Understanding the Whys When UC Treatments Don’t Work for You

Written by Hallie Levine
Medically Reviewed by Melinda Ratini, MS, DO on March 17, 2026

With ulcerative colitis (UC), you may go through periods with little or no inflammation, often called remission. But sometimes symptoms can return, which can be frustrating.

“It’s unfortunately fairly common,” says Ryan Ungaro, MD, a gastroenterologist at the Icahn School of Medicine at Mount Sinai in New York City. “We have many new treatments available to get more patients with UC into remission, but sometimes a therapy doesn’t seem to work anymore.”

Other times, a treatment may not seem to work at all or cause unpleasant side effects. But you have many treatments to choose from, and you’ll likely find a better fit.

“We have many tools in our toolbox to help us manage ulcerative colitis,” reassures Ungaro. “View it as a bump in the road — not a total derailment.” Here’s a closer look at why treatment may not work, or why it’s stopped working, and what to do next.

When symptoms like bloody diarrhea and pain return, you may be tempted to point fingers at your current medication. But there may be other reasons why, so check with your doctor to rule out other causes first.

“It could be your ulcerative colitis treatment not working, but it could also be because of another underlying condition like an infection,” says Ungaro. Your doctor can run tests to check for gut inflammation and other conditions.

C-reactive protein (CRP) levels. High levels in your blood can mean inflammation from a UC flare or some other problem, such as infection. 

Fecal calprotectin and infection. Higher levels of fecal calprotectin, a protein in your stool sample, can mean gut inflammation. Or it can show up with certain bacterial infections, such as Clostridioides difficile (C. diff), E. coli, or salmonella.

Colonoscopy or sigmoidoscopy. A lighted tube shows your doctor the inside of your colon. “It can tell us whether or not there is active inflammation that indicates a UC flare,” says Ungaro.

If other health conditions aren’t causing the problem, your doctor will sit down to discuss new treatments with you.

You have many options to treat your ulcerative colitis. “We typically match treatment to disease activity and severity,” says Ungaro. But even then, you may not find the right medication on the first try.

That can mean trying different medications or combinations before it’s right. Here are the main classes of UC medications:

Aminosalicylates (5-ASAs). Medicines that coat the lining of your colon to treat mild-to-moderate UC.

Immunomodulators. These change your immune system to lower inflammation in moderate-to-severe UC. 

Biologics. These are man-made Y-shaped proteins (antibodies) that search out and block parts of your immune system to help with moderate-to-severe UC.

Small molecules. These tiny man-made chemicals target certain parts of your immune system to lower its “volume,” calming inflammation in moderate-to-severe UC.

Steroids. These very powerful medicines are taken for the short term to avoid serious side effects, but can quickly lower inflammation in your body.

UC medicines work in many ways to block or slow down your immune system. Each one can also stop working for different reasons.

These can lower inflammation and pain inside your gut. Aminosalicylates help up to three-quarters of people maintain mild-to-moderate UC activity.

Working locally on the lining of your intestines, your doctor may suggest:

  • Balsalazide (Colazal)
  • Mesalamine, which comes as a pill (Apriso, Asacol, Asacol HD, Delzicol, Lialda, or Pentasa), suppository (Rowasa and SfRowasa), or enema (Canasa)
  • Olsalazine (Dipentum)
  • Sulfasalazine (Azulfidine and Azulfidine EN-tabs)

Why aminosalicylates may not work

Usually used first, topical mesalamine may help. But if aminosalicylates can’t reach the problematic areas inside your gut, they may not work. So if your symptoms don’t improve after a few weeks, your doctor may add an oral steroid to quickly bring down inflammation. These include:

After two to four weeks, you’ll check in with your doctor. The next step is to add an oral aminosalicylate while you continue topical mesalamine. Taking mesalamine by mouth can help coat the tissues of your intestines.

Taken by mouth, mesalamine may travel further into your gut. But if the medicine still isn’t working after eight weeks, you may need a stronger one. Your doctor will talk to you about other options.

These medicines help calm your immune system and maintain moderate-to-severe UC activity. If aminosalicylates and steroids aren’t working, your doctor may prescribe:

Azathioprine and mercaptopurine can help you slowly stop taking steroids. Cyclosporine and tacrolimus help start treatment to calm sudden, severe UC activity until another medicine works — it’s called rescue therapy.

Why immunomodulators may not work

Immunodulators may not work for everyone because:

  • They block the wrong inflammatory proteins, causing UC inflammation.
  • The medicine isn’t broken down to the active form (genetics).

