Remicade for Crohn’s Disease (infliximab)

General Information

Remicade (generic name infliximab), was the first biologic treatment approved for Crohn’s disease. Remicade is a traditional treatment of Crohn’s disease. It is used in moderate to severe cases of Crohn’s disease (both adult and pediatric), or to treat fistulas. Manufactured by Centocor, it was approved in 1999. In addition to Crohn’s disease, Remicade is also used to treat rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, severe psoriasis and ankylosing spondylitis. In this article, we will focus on the uses of Remicade for Crohn’s Disease.

Administered as an intravenous infusion, it takes 2-3 hours at an infusion center to receive the full dose. When first beginning treatment, patients are given an initial dose, followed by a dose 2 weeks later and a dose 6 weeks after the first. This ramp up is necessary to establish a clinical level of the drug, after which many patients will receive a dose every 6-8 weeks. The standard dosage is 5 milligrams of Remicade for every kilogram of body weight, but some patients who relapse after initially responding can benefit from the higher approved dose of 10mg/kg. A PPD skin test for tuberculosis must be performed prior to starting treatment because Remicade can reactivate tuberculosis in people that have a history of the disease.

How Does Remicade Work?

Remicade is classified as a “chimeric monoclonal antibody against tumor necrosis factor alpha” (TNF-a). To break that down into common terms, a monoclonal antibody is a laboratory made protein which is cloned from a single unique parent cell so that it is specific to one target in the body. Similar to a lock and key mechanism, each monoclonal antibody will only bind to one substance (antigen). In this case, that substance is TNF-a. Remicade is termed “chimeric” because it is produced using a combination of mouse and human DNA sources. When monoclonal antibodies are produced from animal sources alone, there can be problems of rejection and host reactions. This is minimized by building both mouse and human regions into the antibody.

Remicade works by binding to TNF-a and deactivating it. To fully understand how Remicade works, we must discuss why TNF-a is important in the Crohn’s disease process. TNF-a is a protein (cytokine) that is primarily produced by the macrophages as a part of the body’s immune and inflammation response. Macrophages are white blood cells that roam around the body looking for foreign substances to devour. They are a key component of innate immunity, and their response is believed to be dysfunctional in Crohn’s disease. The immune system and the inflammatory response is very complex, but for our purposes, it is enough to know that the macrophages produce the chemical TNF-a either in a defective way or in response to a foreign invader (like a mycobacteria) that they cannot fully recognize. Once TNF-a is released, it begins a chain of inflammatory pathways. It is this inflammatory response that causes the damage in Crohn’s disease. Remicade, by interrupting the action of TNF-a, halts the inflammatory process that leads to disease.

While Remicade binds only to TNF-a specifically, it does so throughout the entire body. Therefore, while the benefit of Remicade relieves the symptoms of Crohn’s disease, it can also impair the immune system from responding to other, unrelated threats. Therefore, infections unrelated to Crohn’s disease can present a much more serious problem for patients when on Remicade. It is for this reason that a test for latent tuberculosis should be performed on each patient prior to beginning treatment with Remicade. In people who have been sick with tuberculosis and then recovered, the disease is contained and walled off in their lungs by the immune system, which forms a type of “jail” around any live bacteria. As long as the immune system remains fully functional, this jail stays intact and the contained tuberculosis cannot cause active disease. But when the patient’s immune system is impaired, either by medications, disease or lifestyle changes such as stress or depression, tuberculosis can escape its containment and cause disease. Therefore, Remicade should not be used in patients who have had tuberculosis.

Side Effects of Remicade

On April 14, 2016, The United States Food and Drug Administration (FDA) issued a Safety Communication concerning TNF-alpha blockers (like Remicade and HUMIRA), Azathioprine and 6-MP. This goal of the alert was to inform patients who were taking these medications that they could be at an increased risk for developing a rare cancer (Hepatosplenic T-Cell Lymphoma or HSTCL) which often results in death. A table with detailed case reports broken down by each drug is included in the alert. Through December 31, 2010, there were 20 reported cases of HSTCL in patients taking Remicade and 5 cases in patients taking both Remicade and HUMIRA. Updated data has been requested. To read the full alert, see the FDA Safety Communication. Patients who are concerned about their risk of HSTCL should consult their health care provider.

Most common side effects of Remicade include:

Respiratory infections, sinus infections, sore throat
Headache
Coughing
Stomach pain
Infusion reactions (fever, chills, chest pain, low/high blood pressure, shortness of breath, rash, itching.)

Serious, but rare, side effects of Remicade include:

Serious infections, including tuberculosis, which spread through the body sometimes resulting in death
Flu-like symptoms
Heart failure, or worsening of previous congestive heart failure
Liver injury
Nervous system disorders
Blood problems
Severe or delayed allergic reactions
Lupus-like syndrome
Psoriasis
Pain/swelling at the injection site
Joint and muscle pain
Cancer

Side effects that happened more frequently in children include:

Anemia
Leukopenia (low white blood cells)
Neutropenia (low neutrophil blood cells)
Flushing
Bone fracture
Bacterial infection
Respiratory allergic reactions
Viral infections

For complete information on Remicade, please see the official site.

Biosimilar Medications to Remicade

Remicade can cost up to $22,000 per year in the United States. Sales of Remicade worldwide are approximately $8 billion. Johnson & Johnson’s United States patent on Remicade expires in 2018 and the European patent expired in February 2015. In June 2013, two biosimilars of Remicade were approved by the European Medicines Agency. Remsima (by Celltrion) and Inflectra (by Hospira) are available in Europe and other parts of the world at a lower cost than Remicade. Many more biosimilar drugs are currently in development. For more information, see the section on Biosimilar Medications.

Potential Interaction of Remicade and MAP

A study from 2012 provides preliminary data which indicates that Remicade could have a detrimental effect on the survival of MAP. According to the authors, the patients treated with Remicade (which inhibits TNF-a production) showed a significant decrease in the levels of MAP antibodies, similar to the levels in negative controls. They also looked at the survival of MAP in the monocytes after treatment with Remicade, and found a significant decrease. This suggests that decreasing TNF-a levels are detrimental to intracellular MAP’s survival, possibly because other immunological pathways are activated which then suppress the growth of MAP. More research needs to be done to figure out why it is beneficial for MAP’s survival to increase TNF-a levels.

Bach H et al. Treatment of Crohn’s Disease patients with Infliximab is detrimental for the survival of Mycobacterium avium ssp. paratuberculosis within macrophages and shows a remarkable decrease in the immunogenicity of mycobacterial proteins. J Crohn’s Colitis 2012; 6:628-9.

In a 2015 study, researchers showed that treatment with Remicade resulted in decreased MAP detection in Crohn’s disease patients, which may be attributed to decreased intestinal permeability.

Additionally, Remicade has been used in combination with AMAT and hyperbaric oxygen therapy to heal resistant fistulas in Crohn’s disease in this 9 patient study.