How Genes Influence The Breakdown Of Azathioprine

What Is Azathioprine?

Azathioprine is an immunosuppressant drug that works by bringing down the activity of the immune system.

It is sold under the brand names Imuran and Azasan and is added to the World Health Organization's (WHO’s) List of Essential Medicines for 2021.

It is available as oral pills or injected in the vein; the dosage depends on the specific requirement.

What Is Azathioprine Used For?

Azathioprine is used to prevent organ rejection after kidney transplantation.

It is also used to treat certain autoimmune diseases like Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), Ulcerative Colitis, and Crohn's Disease.

It is usually used with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), corticosteroids, and other immunosuppressant drugs.

Is Azathioprine A Steroid?

No. Azathioprine is not a steroid.

Instead, it is a steroid-sparing drug.

When taken in combination with steroid drugs, it can decrease the required steroid dosage.

How Does Azathioprine Work?

Azathioprine is a purine analog drug.

Purines are organic compounds required for DNA and RNA production.

The immune system needs DNA and RNA to produce White Blood Cells (WBCs) to fight invaders.

By reducing the number of purines in the body, azathioprine lowers WBC production by the immune system, leading to immunosuppression.

How Long Does Azathioprine Take To Work?

The effects of azathioprine appear gradually.

For autoimmune conditions, it may take anywhere from 6-12 weeks to start working.

For certain autoimmune skin conditions, it may even take up to a year for the drug to show results.

How Effective Is Azathioprine For Crohn's?

Azathioprine is an effective treatment option for Crohn’s and helps decrease the dependency on steroids.

A study of 272 Crohn's disease patients treated with azathioprine reported that the remission rate (remaining symptom-free) for patients treated with the drug for more than six months was 64%.

Side Effects Of Azathioprine

Some of the common side effects of azathioprine are:

Nausea
Vomiting
Diarrhea
Increased risk of stomach infections and abdominal pain
Fatigue
Development of mouth sores and ulcers

Some of the more severe side effects of azathioprine are:

Blood in urine
Bloody stools
Rashes in the skin
Fever
Higher risk of infections
Risk of developing certain types of cancers
Hepatotoxicity (live toxicity)
Kidney damage

About 3.3% of patients on azathioprine may experience pancreatitis (inflammation of the pancreas) in the first six months of treatment.

What Are The Long-Term Effects Of Azathioprine?

People who take azathioprine for more than ten years may have a higher risk of developing certain types of cancers, including skin and lymphoma and myelotoxicity (damage to bone marrow).

Does Azathioprine Make You Gain Weight?

No, azathioprine, by itself, may not lead to weight gain.

However, when used with other steroid drugs, the steroids may cause weight gain.

Azathioprine: Interactions With Other Drugs

Azathioprine may interact with other drugs and lead to changes in drug efficacy or worsen the side effects.

Talk to your doctor if you take azathioprine with any of the following medications:

Febuxostat and Allopurinol (used to treat gout disease)
Rituximab, Infliximab (used to treat autoimmune diseases and certain types of cancer)
Tofacitinib (used to treat autoimmune diseases)
Muscle relaxant drugs
Warfarin (blood thinner medicine)
Cotrimoxazole (used to treat bacterial infections)
Adalimumab (used to treat arthritis)
Tumor Necrosis Factor (TNF) blockers (used to control inflammation)
Vitamin B3 (niacin) supplements

Can You Take Prednisone And Azathioprine Together?

Yes, prednisone and azathioprine can be taken together and are prescribed to improve Crohn’s Disease symptoms.

Studies show that the combination is more effective for treating Crohn’s than prednisone alone.

Azathioprine: Gene-Drug Interactions

The NUDT15 Gene

The Nudix hydrolase 15 gene (NUDT15 gene) provides instructions for producing the NUDT15 protein.

This protein helps in the metabolism of purine analog drugs like azathioprine.

rs116855232 is a Single Nucleotide Polymorphism (SNP) in the NUDT15 gene.

Inflammatory Bowel Disease patients with the TT and CT types of this SNP have an increased risk of developing myelosuppression (a condition causing decreased bone marrow activity) compared to patients with the CC type.

Genotype	Implications
TT	Increased risk of myelosuppression on azathioprine usage
CT	Increased risk of myelosuppression on azathioprine usage
CC	Decreased risk of myelosuppression on azathioprine usage

The TPMT gene

The thiopurine S-methyltransferase gene (TPMT gene) provides instructions for producing the TPMT enzyme.

This enzyme helps break down drugs like azathioprine and decrease immune system activity.

Drugs like azathioprine get converted into active (toxic) forms called thioguanine nucleotides (TGNs) in the body.

The TPMT enzyme helps quickly convert the toxic substance into a non-toxic compound.

Excess of TGNs in the body may lead to life-threatening conditions of myelosuppression.

There are different metabolizer types identified based on the enzyme activity, and these metabolizer types can affect azathioprine efficacy and dosage levels in the body.

