Anti-TNF Medicines

for Inflammatory Bowel Disease (IBD)

KEY POINTS:

Antibodies to tumor necrosis factor (Anti–TNF) medicines are very effective in treating persons with either Crohn’s disease or ulcerative colitis to settle active disease and to maintain improvement (remission) over time.
These drugs work in 2 of 3 patients. It may take a trial of 3-4 months to see if they are effective, although many patients show a positive effect more quickly.
When the medicine has been effective, approximately 1 in 10 patients (10%) have to stop each year, either because the medicine loses benefit over time or because the patient develops an intolerance to the medicine. In most patients these drugs are well tolerated.
As the drugs influence the immune system, there have been concerns for serious infections and cancers developing with use of anti-TNF drugs. These serious outcomes are uncommon.
Cost: These drugs are very expensive. Most are covered under provincial and private drug plans. Coverage may differ depending on the province you live in. When you are considering a treatment it is helpful to check the cost and coverage under insurance plans with your doctor and your pharmacist. (See the fact sheet Managing Costs of Medicine for Inflammatory Bowel Disease for more information.)

Member drugs

Anti-TNF drugs were studied for treatment of Crohn’s disease starting in the late 1990s and soon after for treatment of ulcerative colitis.
The main types used are:

a) infliximab (Remicade or Inflectra or Renflexis) which is administered by an intravenous injection (given directly into the bloodstream through a catheter in the vein) typically over a 2-hour period and given every 8 weeks;

b) adalimumab (Humira) which is administered by an under the skin injection every 2 weeks. This is done with a needle and takes seconds;

c) certolizumab (Cimzia) or golimumab (Simponi) which are administered as injections into the muscle every 4 weeks by a needle and takes seconds.

Note: None of these drugs is available in pill form.

Availability: In Canada, the USA, Australia and in most European countries infliximab and adalimumab are available to be prescribed. Certolizumab and golimumab are not available for treatment of Crohn’s disease and ulcerative colitis in all of these countries.
Biosimilars: The originator drug of infliximab is called Remicade. Recently infliximab drugs have been developed that are biochemically and functionally similar to Remicade. These drugs are called “biosimilars”. They are like generic drugs in relation to name brand drugs. Inflectra and Renflexis are two biosimilar infliximab drugs that are available in North America. The availability of a variety of medicines for the same purpose may reduce the cost of medicines over time.

How do these drugs work?

These drugs have been shown to settle active Crohn’s disease and active ulcerative colitis. They are also used for some other inflammatory conditions such as rheumatoid arthritis and psoriasis.
These medicines contain antibodies which block the protein tumor necrosis factor (TNF). Reducing TNF in the tissue and circulation reduces the inflammatory response in Crohn’s disease and ulcerative colitis.

How well do they work?

Doctors decide to start anti-TNF therapy in persons with Crohn’s disease or ulcerative colitis when they have failed to remain well on other drugs such as azathioprine in Crohn’s disease or 5-ASA in ulcerative colitis. This treatment may also be used when the symptoms are so serious that there is simply not time to wait for less potent drugs to work.
These drugs produce a good response in about 2 of 3 of patients (67%). It may take a trial of 3-4 months to see if they are effective, although in many cases they show a positive effect more quickly. Some patients achieve what is called deep remission. This is when their symptoms are completely gone and a colonoscopy shows healing of the lining of the bowel. Other patients improve considerably but still have some ongoing symptoms.
Once active Crohn’s disease and ulcerative colitis have been settled by anti-TNF medicine, continuing the medicine maintains the response to treatment.
For patients with severe ulcerative colitis requiring admission to hospital infliximab can be effective to settle the disease.
Anti-TNF antibodies can be effective in closing fistulas in persons with Crohn’s disease. Fistulas are tracts that form between the bowel and the skin or between the bowel and other organs like the bladder.
When the medicine has been effective, approximately 1 in 10 patients (10%) have to stop each year, either because the medicine loses benefit over time or because the patient develops an intolerance to the medicine. Sometimes the intolerance is in the form of an allergic reaction when the medicine is being infused (shortness of breath or rash or low blood pressure). Sometimes the intolerance takes the form of a skin rash that does not easily settle. Rarely, the medicine must be stopped because of development of abnormal blood tests relating to the liver.
When these drugs stop working the doses are increased - by giving more drug with each dose or giving the same dose more often. This may restore the effectiveness of the treatment.
People can develop antibodies to the anti-TNF drug and that can render them ineffective or be associated with allergic reactions to the drugs.
Combination treatment: For infliximab and possibly some of the other medicines, the drug reduces symptoms and inflammation more if the drug is used together with an immunosuppressive medicine such as azathioprine (Immuran) or 6-mercaptopurine (Purinthol). Infliximab can be used together with methotrexate instead of azathioprine or 6-mercaptopurine to improve outcomes by reducing the development of antibodies to the drugs.
Nonresponse: The best way to determine why a patient is not responding or losing response to these drugs is to measure blood levels of the drug and antibodies to the drug. If antibodies to the drug are present, especially at a high level, the drug will not be effective. If blood levels of the drug are high and the patient has lost response to the drug this would be a sign to switch drugs. If blood levels of the drug are low then the dose of the drug should be increased.
Duration of treatment: It is usually recommended that the treatment is continued for several years when it has worked well. If the medicine is stopped shortly after the improvement, the inflammation is likely to return. There are some experts who believe that once the medicine is started it should never be stopped if it continues to be effective.
Stopping anti-TNF therapy: Either the patient or their doctor may consider discontinuing the therapy after they have used it for several years. The best time to discontinue the medicine is not clear and which patients will remain well despite stopping anti-TNF therapy is not clear. When patients stop anti-TNF therapy, some may get recurrent disease even within a year. Beyond one year some others may have the return of active disease (relapse). However, the majority can have their disease settled by restarting the anti-TNF therapy. A person stopping anti-TNF therapy should have no evidence active inflammation, either at endoscopy or by blood markers. If there is evidence of active inflammation and the drug is stopped there is a high likelihood of the inflammation and symptoms recurring.

