RTCure

Rheumatoid arthritis (RA) affects more than 18 million people worldwide and there is no cure. But most people are diagnosed when the disease is already at a chronic point. RTCure wanted to investigate what would happen if people in the very early stages of the disease – those who still do not have severe symptoms – received treatment. Would it be possible to prevent the onset of this disease, or at least slow its progression?

The results from the project indicate that yes, this is possible.

The RTCure project was the most extensive and ambitious project in the world developing diagnosis, new therapies and immunosurveillance techniques for people in the very early stages of rheumatoid arthritis, where no joint inflammation is present.

Before RTCure started, there was a good understanding of how an over-active immune system caused inflammation in people with rheumatoid arthritis, but what wasn’t clear was how the immune system became over-active in the first place. RTCure wanted to expand on the knowledge in this field and delve into what is happening on the cellular level when someone is on the brink of developing arthritis.

Who’s at risk?

The first thing to do was to figure out a way of identifying the people who are in the early stages of arthritis. The RTCure project successfully discovered a series of biological indicators – biomarkers – that were associated with this pre-arthritis stage and could be identified using blood tests.

The researchers then characterised people according to the degree of auto-immune processes taking place in the body, the number of auto-antibodies (or ACPA) present in the blood, and outward symptoms such as pain, and were able to successfully identify the group that were at risk of developing arthritis.

The window of opportunity

The next step was to map the journey of a patient from the very early, symptom-free stage (when the only indication of disease is by the presence of certain proteins in the blood) through to the onset of pain and finally, full-blown rheumatoid arthritis. They posited that there is a window of opportunity for interventions – when the patient first starts to experience symptoms like joint pain.

To investigate whether their theory was right, the researchers set up a clinical trial to see if the symptoms of the group of patients that were beginning to experience pain would improve if they were given a known anti-inflammatory arthritis drug, abatacept. The results of the APPIPRA trial were very promising – the at-risk patients that were given abatacept remained arthritis-free while taking the drug, and began to descend into arthritis when the treatment was stopped. The arthritis of the control group progressed much more rapidly. The conclusion was that abatacept could effectively halt the progression of the disease if given to patients with the early signs of arthritis.

However, recruitment for the clinical trial was not straightforward, and also raised some ethical questions – is it right to administer medication to a person who is not yet sick and may never develop rheumatoid arthritis?

In this case, the benefits outweigh the risks. Preventative medicine is a growing field – every day, people take cholesterol-lowering medication and anti-hypertensives, and it may be that a proportion of those people would never have suffered from the associated diseases that these medications seek to prevent. Many of the people within the test group already have to adjust their daily activities because of joint pain, so although they may never progress to the full-blown disease they are still negatively affected by it. The people who took the abatacept treatment reported feeling less tired, noticing an improvement in their physical, emotional and functional wellbeing, sleeping better, reduced levels of anxiety and reduced work instability, so the treatment clearly improved their quality of life. On top of that, European governments are placing more and more emphasis on preventative treatments, as prevention is deemed to be better than cure.

New tolerising therapies

A new brand of treatments for arthritis called tolerising treatments are gaining traction, and the results of the RTCure project are actively supporting clinical trials that are currently investigating these treatments, such as the AUTO-DECRA-2 trial.

The premise behind tolerising treatments is that a person’s own white blood cells should be re-trained to correctly recognise the body’s own cells and halt the auto-immune attacks. In essence, the immune system can be re-taught to tolerate its own cells. The RTCure project developed a range of tools and methodologies that can support the development of these treatments.

For instance, one key question that the RTCure project explored was which antigen-specific immune reactions are present in RA patients and how do their numbers and phenotypes change due to the use of different therapies. An improved understanding of the antigens or proteins that the immune system reacts to will help to develop more precise and targeted therapies. RTCure also implemented methodologies to identify antigen-specific immune reactions, which can form the basis of tolerising therapies.

In addition, the RTCure project identified concrete immune phenotypes associated with improvements in rheumatoid arthritis, including disease remission.  The project then developed platforms for immune monitoring which allow scientists to evaluate subtle changes in the immune system which can indicate disease remission. These immune monitoring tools are particularly useful in the development of new tolerising therapies, because they are sensitive to smaller changes in the body which may be non-symptomatic, and they indicate to a researcher whether a particular treatment is having an effect. Both of these developments enable researchers to monitor disease progression or remission, and help to indicate the success of the tolerising treatments.

For many of these tolerising treatments, the body’s white blood cells are extracted, treated and then re-injected back into the body. RTCure’s research delved into how this could be done more effectively – for example the project developed a procedure for removing and injecting white blood cells into lymph nodes. This will be used in the AUTO-DECRA-2 trial, which seeks to compare whether the tolerising treatment established in the first AUTO-DECRA trial will work better if administered via the lymph nodes, the knee joints or the thigh. 

Re-shaping and standardising the status quo in experimental methods

Developing tolerising therapies involves monitoring what changes are happening to cells during a treatment. This is done by analysing cells within the blood, but there are many ways to do this and laboratories tend to have their own individual methods. One key achievement of RTCure was the successful establishment of common protocols for monitoring cells that were adopted by multiple labs. This means that the data is comparable across labs investigating these tolerising therapies.

A large amount of data was then generated – millions of cells were being analysed – so the RTCure project also set up a series of data analysis pipelines and algorithms to better sort this data. Again, these pipelines and algorithms were shared with many labs so that there is now a network of laboratories working on tolerising therapies for rheumatoid arthritis that are all using common methodologies and data analysis algorithms.

Laying the foundations for tolerising treatments

Overall, the strides made by the RTCure project will form the basis for tolerising therapies and accelerate the rate at which these innovative treatments reach the market. Thanks to RTCure, there is an established network of laboratories employing common data collection and analysis protocols to ensure that researchers can have access to more robust, comparable data. RTCure also investigated new methodologies and procedures that will become the backbone of future clinical trials for rheumatoid arthritis tolerising therapies. Most importantly, RTCure proved that treating people that are at risk of rheumatoid arthritis – but do not yet have the disease – can have an impact on their quality of life and reduce the progression of disease, resulting in more healthy years for the patient. They showed, once and for all, that rheumatoid arthritis can be prevented if treated early enough.