There are many ulcerative colitis (UC) medicines available today, but they may not work for everyone. In fact, some research suggests that over half of people taking advanced UC therapies like biologics don’t reach remission.
This lifelong condition can inflame the lining of your colon and rectum. Without treatment, the walls of your colon can weaken to create painful, open sores that can seriously lower your quality of life.
“We’ve hit a therapeutic ceiling with our current therapies,” says Benjamin Cohen, MD, clinical director for inflammatory bowel diseases at the Cleveland Clinic in Cleveland, Ohio. “We’re lucky to have many new kinds of drugs available, but most patients plateau on them at some point.”
This means that after a while, a treatment that once worked can stop or work less. So sometimes, doctors see better results if they add two different therapies together — it's called combination therapy.
Are two medicines better than one?
For some people, one medicine works very well — even without complete remission. But for many, using two medicines at once works best. Adding more than one medicine together may strengthen your treatment.
“Ulcerative colitis is such a complex disease, affecting many different pathways. It often responds better to more than one drug,” says Ugonna Iroku, MD, a gastroenterologist at the Icahn School of Medicine at Mount Sinai in New York City.
Blocking the Right Inflammatory Pathways
Some inflammation in your colon is harder to treat than others, depending on the type of medicine you’re using. That’s because each medicine works differently inside your body.
“Ulcerative colitis is a very complicated disease,” says Iroku. “There are over 200 genes associated with it — all [turn on] different inflammation pathways in your gut.”
These inflammatory pathways may also link to why some medications don’t work. Medicine can fail if the inflammatory proteins causing UC aren’t blocked.
“Ulcerative colitis is such a complex disease, affecting many different pathways,” says Iroku. “It often responds better to more than one drug.”
Starting UC Treatment
Your doctor may suggest aminosalicylates (5-ASAs) in enema, topical, and oral forms at first. But they may add a steroid if mixing 5-ASAs doesn't lower pain and inflammation in your gut. After a few weeks, your doctor will likely suggest a biologic medicine to target a UC inflammation pathway. Here are some of the UC biologics they may use.
Anti-tumor necrosis factor (anti-TNF)
Anti-TNF medicines block the TNF-alpha protein to lower gut inflammation.
- Adalimumab (Humira) and biosimilars — medicine-copies that act like the biologic
- Golimumab (Simponi)
- Infliximab (Remicade) and biosimilars
Integrin receptor antagonists
This biologic targets the integrin receptor protein to trap white blood cells inside lymph nodes, preventing inflammation.
- Vedolizumab (Entyvio)
Interleukin (IL) antagonists
Block the IL-23 protein that drives inflammation.
Interleukin (IL) antagonists
Block the IL-12 and IL-23 proteins that drive inflammation.
- Ustekinumab (Stelara) and biosimilars
Using more than one type of therapy, your doctor can combine the best treatments for your health. “No one single drug can block all these pathways in a universal way,” says Iroku. “But if we add a second medication on, we may see more success.”
Combined UC Treatment
Although biologics work for some, they may not work for up to 40% of people with UC. So your doctor may combine medicines, or try another type of therapy like targeted small molecules.
Add an immunomodulator
Infliximab plus azathioprine (Imuran) is one of the most common combinations. The immunomodulator, azathioprine, plus an anti-TNF biologic may help heal your mucus lining and gut sores. But it may also calm down any overactive immune response to the biologic medicine.
“Patients sometimes develop antibodies to biologics, especially when they use anti-TNF medications, which means these drugs work less efficiently,” says Cohen. “When you combine them with an immunomodulator, it sometimes blunts this response.”
One key study showed that people with UC were almost twice as likely to reach remission after taking infliximab plus azathioprine for 16 weeks compared to the biologic alone. Some studies suggest taking an immunomodulator to quiet your immune system may help your biologic work longer, preventing anti-drug antibodies later on.
Targeting different immune pathways
Doctors usually add an immunomodulator or targeted small molecule to your biologic, or two biologics together. “The idea is to combine biologics that work on different molecules, to target more than one pathway,” says Iroku.
The VEGA study combined guselkumab (IL-23 antagonist) and golimumab (anti-TNF) together. Over 80% of people with UC taking this combination went into clinical remission. But only about 60% who took guselkumab and 75% who took golimumab alone reached remission.
