Meds & Escalation
If your gastroenterologist has brought up azathioprine, 6-mercaptopurine, or methotrexate, you're probably trying to figure out what these drugs actually do and why your doctor chose one over another. Immunosuppressants occupy a specific role in Crohn's treatment: they dial down the overactive immune response driving inflammation in your gut. But the category covers several drugs with different mechanisms, different evidence bases, and different reasons your GI might reach for one instead of another. Here's what you should know about each option, including the ongoing debate around mesalamine.
Azathioprine and 6-Mercaptopurine: The Thiopurine Workhorses
Azathioprine (often sold as Imuran) and 6-mercaptopurine, or 6-MP (sold as Purinethol), are the most commonly prescribed immunosuppressants for Crohn's disease. They belong to a class called thiopurines. Azathioprine is actually a prodrug that converts into 6-MP in your body, so the two drugs are closely related, though dosing and side effect profiles differ slightly.
These medications work by interfering with DNA synthesis in rapidly dividing immune cells, reducing the inflammatory attack on your intestinal lining. A meta-analysis in the Annals of Internal Medicine found that azathioprine and 6-MP are effective for both treating active Crohn's disease and maintaining remission. Patients treated for longer than six months achieved remission rates around 64%. A 2023 real-world study in the Journal of Clinical Medicine confirmed their long-term safety and effectiveness in clinical practice outside of controlled trials.
The major limitation is timing. Thiopurines have a slow onset of action, typically three to six months before they reach full effect. This is why your GI will often prescribe a corticosteroid like prednisone alongside them to control symptoms while waiting for the immunosuppressant to kick in. Standard dosing for azathioprine in Crohn's disease is 1.5 to 2.5 mg/kg/day, adjusted based on blood work and how you respond.
Common side effects include nausea, lowered white blood cell counts, pancreatitis, and liver enzyme elevations. Regular blood monitoring is required throughout treatment, typically every few months, to catch problems early. There is also a small but real increased risk of certain cancers, including hepatosplenic T-cell lymphoma, a rare but serious cancer reported primarily in young men on long-term thiopurine therapy.
Why Your Doctor Orders a TPMT Test First
Before starting azathioprine or 6-MP, your gastroenterologist should order a thiopurine methyltransferase (TPMT) test. This blood test measures the activity of an enzyme that metabolizes thiopurines in your body. The reason this test matters is straightforward: about 10% of people have lower-than-normal TPMT activity, and roughly 1 in 300 people are severely deficient.
If your TPMT activity is low, your body cannot break down the drug effectively, leading to a dangerous buildup of toxic metabolites that can cause severe myelosuppression, a condition where your bone marrow stops producing enough blood cells. In people with zero TPMT activity, this can be life-threatening. The FDA updated prescribing labels for both 6-MP and azathioprine to recommend TPMT testing before starting therapy.
Your doctor may also test for NUDT15, another enzyme involved in thiopurine metabolism that is particularly relevant for patients of East Asian descent. If your TPMT or NUDT15 levels come back low, your GI can either reduce the dose significantly or choose a different medication entirely. This is one of the more practical examples of pharmacogenomics, using genetic information to make drug therapy safer.
Methotrexate: Stronger Evidence in Crohn's Than in UC
Methotrexate occupies an interesting position in Crohn's treatment. While it's sometimes grouped generically with "immunosuppressants," its evidence base for Crohn's disease is notably stronger than for ulcerative colitis. Two landmark trials from the 1990s established its effectiveness. The first, published in the New England Journal of Medicine in 1995, showed that 25 mg of intramuscular methotrexate weekly was significantly better than placebo for inducing remission in steroid-dependent Crohn's, with 39% achieving remission compared to 19% on placebo. Patients on methotrexate also needed substantially less prednisone.
For maintenance of remission, Cochrane reviews found moderate-quality evidence that 15 mg weekly by injection keeps Crohn's in check, with about 65% maintaining remission after 40 weeks compared to lower rates on placebo. Methotrexate also works somewhat faster than thiopurines, typically reaching therapeutic effect in 8 to 12 weeks rather than three to six months.
There are trade-offs. Methotrexate is given by injection (subcutaneous or intramuscular), which some patients find inconvenient. It cannot be used during pregnancy due to serious risks of birth defects. Side effects include nausea, mouth sores, fatigue, and potential liver damage with long-term use, requiring regular blood tests. Your doctor may prescribe folic acid supplements to reduce some of these side effects. Despite these limitations, methotrexate is an important option, particularly for patients who cannot tolerate thiopurines or who need an alternative to azathioprine for combination therapy.
Combination Therapy: Why Two Drugs Can Be Better Than One
One of the most important findings in Crohn's treatment over the past two decades came from the SONIC trial, published in the New England Journal of Medicine in 2010. This randomized, double-blind study of 508 adults with moderate-to-severe Crohn's disease compared three approaches: infliximab alone, azathioprine alone, and the combination of both.
The results were clear. At 26 weeks, 56.8% of patients on combination therapy achieved steroid-free remission, compared to 44.4% on infliximab alone and 30% on azathioprine alone. Mucosal healing, a deeper measure of disease control that examines the actual lining of the intestine, occurred in 43.9% of the combination group versus 30.1% on infliximab alone and 16.5% on azathioprine alone.
The mechanism behind this benefit involves pharmacokinetics. Adding azathioprine to infliximab reduces the formation of antibodies against the biologic drug, which helps maintain higher and more consistent drug levels. This means the biologic works better for longer. If your doctor prescribes an immunosuppressant alongside a biologic like infliximab or adalimumab, the immunosuppressant's primary job may be protecting the biologic from your immune system rather than directly suppressing inflammation on its own.
Safety data from SONIC was reassuring. Serious infections occurred at similar rates across all three groups, ranging from 3.9% to 5.6%. The combination did not appear to carry dramatically higher infection risk than either drug alone.
The Mesalamine Question for Crohn's Patients
Mesalamine (sold as Pentasa, Asacol, Lialda, and other brands) is technically an anti-inflammatory rather than an immunosuppressant, but it comes up frequently in conversations about Crohn's medication. Many Crohn's patients are prescribed mesalamine, and the honest reality is that evidence for its effectiveness in Crohn's disease is weak.
The 2025 ACG clinical guideline for Crohn's disease management now strongly recommends against using mesalamine for both induction and maintenance of Crohn's disease. High-dose mesalamine may have modest benefit for mild Crohn's colitis in some patients, but for most presentations of Crohn's, including small bowel disease, the evidence simply does not support it.
Why is it still so widely prescribed? Mesalamine has an excellent safety profile, which makes it an appealing first-line option for doctors who want to avoid jumping to stronger medications. There is also a real-world observation that a subset of Crohn's patients does seem to respond to mesalamine, even though clinical trial data does not show a strong overall benefit. The gap between guideline recommendations and community practice remains wide.
If you are currently on mesalamine for Crohn's disease, this does not mean you should stop taking it without talking to your gastroenterologist. But it is worth having a direct conversation about whether your current treatment is matched to the severity and location of your disease, especially if your symptoms are not well controlled.
Making Informed Decisions About Your Treatment
Understanding the rationale behind your prescribed immunosuppressant can help you engage more effectively with your care team. Ask your GI why they chose a particular drug, what monitoring you will need, and what timeline to expect before judging whether it is working. Immunosuppressants take months to reach full effect, and evaluating their impact requires consistent tracking of your symptoms over time rather than relying on how you feel on any given day.
Immunosuppressants take months to work. Track your symptoms consistently with Aidy so you and your GI can evaluate effectiveness with real data, not guesswork.