What are immunomodulators?
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Immunosuppressants, also called immunomodulators, are conventional therapies as they have been around for a long time. They were first used in people who needed to safely receive organ transplants and it was later starting to be used to treat inflammation in people with inflammatory bowel disease.
Examples of immunosuppressants include methotrexate (e.g. Metoject®, Rheumatrex®), azathioprine (Imuran®), 6-mercaptopurine (e.g. Purinethol®) , cyclosporine (Neoral®), tacrolimus (e.g. Astagraf XL®, Envarsus XR®) and ixekizumab (Taltz®).
How do immunomodulators work?
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Immunomodulators work by reducing IBD inflammation. They impact the number or function of immune cells (cells of the immune system) and by doing so, they suppress the immune system in order to reduce inflammation caused by these type of cells in your body.
Thiopurines (azathiopurine, 6-mercaptopurine)
These medications kill inflammatory cells (cells that cause inflammation), called T cells, by blocking its TcR pathway responsible for cell survival.
They also block the ability of inflammatory cells to build DNA, by inhibiting the production of the chemical 'purine' found in DNA, and this prevents the production of inflammatory cells.
It stops an enzyme (or a protein), called dihydrofolate reductase, from functioning. As a result, this reduces the production of DNA, RNA, thymidylates (enzymes important for DNA production), and proteins. In turn, this process leads to lower levels of inflammation.
These medications are less commonly used, but mostly among people who are hospitalized.
They work by blocking calcineurin, an enzyme or protein responsible for a type of inflammatory cells (cells that cause inflammation) called T cells. By preventing their activation, there are fewer active T cells in the body and therefore less inflammation.
Who are immunomodulators used for?
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Thiopurines: Oral pills
These medications are used to treat both Crohn's disease and ulcerative colitis.
Some people with IBD are on these medications alone to treat their disease but also to try to reduce their need for steroids.
They can also be used in combination with biologics to improve their efficacy, e.g. people with IBD could be taking Remicade® and Imuran® at the same time. This is because sometimes two treatments are better than one as you can get a better response and the immunomodulators boost the blood levels of biologics. This combination can also reduce of developing antibodies (an immune system response) to the drugs.
These medications are also used much less frequently over time due to the long-term safety issues associated to them.
Methothrexate: Oral pills, Subcutaneous injections (under the skin), Injections into the muscle
Methothrexate is used to treat Crohn's disease. Just like thiopurines, some people with IBD are on this medication alone to treat their disease, or in combination with biologics for the same reasons, but also to try to reduce their need for steroids.
It is also helpful for arthritis and is therefore prescribed for people with Crohn's or colitis who also have arthritis.
However, data on methothrexate in colitis has not been very convincing so far and hence, this medication is not considered effective to treat colitis when used alone.
Cyclosporine: Oral pills, Injections, IV infusions
Cyclosporine is not typically used by people with IBD, but instead it is used only rarely for people with severe colitis who are hospitalized.
How effective are immunomodulators?
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Here is a summary of the effectiveness of immunosuppressants in managing active IBD and preventing relapse during remission:
Active ulcerative colitis
The immunosuppressant cyclosporine is effective at inducing remission in active UC.
The immunosuppressants azathioprine, 6-mercaptopurine, methotrexate, and tacrolimus are NOT effective at inducing remission in active UC.
Inactive ulcerative colitis (remission)
Active Crohn's disease
Inactive Crohn's disease (remission)
Talk your health care provider or IBD specialist for more information.
Side effects and risks of use
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People on these treatments should get regular blood tests done to monitor aspects like your liver condition and your blood counts because in some patients, immunosuppressants impact the bone marrow and this leads to their levels of white blood cells (cells that are part of the immune system) to go down.
Azathioprine and 6-mercaptopurine
Adverse effects of azathioprine and 6-mercaptopurine can include nausea, allergic reactions, acute pancreatitis (inflammation of the pancreas), hepatitis (inflammation of the liver), increased risk of infection, malignancy (small but increased long-term risk of developing lymphoma and non-melanoma skin cancer), and myelosuppression (bone marrow suppression).
Bone marrow is where blood cells are made, and suppression of bone marrow means fewer white blood cells, red blood cells, or blood clotting cells in the body. As bone marrow suppression can happen anytime during therapy, patients are recommended to have regular blood tests to check for leucopenia, which is a reduction of white blood cells.
If you develop severe flu-like symptoms or abdominal pain while taking azathioprine or 6-mercaptopurine, stop the medication and call your doctor immediately.
Adverse effects of methotrexate include hepatoxicity (liver damage), pneumonitis (inflammation of the lung), increased risk of infection, malignancy, alopecia (hair loss), stomatitis (a sore of inflammation inside the mouth), and myelosuppression.
If you develop shortness of breath and cough while on methotrexate, you might be having an allergic reaction and should call your doctor immediately.
Methotrexate is also teratogenic (contraindicated in pregnancy), meaning that pregnant people should not be taking this drug. You have to use adequate contraception and be aware that this medication can cause pregnancy loss. In fact, it was used historically to induce abortions because it has such a strong effect on pregnancy.
This medication should be taken with folic acid to reduce some of the side effects associated with methotrexate.
Cyclosporine and Tacrolimus
Adverse effects of cyclosporine and tacrolimus include renal toxicity (kidney damage), hypertension, hirsuitism (excessive body hair), headache, opportunistic infections (infection caused by bacteria, viruses, fungi, or protozoa), seizures, and paresthesia (tingling in the legs, arms, hands, or feet).
Immunizations and vaccinations
If you are taking immunosuppressants, you should avoid having live vaccines from three weeks before starting this type of drug. You should not have vaccines during the time you are on immunosuppressants, up until three to six months after stopping. You should also avoid anyone who has recently had live vaccine, and avoid the nasal flu vaccine.
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Video: Immunomodulators and Inflammatory Bowel Disease
Watch this 7 min video to learn more about immunomodulators/immunosuppressants used in the treatment of Crohn's disease and ulcerative colitis, including how these medications work in IBD, what they are used for, which types of patients can access these medications, potential benefits, side effects, and risks.
Speaker: Dr. John K. Marshall (MD, MSc, FRCPC, CAGF, AGAF), Professor of Medicine, Director, Division of Gastroenterology, McMaster University.