Infliximab
(This information sheet is relevant to the United Kingdom )
Anti TNFa monoclonal antibody is a new type of drug for treating Crohn’s Disease, which aims to block part of the process of inflammation. The first of this new type of drug to be given a licence for prescription is infliximab (Remicade). This has been commercially available in the UK since September 1999. A number of other Anti-TNFa drugs, made by different companies, are in the process of undertaking clinical trials (and may become available for treatment in the coming years.)
Introduction
Crohn’s Disease is a chronic (ongoing) illness in which patches of inflammation occur in the digestive tract anywhere from the mouth to the anus. The cause is not known and there is no cure, but there are medications which reduce the inflammation. They do this by blocking some of the biochemical processes which make up the process of inflammation. Newer treatments aim to block just those biochemical activities which are most important in Crohn’s Disease.
What is TNFa and why is it important?
Studies have shown that a group of chemicals called pro-inflammatory cytokines are involved in making the intestine inflamed in Crohn’s Disease. Amongst them is one called ‘tumour necrosis factor alpha’ (TNFa). This is made within the white blood cells and is released in inflamed tissue. It may be a major factor in Crohn’s Disease, since it is found in high concentrations in the lining of the inflamed intestine. Anti-TNFa, a monoclonal antibody, neutralises this, and thus may halt inflammation and relieve the symptoms.
What is an anti-TNFa monoclonal antibody?
An antibody is a special protein molecule made by white blood cells to allow the body to combat foreign invaders such as bacteria or viruses. For each foreign invader there is a specific antibody.
Using special techniques, researchers have used genetically engineered mouse cells grown in the laboratory to make antibodies which specifically block the inflammatory cytokine TNF
a, with the idea that the antibody will neutralise a major component of the inflammation. Infliximab is an antibody that works against TNFa.
Does anti-TNFa monoclonal antibody work?
If these drugs work, then they should reduce inflammation and consequently bring a reduction in symptoms. Research studies have shown this to be the case for infliximab, in a majority of Crohn’s patients (using the Crohn’s disease activity index as a marker of success). The studies have shown that infliximab can suppress disease activity after only one dose and may also offer benefit over an average period of 14 weeks.
The drug has to be given as an infusion direct into a vein and this has to be done in hospital.
Can infliximab be used repeatedly?
Infliximab infusions may be repeated every six to eight weeks. If the interval is longer (e.g. more than four months) there is a high risk of antibodies developing against the mouse antibody (which contains a small amount of mouse protein). This negates the therapeutic effects of the infliximab and causes a febrile allergic reaction. Because of this, infliximab will usually be used in patients who are already receiving the suppressive drugs such as azathioprine, 6-mercaptopurine or methotrexate. These drugs suppress the development of antibodies against the infliximab and allow much more flexibility with regards to subsequent repeated use of infliximab.
Is infliximab safe?
It has been used now in several hundred individuals with either rheumatoid arthritis or Crohn’s Disease. It seems very safe in the short term but there is a risk of exacerbation of underlying tuberculosis (TB). Because of this, patients need to be checked to exclude TB (chest x-ray and possibly a skin test) before receiving infliximab. Infliximab should be avoided in cases of sepsis e.g. Crohn’s related abscess or significant stricturing (narrowing) of the intestine. Long term safety beyond two years or so is still uncertain.
The availability of infliximab
In the UK, the National Institute for Clinical Excellence (NICE) has recommended that infliximab be used as a treatment for Crohn’s Disease within the National Health Service if all three of the following conditions are fulfilled:
1. “The person has severe active Crohn’s Disease. People with severe active Crohn’s Disease will be in very poor general health. They will have severe symptoms of the disease such as weight loss, severe pain and frequent diarrhoea. In addition to symptoms such as these, new fistulas may be developing and the disease may be affecting parts of the body away from the intestines. The doctor can measure the severity of the disease by comparing a patient’s symptoms with a standard checklist that can be used to calculate a severity ’score’. Two ’scoring measures’ that are often used are the Crohn’s Disease Activity Index (or CDAI) and the Harvey-Bradshaw Index. Severe active Crohn’s Disease would usually have a score of 300 or more on the Crohn’s Disease Activity Box or at least 8 to 9 on the Harvey Bradshaw Index.
and
2. Treatment with immunomodulators and corticosteroids has not worked, or has caused side effects that make it impossible or unsafe for the person to take them.
and
3. Because of the person’s condition, surgery would not be the right form of treatment.
Infliximab treatment can be repeated for someone who matched criteria 1-3 (above) for treatment with infliximab and who responded to the initial treatment but whose condition then got worse. The doctor should explain the likely risks and benefits of repeating the treatment with infliximab before a decision is made about whether to give another round of treatment.
NICE recommends that infliximab should be prescribed by a gastroenterologist (a doctor who specialises in treating diseases of the gastrointestinal tract) who is experienced in treating people who have Crohn’s Disease.
NICE recommends that infliximab should not be used to treat people who have Crohn’s Disease with fistulas unless they fulfil the other criteria for severe active Crohn’s Disease described in all three points above.”
Other Drugs
There are other drugs being produced that target particular chemicals in the inflammatory process. These drugs are sometimes called ‘biologics’.
At the time of writing, infliximab is the only biologic being prescribed in the UK, however there are approximately twenty other biologics undergoing trials. Some of these are targeted against TNF
a and others are aimed at neutralising other inflammation chemicals such as interleukins.
It seems only a matter of time before more of these new drugs will become available for treatment of IBD (UC as well as Crohn’s), as well as other inflammatory disease.
Summary
It is generally agreed that TNFa is an important factor in the cause of Crohn’s Disease and because of its increased presence in the lining of the intestines in Crohn’s patients, it seems logical that neutralising TNFa could be a potentially important treatment.
Initially, infliximab use will be restricted to patients with difficult fistulae and those who are not responding well to standard medical treatment.
It is clear that more work is needed. The pattern of dosage is not yet firmly established and there is debate as to how long one course of treatment will last. It is also thought that current anti-TNF
a drugs may not be TNFa specific, but may have a more general effect on the ability of white cells to suppress inflammation. Clinical trials so far suggest that anti-TNFa monoclonal antibody is safe, but some doctors have concerns about long-term safety.
Whilst this new treatment looks promising as an important treatment for Crohn’s Disease, there is still insufficient information to be certain about its future role.
Further Information
A leaflet about the NICE guidance on infliximab is available from NACC or directly from NICE, 11 Strand, London WC2 5HR, website www.nice.org.uk
© NACC, October 2002
Updated July 2003