Learn More About COMBINE

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MORE about the medications being studied:

Anti-TNF medications, often called ‘biologics’, are medicines that are often used in the treatment of Crohn’s disease and Ulcerative Colitis – both in kids and adults. This family of medications is also used for other conditions such as Rheumatoid Arthritis and psoriasis. COMBINE will enroll kids with moderate to severe Crohn’s disease who are about to start on anti-TNF therapy for the first time.

There are two major anti-TNF medications in use currently, infliximab (brand name: Remicade®) and adalimumab (brand name: Humira®). TNF (Tumor Necrosis Factor) is a protein that is created by the body, and acts like a messenger that is sent by the body to produce inflammation. Both anti-TNF medicines are antibodies that are designed specifically to bind to and block the action of TNF. In IBD, there is a lot of TNF, which triggers the inflammation of the gut during active disease.

Because anti-TNF medicines are proteins, and proteins are broken down in the stomach, anti-TNF medications must be given by an injection instead of a pill. For infliximab (Remicade®) the medicine is given intravenously (IV), typically in a clinic or infusion center. In contrast, adalimumab (Humira®) is injected under the skin and many people inject this medication at home.

Anti-TNF medicines cause immune-suppression - that is, they reduce the strength of the immune system. The immune system protects the body from infections. It is constantly on the look-out for abnormal cells, like germs and abnormal cells from our own bodies. When it finds these cells, it is supposed to target and destroy them before germs cause infections or abnormal cells from the body become cancer. In many diseases that involve the immune system, like in IBD, part of the immune system causes inflammation by attacking normal cells of the body.

While the ability for anti-TNF medications to calm down the part of the immune system that causes inflammation and damage to the gut during IBD is a good thing, it also means that part of the body’s natural defenses are weakened. So people taking anti-TNF medications are at greater than normal risk for certain infections. In addition, as the immune system is important for protecting against different types of cancers and anti-TNF medicines are associated with a small but increased risk of some cancers like lymphoma. It is important to talk to your health care provider about the risks and benefits of anti-TNF medications.

Though anti-TNF medicines are generally more effective than other medicines for IBD, their effectiveness can sometimes wear off over time. Since anti-TNF medicines are proteins that are not made by the body, the immune system can sometimes start to recognize them as foreign intruders, and can start to target them for destruction. The immune system does this by making antibodies against the medicine. Antibodies are proteins that are used by the body as messengers, which mark the thing (in this case the anti-TNF medicine) for destruction. When the body makes antibodies targeted at an anti-TNF medicine, this can result in the medicine being chewed up quickly, so it doesn’t work. Sometimes antibodies to the medicine can even lead to allergic reactions.

Methotrexate (brand names: Trexall® or Rheumatrex®) is a type of drug often called an immunomodulator. It blocks the production of folic acid (folate), one of the B vitamins that is important for many cells in the body, especially those that are growing and multiplying rapidly. Methotrexate works by starving the cells of folate, making it harder for them to grow and multiply. For this reason, it is used in the treatment of cancer at higher doses than those typically used in IBD. In IBD, it often works at lower doses. How methotrexate works to help patients with IBD is not completely clear, but it may be that it slows down the division of immune cells that can cause inflammation, as well as cells in the gut. Methotrexate may also have other anti-inflammatory properties. Both an oral and an injectable form of methotrexate are used in IBD.

Since other cells in the body also need folate, people taking methotrexate are given a supplement of folate or folinic acid to protect these normal cells. Folinic acid bypasses the blockage produced by methotrexate and seems to be effective at protecting normal cells while not interfering with the effectiveness of methotrexate.

Like anti-TNF medications, methotrexate can cause suppression of the immune system and, therefore, increase the risk of infection. Methotrexate can also increase the risk of lymphoma, although this risk is thought to be less than that with anti-TNF drugs. Nausea is one of the most common side effects of the drug, and is somewhat more likely in those taking methotrexate pills compared to the injected form.

More about using anti-TNF drugs and immunomodulators like methotrexate, alone and together:

Although anti-TNF drugs have dramatically improved IBD remission rates, there are many patients who do not respond to them, or initially respond and then don’t maintain a response over time. This has led a number of specialists to combine anti-TNF medications with an immunomodulator, like methotrexate. Since these two types of medication work in different ways, the idea is that together they could be more effective. However, combining these families of medications also can increase risk of side effects including infection risk, and potentially cancers.

The other reason that the two medicines are often combined together is that methotrexate reduces the likelihood of the immune system creating antibodies to the anti-TNF medicine. This means that patients who are on methotrexate along with an anti-TNF medicine seem less likely to lose response to the anti-TNF medicine over time.

More about the use of anti-TNF medications and immunomodulators and the risks from IBD:

There is very limited information about using anti-TNF drugs and immunomodulators like methotrexate together in kids. In adults, there have been only a few studies that have looked at this approach. In general, these find that adults on both medicines together remain in remission longer than adults on only one medicine. In a few pediatric studies, it also appears as if treating with two medicines may lead to longer remission, but the studies have generally been too small or went over too short a time to be sure if there was a real difference between the treatment groups. It can sometimes take a long time to find out if one treatment is better than another, especially when it comes to rare events like serious infections or cancer.

While people on two a combination of 2 medicines may have a better chance of being in remission, there is an increased risk of infection, and there may be a slightly increased risk of cancer too. Cancers do happen in people with IBD on these and other medicines. But cancers are so rare that it’s hard to know what the true risk is from the medicines. So combination therapy comes with a possible trade-off: More effectiveness; longer effectiveness; but increased risk.

It is also important to mention that there is also a risk to not controlling IBD. Inflammation in Crohn’s disease leads to bowel strictures, which can require surgery. Severe inflammation from Crohn’s disease can cause fistulas, which are abnormal openings from the bowel to the skin or other organs. Severe inflammation from ulcerative colitis also leads to an increased risk of needing surgery. Ongoing inflammation in colitis (ulcerative colitis or Crohn’s of the colon) leads to an increased risk of colon cancer.

So there are risks to both using these medicines, which are generally more effective, and to not using them. Since there are good reasons to both use and not use combination therapy, and there’s no clearly right answer, we designed this study to help us all figure out what’s the best treatment for kids with IBD.