If you’ve been diagnosed with Crohn’s disease or ulcerative colitis, your doctor may have mentioned azathioprine, mercaptopurine, or methotrexate. These immunomodulators work by calming an overactive immune system. Understanding how they work and what to expect can help you feel more confident about your treatment.
What are immunomodulators?
Immunomodulators are medications that adjust immune system activity. In inflammatory bowel disease (IBD), the immune system mistakenly attacks the gut lining, causing chronic inflammation, ulceration, and symptoms such as diarrhoea, abdominal pain, and bleeding. Immunomodulators reduce this excessive immune response, helping to control inflammation and maintain remission.
The three most commonly prescribed immunomodulators for IBD are azathioprine, mercaptopurine, and methotrexate. Each works slightly differently, but all share the same goal: to reduce the number and activity of immune cells that drive gut inflammation.
How azathioprine and mercaptopurine work
Azathioprine and mercaptopurine are closely related. Azathioprine is converted in the body into mercaptopurine, which is then broken down into active compounds called thioguanine nucleotides. These compounds interfere with DNA and RNA production inside immune cells, particularly T-cells and B-cells, which are key players in inflammation.
By slowing the growth and division of these immune cells, azathioprine and mercaptopurine reduce the immune attack on the gut lining. This process takes time, which is why these drugs are not used to treat acute flares. Instead, they maintain remission and reduce relapse risk once inflammation has been controlled with other treatments, such as corticosteroids or biologics.
How methotrexate works
Methotrexate works through a different mechanism. It blocks an enzyme called dihydrofolate reductase, which cells need to produce folate, a B-vitamin essential for DNA synthesis and cell division. Without enough folate, rapidly dividing immune cells cannot function properly, and inflammation is dampened.
Methotrexate also increases levels of adenosine, which reduces pro-inflammatory signals from immune cells. This dual action makes methotrexate particularly useful in Crohn’s disease, though it is less commonly used in ulcerative colitis.
Because methotrexate interferes with folate metabolism, patients are usually prescribed folic acid supplements to prevent side effects such as nausea, mouth ulcers, and fatigue.
When are immunomodulators prescribed?
Immunomodulators are typically used in the following situations:
Steroid-dependent disease: If you need repeated corticosteroid courses to control symptoms, your doctor may add an immunomodulator to help you taper off steroids safely.
Steroid-refractory disease: When steroids alone are insufficient to achieve remission, an immunomodulator may provide additional immune suppression.
Maintenance therapy: Once remission is achieved, immunomodulators help keep inflammation under control and reduce the likelihood of flares.
Combination therapy with biologics: Immunomodulators are sometimes prescribed alongside biologic drugs such as infliximab or adalimumab. This combination can improve biologic effectiveness and reduce the risk of developing antibodies against them.
What to expect when starting treatment
Immunomodulators take time to work. Azathioprine and mercaptopurine can take 8 to 12 weeks to show full effect, and methotrexate may take 6 to 12 weeks. During this period, your doctor may continue other treatments to manage symptoms.
Because these drugs suppress the immune system, regular blood tests are essential. Your doctor will monitor your white blood cell count, liver function, and other markers to ensure the medication is working safely. In the early weeks, blood tests are usually performed weekly or fortnightly, then less frequently once your dose is stable.
Some patients experience side effects such as nausea, fatigue, or increased susceptibility to infections. These are usually mild and manageable, but report any new or worsening symptoms to your healthcare team. Serious side effects are rare but can include liver toxicity, bone marrow suppression, and pancreatitis.
Genetic testing and dose optimisation
For azathioprine and mercaptopurine, genetic testing can help predict how well you will metabolise the drug. An enzyme called thiopurine methyltransferase (TPMT) breaks down these medications. People with low or absent TPMT activity are at higher risk of serious side effects and may need a lower dose or alternative treatment.
Some clinics also measure active drug metabolite levels in your blood to ensure you are receiving the most effective dose. This therapeutic drug monitoring can help optimise treatment and reduce side effect risk.
Immunomodulators and the microbiome
Emerging research suggests that immunomodulators may influence the gut microbiome, the community of bacteria and other microbes in your intestines. Some studies show these drugs can shift the balance of gut bacteria in ways that may support a healthier, less inflammatory environment. However, this research is still developing, and the clinical significance is not yet fully understood.
Practical takeaways
- Immunomodulators take weeks to work, so patience is important. They are not designed to treat acute flares.
- Regular blood tests are essential to monitor safety and effectiveness. Keep all scheduled appointments.
- If prescribed methotrexate, take your folic acid supplement as directed to reduce side effects.
- Report any signs of infection, unusual bruising, severe fatigue, or yellowing of the skin to your doctor immediately.
- Genetic testing for TPMT can help guide dosing decisions for azathioprine and mercaptopurine.
- Immunomodulators are often used in combination with other treatments. Follow your full treatment plan as prescribed.
Conclusion
Azathioprine, mercaptopurine, and methotrexate are established and effective treatments for maintaining remission in IBD. By reducing overactive immune system activity, they help control gut inflammation and reduce the need for repeated corticosteroid courses. While they require regular monitoring and take time to work, they play a vital role in long-term disease management. If you have questions or concerns about your treatment, speak with your gastroenterology team.
References
- Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2009;(1):CD000067. doi:10.1002/14651858.CD000067.pub2
- Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2007;(1):CD000478. doi:10.1002/14651858.CD000478.pub2
- Patel V, Macdonald JK, McDonald JW, Chande N. Methotrexate for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2009;(4):CD006884. doi:10.1002/14651858.CD006884.pub2
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- Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153(3):827-834. doi:10.1053/j.gastro.2017.07.032
- Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118(4):705-713. doi:10.1016/s0016-5085(00)70140-5
- Chaparro M, Ordás I, Cabré E, et al. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm Bowel Dis. 2013;19(7):1404-1410. doi:10.1097/MIB.0b013e318281f28f
- Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-1395. doi:10.1056/NEJMoa0904492
This article is intended for informational and educational purposes only. It does not constitute medical advice and should not be used as a substitute for professional medical guidance, diagnosis, or treatment.