative colitis. The remission rates increased in patients who were on the drug for more than 6 months.
How do 6-MP and Azathioprine Work?
Immunomodulators and immunosuppressant medications generally work by hindering the activity of white blood cells, which are at the core of the immune response. For many years, the prevailing theory of Crohn’s disease was that the immune system was attacking itself, and Crohn’s was called an “autoimmune” disease. Recently, the theory of Crohn’s disease has shifted away from an autoimmune model. Now, Crohn’s is termed an “immune related” disease, where a variety of factors (genetics, environment, bacteria, and unknown factors) cause a heightened immune response resulting in chronic inflammation and the damage seen in Crohn’s disease. Prior to this paradigm shift, many traditional treatments for Crohn’s disease sought to decrease this heightened immune response. In general, the immunosuppressant medications used in Crohn’s disease are based on the earlier autoimmune theory of Crohn’s disease, but they remain effective for some cases of Crohn’s disease. (For an alternate mechanism and theory of Crohn’s disease, see A Brief History of MAP and Crohn’s.)
For this section, recall that Azathioprine is converted to 6-MP in the body, so the main discussion here will focus on the activity of 6-MP which is the end product of Azathioprine. 6-MP and Azathioprine are fairly effective immunosuppressants which are able to keep about two-thirds of patients in remission. They work by altering the creation and function of DNA by competing with purine derivatives. Purine derivatives are organic compounds that are part of DNA.
To understand this further, a quick science lesson is in order. For life to exist, cells in the body must divide and make new cells. To make a new cell, the DNA in the original cell must double so each cell can have a complete copy. At its most basic structure, DNA is made up of four major bases (adenine, cytosine, thymine, and guanine or A, C, T, G) which link together to form the double helix structure that is the classic representation of DNA. T and C bases are grouped together as pyrimidines while A and G are collectively known as purines. Each pyrimidine links with a specific purine to make a “rung” of the DNA “ladder.” (See the photos in this section for a pictorial representation.)
So what does this have to do with how 6-MP and Azathioprine make Crohn’s disease patients feel better? Both of these medications inhibit a chemical necessary to make the purines A and G. Therefore, DNA replication and creation of new cells is limited because resources get scarce, so the body stops making new cells. These medications are particularly potent against the white blood cells called T and B cells, thought to be overproduced in Crohn’s disease. By limiting the ability of the body to produce too many T and B cells, inflammation may decrease and patients begin to feel better. (Other cells in the body have ways around the inhibitory actions caused by 6-MP and Azathioprine, so the hope is that only the white blood cells which are causing the symptoms will be destroyed.)
Another proposed mechanism of action for 6-MP and Azathioprine is that they may incorporate incorrect chemicals into DNA synthesis, which makes the DNA function incorrectly, thus inhibiting the production of new T and B cells. They may also block a different class of necessary chemicals, which results in T-cell death.
Side Effects of 6-MP and Azathioprine
On April 14, 2016, The United States Food and Drug Administration (FDA) issued a Safety Communication concerning TNF-alpha blockers (like Remicade and HUMIRA), Azathioprine and 6-MP. This goal of the alert was to inform patients who were taking these medications that they could be at an increased risk for developing a rare cancer (Hepatosplenic T-Cell Lymphoma or HSTCL) which often results in death. A table with detailed case reports broken down by each drug is included in the alert. Through December 31, 2010, there were 12 reported cases of HSTCL in patients taking Azathioprine and 3 reported cases of HSTCL in patients taking 6-MP. To read the full alert, see the FDA Safety Communication. Patients who are concerned about their risk of HSTCL should consult their health care provider.
Severe side effects can occur when taking 6-MP and Azathioprine including:
- Sore throat and mouth sores.
- Increased risk of infection.
- Easily bruising or bleeding, or pinpoint red dots on the skin.
- Yellowing of the eyes and skin.
- Painful or difficult urination, or dark colored/bloody urine.
- Black, tarry or bloody stools.
- Allergic reactions, which can manifest as dizziness, itchiness, rash, swelling or trouble beathing.