Phenotype	Implication	Recommendations for using azathioprine
Normal metabolizers	Low concentrations of TGN metabolites	Normal doses can be used
Intermediate metabolizers	Slightly higher concentrations of TGN metabolites	Start with a reduced dosage before dosage adjustment
Poor metabolizers	Very high concentrations of TGN metabolites	Consider alternative medications or start with very low doses

There are multiple star alleles noted in the TPMT gene.

Star alleles are used to name different haplotypes.

A haplotype is a group of gene changes that are inherited together.

Normal metabolizers have two copies of the normal-function allele (*1) of this gene.
Poor metabolizers have two copies of the no-function alleles (*2, *3A, *3B, *3C, *4) of this gene.
Intermediate metabolizers have one normal-function and one no-function alleles (*1 and*2, *1 and*3A, *1 and *3B, *1 and *3C, or *1 and *4) of this gene.

Recommendations To Use Azathioprine

Usage With TNF Blockers

Tumor Necrosis Factor (TNF) blockers are drugs used to block the activity of TNF.

TNF is a protein that causes inflammation and worsens the symptoms of different autoimmune conditions.

A combination of TNF blockers and immunomodulatory drugs like azathioprine may increase the risk of developing hepatosplenic T-cell lymphoma (HSTCL).

HSTCL is a very aggressive T-cell lymphoma common in young children and adolescents.

A 2011 study reports an increased risk of developing HSTCL in autoimmune patients who receive a combination of TNF blockers and immunomodulators.

Azathioprine Hypersensitivity

Azathioprine hypersensitivity is a rare but serious condition in about 2% of the patients treated with the drug.

The following symptoms of azathioprine sensitivity occur just weeks after administering the drug.

Fever
Abdominal pain
Cutaneous eruptions (hives, rashes, pus-filled boils, and blisters in the skin)
Low blood pressure

Usage In Pregnant and Lactating Women

Azathioprine use in pregnancy may affect the unborn fetus and lead to congenital abnormalities.

A 2003 population-based cohort study in the Danish population reports a 7-fold increased risk of congenital abnormalities in pregnant women who used azathioprine.

They also had a 20-fold increased risk of experiencing perinatal mortality (miscarriages).

Some studies also report an increased risk of congenital abnormalities in children whose fathers were on azathioprine before conception.

There are reports of azathioprine being expressed in breastmilk.

If you are a lactating mother, talk to your doctor to weigh the risks and benefits of breastfeeding while on the drug.

Usage In People With Existing Liver or Kidney Conditions

Since azathioprine may lead to liver or kidney damage, it needs to be used with caution in people with existing liver or kidney conditions.

The doctors may adjust the dosage accordingly and recommend periodical Complete blood count (CBC) and Liver Function Tests (LFT) to rule out liver and kidney damage.

Usage In People With Active Clinical Infections

People with active infections may not be recommended to use azathioprine until the condition goes away.

Since the drug is an immunosuppressant, it may worsen the effects of the infection.

Azathioprine And Skin Cancer

A meta-analysis studied the relationship between azathioprine usage and the risk of Squamous Cell Carcinoma (SCC) of the skin.

SCC is a very common type of skin cancer due to UV exposure.

According to the study, using azathioprine significantly increased the risk of developing SCC.

If you are on azathioprine, limit sun exposure and avoid tanning booths and beds.

You may also be asked to use sunscreens regularly to bring down the risk of developing SCC.

Drug Overdose

Azathioprine overdose may lead to vomiting, fever, rashes, and chills in the body.

If you think you have overdosed on the drug, rush to the nearest Emergency Room or dial 911.

Genetic Testing

Genetic testing will help understand how quickly the body converts TGNs into inactive forms, making dosage planning more customized.

It can also help doctors understand the risk of developing myelosuppression and decide between using azathioprine and other immunosuppressants.

Analyze Your Genetic Response to Azathioprine

Summary

Azathioprine is an immunosuppressant drug that reduces immune system activity.
Azathioprine is used to prevent organ rejection in kidney transplant patients and manage autoimmune conditions like Crohn’s Disease, Rheumatoid Arthritis, and Inflammatory Bowel Disease.
Azathioprine is a purine analog drug and prevents the body from producing enough White Blood Cells (WBCs).
Some of the common side effects of azathioprine are nausea, vomiting, diarrhea, and ulcers.
Azathioprine may increase the risk of developing certain types of cancers.
Azathioprine may interact with blood thinners, immunosuppressant drugs, muscle relaxants, and anti-inflammatory drugs and lead to changes in drug efficacy or worsen the side effects.
NUDT15 and TPMT gene changes may lead to an increased risk of myelosuppression (decreased bone marrow activity) when azathioprine is used.
Using azathioprine with Tumor Necrosis Factor (TNF) blockers may increase the risk of developing hepatosplenic T-cell lymphoma (HSTCL).
People with existing liver and kidney conditions and active infections should use azathioprine with caution.
Azathioprine may cause congenital abnormalities in babies when used during pregnancy. It may also be expressed in breastmilk.
Azathioprine may increase the risk of developing Squamous Cell Carcinoma (SCC) of the skin.
Genetic testing will help understand a person’s risk of developing myelosuppression with azathioprine usage.