Common combinations
Some studies have looked at which UC medicines doctors use together. Here are some common combinations:
- Vedolizumab to block integrins and ustekinumab to stop IL-12 and IL-23
- Vedolizumab plus an anti-TNF biologic
- Tofacitinib to block Janus kinase (JAK) enzymes plus an anti-TNF biologic, ustekinumab, or vedolizumab
Just under half of people taking vedolizumab plus ustekinumab reached remission, clinical and endoscopic. That means the lining of the colon appeared healed when examined by a doctor.
Is Combination Therapy Right for You?
For some people, one medicine works very well — even without complete remission. But for many, using two medicines at once works best, especially if other treatments aren’t working.
The recent VEGA study actually found that taking more than one medicine may cause fewer side effects than taking just one. That’s because a medicine that slows your immune system may help calm inflammation and ease your symptoms. And newer medicines can target specific immune pathways, lowering side effects.
So your doctor may not suggest combined therapy at first, to keep side effects as low as possible. “We always try monotherapy first, since the more drugs you add, the more side effects you can experience,” says Iroku.
Monotherapy is using one medicine. Some earlier studies showed serious side effects in about 30% of people taking two biologics to treat UC.
Weigh the risks and benefits
Keep in mind that these combinations aren’t approved by the FDA, and their safety is unclear. “Early data shows that these types of combination therapies may lead to less inflammation, and patients may feel better,” says Iroku. “But we don’t know yet if it’s safe.”
“These drugs suppress your immune system, which is why we often see these side effects,” says Iroku. Combined treatment may weaken your immune system and side effects can include:
- Colds
- Stuffy nose
- Headaches
- Infections and low white blood cell count
- Fever
- Anemia and low red blood cell count
Some research suggests that combined therapy may slightly raise the chance of an infection, and sometimes, even cancers, such as lymphoma. “For most patients, the benefits outweigh the risks,” says Iroku.
Adding medicines together may strengthen your treatment. “The research we do have is reassuring, because it doesn’t show combination therapy has increased side effects,” says Cohen.
Insurance Coverage for Newer Therapies
There’s another wrinkle with combination therapy: insurance coverage. Mixing a biologic with an immunosuppressant is usually covered, but newer combinations are not. “They’re not FDA-approved for this use, so we often run into issues with two drugs together not being covered,” says Iroku.
A great way to get newer combination therapies covered is to consider a clinical trial. You can try:
- Asking your doctor about which trial they might suggest
- Visiting clinicaltrials.gov for the latest UC trials
- Checking out the Crohn’s & Colitis Foundation for clinical trials
Your doctor may prescribe these medicines together, even though they’re not approved to take at the same time.
“If insurance won’t cover it, there are some things we can do to work around it,” says Iroku. “Oftentimes, we have this dual therapy for a short period of time, like one or two months, to see if it calms inflammation and reduces symptoms. Then, when they improve, we switch back to monotherapy, or one drug.”
Your doctor might help lower the cost if they give you medication samples, he says. Or they may switch you to the second medicine before the first one runs out, overlapping the two for a few weeks. So it’s worth asking about combination therapy to help you reach and stay in remission.
FAQs About Combination Therapy
Why do you suggest combination therapy to treat my UC?
Your doctor may suggest adding another medicine if your current treatments aren't working, if you still need steroids, or if your moderate-to-severe UC symptoms aren’t going away. Infliximab plus azathioprine is one of the most common combined treatments for UC. “Ulcerative colitis is such a complex disease, affecting many different pathways. It often responds better to more than one drug,” says Iroku.
What sort of side effects should I expect after starting combination therapy?
A biologic or a JAK inhibitor can raise your risk for upper respiratory infections, rash, headache, and nausea. Much more rarely, you may get a serious infection, such as tuberculosis, or even lymphoma.
How will you tell whether combination therapy is working?
Your doctor can run tests to check for inflammation. “They’ll often check biomarkers of inflammation, like fecal calprotectin and c-reactive protein, to see how your gut is doing, even if you feel well,” says Cohen. “We may also want you to have a colonoscopy, to confirm that you’ve achieved mucosal healing.”
What is the next step if I can’t tolerate treatment or it doesn’t work?
Talk with your doctor about your UC treatment plan and goals. That way, you’ll know which medicines you’ll try next. “Just remember that every treatment, whether it’s a monotherapy or a combination treatment, has its pros and cons,” says Cohen. “Combination therapies are just another tool in our toolbox to help our patients with UC improve symptoms and maintain a better quality of life.”
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