- Suppression of the bone marrow, causing a large decrease in white cell count or anemia.
- Risk of developing cancers, as these medications are human carcinogens.
- Impaired liver function.
- Hair loss.
Less serious, more common side effects of 6-MP and Azathioprine include:
- Nausea, vomiting, diarrhea and abdominal pain.
- Swollen joints.
- Loss of appetite.
- Skin rash.
- Darkening of the skin.
- Generally feeling ill.
Potential Interaction of 6-MP and Azathioprine on MAP
One 2008 study looked at the presence of MAP DNA in patients who were treated with traditional Crohn’s disease therapies vs. controls. The hypothesis was that MAP is detected in few Crohn’s patients because the traditional treatments for Crohn’s disease have unknowingly been killing MAP as well as reducing inflammation. The study concluded that while both Azathioprine and 6-MP are likely acting as anti-MAP agents, 6-MP actually clears MAP DNA from the blood of IBD patients. The researchers found nearly the same percentage of MAP DNA in the blood of controls vs. those on Azathioprine. But no MAP DNA was found in the blood of patients on 6-MP, compared to a significantly higher percentage of MAP DNA in the blood of controls. Therefore, 6-MP may be a potent anti-MAP agent. The study has its limitations, and the authors freely admit that the presence of MAP DNA as measured in the study does not equate to viable MAP cultures.
This 2008 study by Sung Jae Shin and Michael T. Collins looked at the effect of a variety of treatments on MAP and other mycobacterial species in culture. The article concluded that both 6-MP and Azathioprine had antibacterial activity against MAP in vitro, though they did not kill MAP. The amount of Azathioprine to inhibit MAP was about double that of 6-MP. Additionally, when combined, 6-MP actually inhibited the ability of Ciprofloxacin to kill MAP! The MAP that was isolated from human samples was more susceptible to these medications than the MAP from cattle samples. Interestingly, these medications were ineffective against other mycobacterial strains tested, even at very high doses. Because these traditional treatments in Crohn’s disease have a negative effect on the survival of MAP, the findings in this study have implications for other research studies which attempt to measure the effectiveness of Anti-MAP antibiotic therapy (AMAT) in contrast to controls on traditional treatments. In other words, now that we know that traditional treatments like 6-MP may kill MAP, any study which measured AMAT vs. control patients taking 6-MP must be re-evaluated since 6-MP affects MAP.
Following on the research above, a group of researchers (which included Michael T. Collins) studied the effects of 6-MP when combined with some of the traditional Anti-MAP antibiotics. In the 2009 article, the researchers looked at the effect on human MAP strains when treated with 6-MP and Anti-MAP antibiotics in vitro. Of the 8 antibiotics that were combined with 6-MP, the most synergy was between 6-MP and azithromycin, which was effective against 7 out of 9 human MAP strains and had the lowest average Minimum Inhibitory Concentration (which is the amount of the drug necessary to stop growth of the organism.) Clarithromycin, rifampicin, rifabutin and ethambutol also showed a lesser degree of synergy with 6-MP in their inhibition of MAP but required a higher dosage to inhibit growth. Amikacin, ciprofloxacin and clofazimine showed no synergy with 6-MP. None of the antibiotics tested were antagonistic when combined with 6-MP.
Another published study directly examined the effect of Azathioprine on MAP in vitro. In 2013, a group of researchers examined 342 blood samples from patients with Crohn’s disease, Ulcerative Colitis and healthy controls. Previous studies had found higher antibody levels to a MAP specific protein (PtpA) in Crohn’s disease patients than in controls, which seems to indicate that the immune system is fighting a MAP infection. The researchers hypothesized that standard Crohn’s disease treatments could have some MAP killing effect, and measured the patient’s antibody levels in light of each treatment. Indeed, they found lower antibody levels in Crohn’s disease patients treated with Azathioprine vs. untreated controls. However, there was no difference in the results when treatment with Azathioprine was combined with either 5-ASA or steroids. This indicates that Azathioprine negatively affects the growth of MAP in vitro.