Developing ways for doctors to deliver more personalised treatment

What this research looked at  

Infliximab and adalimumab are anti-TNF medicines, used to treat people with moderate to severe active Crohns Disease or Ulcerative Colitis.  They work by blocking a protein called tumour necrosis factor (TNF).  TNF causes inflammation as part of the normal immune response. In people with Crohn’s or Colitis, too much TNF is produced. This causes chronic inflammation.   

Generally, anti-TNFs are very effective at reducing inflammation and improving symptoms. But over time they stop working for many people.  One of the main reasons for this is because people develop an immune response to the anti-TNF medicine.  The body sees the anti-TNF medicine as a potential threat and makes antibodies against it. These antibodies stop the medicines from working. This is known as immunogenicity. The antibodies can also cause side effects such as skin rash, difficulty in breathing, and low blood pressure.   

To reduce the risk of forming these antibodies, many people are also treated with an immunosuppressant medicine, such as azathioprine or methotrexate.  These medicines can also cause side effects, and using two different types of medicines together can increase the risk of infections, as the immune system is further suppressed.  It is currently not known why some people develop antibodies against anti-TNF medicines while others can successfully remain on the treatment for years with no formation of antibodies.  Initial research in this area suggests that genetics may play a role.  

The researchers are aiming to enable safer, longer-lasting, and more cost-effective anti-TNF treatment, by developing a new way for doctors to treat patients.  The ability to predict which people are more at risk of developing unhelpful antibodies before starting medication could allow more personalised treatment.  Those at high risk would receive immunosuppressive drugs in addition to anti-TNF treatment, while those at low risk may receive anti-TNF treatment only. Furthermore, the research will lead to predictions in who may develop side effects to anti-TNF treatment so that they can be avoided in those at high risk.  

To do this, the researchers used data and specimens already collected as part of the personalised anti-TNF therapy in Crohn's disease study (PANTS) and IBD BioResource, with three specific goals in mind:  

1. Explore the best ways to measure antibodies to anti-TNF medicines.  
2. Investigate factors specific to the patient and treatment that may predict an individual’s risk of developing immunogenicity.  
3. Improve existing methods and explore new treatments to reduce this risk.  

What the researchers found

The presence of anti-TNF antibodies was common in people with Crohn’s or Colitis before starting treatment. 

The researchers defined and applied new levels for measuring anti-TNF antibodies. When they applied these, more people treated with adalimumab than infliximab were reclassified as antibody positive. They also found that people who had antibody concentrations at or above the new level at the start of treatment were more likely to have stopped responding to treatment after a year than those with lower antibody concentrations.

From the data, the researchers were able to estimate how many people treated with infliximab or adalimumab lost response after 1, 2, or 3 years of treatment. They were also able to identify what factors were associated with the loss of response.

As part of a separate study, the researchers looked at the choice of a second biologic medicine in people who had already tried an anti-TNF. They found that in people treated with both infliximab and adalimumab, those who developed antibodies to the first anti-TNF were more likely to develop antibodies to the second anti-TNF. This happened regardless of which order they tried them in. Starting an immunosuppressant such as azathioprine or methotrexate, at the same time as switching to a second anti-TNF improved the long-term response in people who had already had immunogenicity to the first anti-TNF.

The researchers found two possible protein biomarkers that were associated with immunogenicity. But they need to do more research to confirm this. Biomarkers (or biological markers) are markers that can be measured to tell us what is happening inside the body.

What the researchers think this could mean for people with Crohn's and Colitis

By gaining a better understanding of immunogenicity to anti-TNF treatment, the researchers expect that:

• Doctors and patients will be able to make more informed decisions about whether to add an immunosuppressant to anti-TNF treatment.
• We will be able to better understand in which order to use biologic medicines in people with Crohn’s or Colitis.

It is hoped that further studies will build on the work to identify protein biomarkers. This in turn may help in the development of new biologic treatments for Crohn’s and Colitis.

Who is leading this research:  Dr Tariq Ahmad, University of Exeter  
Our Funding: £120,000  
Duration: 36 months  
Official title of application: Reducing Risk, Improving Outcomes: Development of Personalised Strategies to Reduce the Impact of Immunogenicity to Anti-TNF Therapy