Side effects

Generally, these drugs are well tolerated.
Allergic reactions: With prolonged use, some patients develop allergic reactions during the intravenous administration of infliximab. These reactions can include shortness of breath, low blood pressure or skin rash. Sometimes, if the infusion is slowed and given over a longer period, the allergic reactions do not occur. At other times, these reactions can not be diminished and the drug must be discontinued.
Injection reactions: Some patients receiving the under the skin or into the muscle injections develop red and sometimes painful reactions at the site of injection. Sometimes these diminish with time.
Skin rash: Occasionally patients (less than 5 in 100 or 5%) will get a skin rash with anti-TNF drugs. Most of the time this can be easily treated with creams. Rarely, the drug needs to be stopped.

Complications

Serious infections: These are uncommon. They occur in less than 1 of 100 persons (1%). Because tuberculosis can be reactivated with anti-TNF drug use, patients are tested for tuberculosis before starting the drug. There is also an increased risk of reactivation of varicella zoster the virus that causes shingles. While this is rarely life threatening, persons affected by shingles can have pain in the area where the shingles rash emerges. If a person is using anti-TNF therapy and get a fever they should report this to their doctor. If fever persists dosing of the anti-TNF may be delayed.
Skin cancer: There is a small increase in the risk of skin cancer for long term users of these drugs. It is important to use sunscreen in the sun.
Lymphoma: There is small increase in the risk of developing lymphoma (cancer in the lymph glands). The risk is further increased when there is combination use with azathioprine (Immuran) or 6-mercaptopurine (Purinthol) together with the anti-TNF. The anti-TNF is more effective when used with azathioprine or similar drugs and hence this benefit far outweighs the rare risk of getting a lymphoma. Another option is to use methotrexate wbith the anti-TNF medicine instead.
Most experts suggest that the benefits of these immune suppressive medicines outweigh the risk because having poorly controlled IBD has serious health effects also. For more information see the Fact Sheet about Inflammatory Bowel Disease and Cancer.

Anti-TNF medications in pregnancy

This class of drugs is generally considered safe for pregnancy. (See the Fact Sheet on IBD and Pregnancy for detailed information about IBD and its treatment during pregnancy.)
Stopping or delaying these drugs during pregnancy may increase the risk of a flare of disease which is a problem for the health of the mother and the child. Hence, it is recommended that women can safely continue these medications throughout their pregnancy. If it is decided to stop the medicines during pregnancy, to reduce the chance that the newborn baby will have any circulating drug, then the time to stop is the beginning of the third trimester
Breastfeeding: Small amounts of these drugs are found in breast milk, but it is recommended that women can breastfeed while using these medications.
Early vaccinations: If these drugs are used after 22 weeks of pregnancy, the infant cannot receive live vaccines the first 6 months of life. Live vaccines include rotavirus vaccine and measles/mumps/rubella (MMR) vaccine. Other routine (non-live) vaccinations recommended through public health for the first 6 months are safe.

References

Bernstein CN. Treatment of IBD: Where we are and where we are going. American Journal of Gastroenterology 2015; 110:114-126.

Bernstein CN. Does everyone with IBD need to be treated with combination therapy? Current Opinion in Gastroenterology 2016; 32: 287-293.

Jones JL, Kaplan GG, Peyrin-Biroulet L, Baidoo L, Devlin S, Melmed GY, Tanyingoh D, Raffals L, Irving P, Kozuch P, Sparrow M, Velayos F, Bressler B, Cheifetz A, Colombel JF, Siegel CA. Effects of concomitant immunomodulator therapy on efficacy and safety of anti-tumor necrosis factor therapy for Crohn's disease: A meta-analysis of placebo-controlled trials. Clinical Gastroenterology & Hepatology. 2015;13(13):2233-2240.

Samaan MA, Bagi P, Vande Casteele N, D'Haens GR, Levesque BG. An update on anti-TNF agents in ulcerative colitis. Gastroenterology Clinics of North America. 2014;43(3):479-494.

Singh S, Pardi DS. Update on anti-tumor necrosis factor agents in Crohn disease. Gastroenterology Clinics of North America. 2014; 43(3):457-478.

Slevin SM, Egan LJ. New Insights into the Mechanisms of Action of Anti-Tumor Necrosis Factor-α Monoclonal Antibodies in Inflammatory Bowel Disease. Inflammatory Bowel Diseases. 2015;21(12):2909-20.

Targownik LE, Bernstein CN. Infectious and malignant complications of TNF inhibitor therapy in IBD. American Journal of Gastroenterology 2013; 108: 1835-42.

Last reviewed: March 2020

For more information about IBD and its treatment please visit: www.crohnsandcolitis.ca

Disclaimer: This information is provided for educational purposes only. Always consult a qualified health care professional for your specific care.

Source: This summary provides scientifically accurate information. It was prepared in a research review by researchers with the IBD Clinical and Research Centre, University of Manitoba with assistance from colleagues in Canada and internationally.

Acknowledgement: Preparation of this material was supported by funding from the Canadian Institutes of Health Research.

2017 Charles N. Bernstein, John R. Walker on behalf of Manitoba IBD Clinical and Research Centre. This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License. You are free to copy and distribute this material in its entirety, as long as it is not altered in any way (no derivative works).