These medicines are usually combined with others to treat moderate-to-severe UC, usually a biologic.

Used mainly for moderate-to-severe UC, biologics work to block or dampen your immune system. Biologics can quiet specific inflammatory pathways that get overactive and cause UC.

Tumor necrosis factor-alpha (TNF-alpha)

Anti-TNF medicines bring down levels of the inflammatory protein called TNF-alpha to lower UC activity. Your doctor may prescribe:

  • Adalimumab (Humira) or biosimilars such as Abrilada, Amjevita, Cyltezo, Hadlima, Hulio, Hyrimoz, Idacio, Simlandi, Yuflyma, or Yusymri
  • Golimumab (Simponi)
  • Infliximab (Remicade) or biosimilars such as Avsola, Inflectra, Ixifi, Renflexis, or Zymfentra
  • Risankizumab (Skyrizi)

Integrins

Vedolizumab (Entyvio) is an integrin receptor antagonist that blocks the surface protein called integrin. This keeps your white blood cells from reaching the lining of your colon to lower inflammation.

Interleukins

Interleukin antagonists lower the levels of inflammatory proteins called interleukins:

  • Guselkumab (Tremfya) blocks interleukin-23.
  • Mirikizumab (Omvoh) also blocks interleukin-23.
  • Ustekinumab (Stelara) blocks both interleukin-12 and interleukin-23. Biosimilars include Imuldosa, Otulfi, Pyzchiva, Selarsdi, Starjemza, Steqeyma, Wezlana, or Yesintek.

Why biologics may not work

Here are some common reasons why biologics may stop working:

The wrong inflammatory protein gets blocked. “These drugs all work on different pathways, so we sometimes have to try two or three before we find the right one,” says Ungaro. 

The biologic dose isn’t high enough. “When someone has a very high inflammatory burden, they may need a very high dose of a biologic initially,” explains Ungaro.

Natural immune responses prevent your medicine from working. A blood test can check for this, called antidrug antibodies. “We see this most commonly with the anti-TNF biologics, like infliximab or adalimumab,” explains Ungaro. 

If your biologic isn’t working after eight weeks, your doctor may switch you to another one that works on a different immune pathway.

These small chemical medicines may be a good fit if other UC medicines don’t work or your body clears them too quickly. There are two main types that treat moderate-to-severe UC.

Sphingosine-1-phosphate (S1P) receptor modulators. Block a special protein (S1P receptor) found on the surface of white blood cells to prevent damaging the lining of your colon. Your doctor may suggest:

  • Etrasimod (Velspity)
  • Ozanimod (Zeposia)

S1P receptor modulators can help start treatment and maintain remission.

Janus kinase (JAK) inhibitors. Stop specific enzymes, called JAK enzymes, from triggering inflammation, such as:

  • Tofacitinib (Xeljanz)
  • Upadacitinib (Rinvoq)

Your doctor will likely suggest a JAK inhibitor if other medications aren’t working. “We generally turn to them after we’ve tried several other drugs,” says Ungaro. 

Why small molecules may not work

Although very effective, these medicines don’t work for everyone, says Ungaro. They may not work because the specific protein or immune pathway causing UC isn’t blocked. Or the medicine dose is too low.

But it’s not always clear why these medicines don’t work for everyone. For example, after a year of clinical trial testing, only about a quarter of people taking ozanimod stayed in remission.

About 20%-30% of people with UC eventually need surgery. If your treatments aren’t working or you’re still taking steroids, your doctor may suggest surgery.

“If you are hospitalized for repeat flares or feel that your symptoms are still debilitating, even when you’ve tried multiple medications, then you may want to consider it,” says Ungaro. “For some patients, it can really improve the quality of their life, and allow them to resume many activities.”

With many options to choose from, the most common type is an ileal pouch with anal anastomosis, also called J-pouch surgery. Your surgeon removes your colon and rectum before making an internal pouch that holds your bowel movements. 

You’ll often feel much better after surgery, but there are also risks for complications. You and your doctor will decide what’s best.

It can feel frustrating when you have to try so many different medicines. But using trial and error to reach remission isn’t uncommon with ulcerative colitis.

“While we have many drugs out there, most only get 30% to 40% of people into remission after one year,” says Ungaro. “There’s still a large treatment gap out there that we are trying to fill.”

Working closely with your doctor can help you stay on top of your UC. “Stay up-to-date on visits, keep track of your symptoms, and let them know anytime you think a treatment isn’t working,” says Ungaro. Together, you both can come up with a new treatment plan to better manage your ulcerative colitis.

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