RESOLVE: towards early, targeted restoration of immune resolution in RA

We are working on a new treatment strategy for people with rheumatoid arthritis (RA). Inflammation is a naturally, and pro-actively, self-limiting response. It is switched on to fight infection and repair tissue injury and switched off once these dangers are overcome.

People with RA cannot effectively turn off inflammation in the joint and this causes progressive destruction of tissue, significant loss of function, pain and fatigue. We have learned more about how joint inflammation is turned on, and kept on, in RA over the last decade. Molecules that are created upon tissue damage activate inflammation.

This response is normally switched off shortly after injury, but in people with RA this does not happen.

A vicious cycle ensues in which inflammation causes further tissue damage, releasing even more damage-associated stimuli, eventually leading to uncontrolled inflammation. Our study aims to restore these off switches: a powerful way to reinstate immune control in RA.

It is not possible to do this at present because we do not know how inflammation activated by damage-associated stimuli is turned off, and why these control mechanisms fail in RA. Our recent work is starting to shed light on these questions.

We have discovered that damage-associated pro-inflammatory molecules appear in the joint very early in disease, and that people with high levels are more likely to develop RA, to have severe joint damage and to respond poorly to treatment.

Antibodies that recognize modified variants of damage-associated molecules can be detected in around 50% of people with RA. We discovered these antibodies, up to 15-years before any disease symptoms, in 1 in 5 people who developed RA.

The modified damage-associated molecules to which these antibodies bind are much more pro-inflammatory than non-modified molecules.

We found that this is because they are altered in a way that prevents them from turning on an anti-inflammatory pathway that would ordinarily limit their pro-inflammatory action. This modification may therefore explain why this subset of RA patients do not effectively turn off joint inflammation. Finally, we developed a peptide that can turn this anti-inflammatory pathway back on in healthy immune cells.

Here, we will examine whether this peptide turns on anti-inflammatory pathways in immune cells from people with RA, and assess if this peptide can turn off inflammation in more complex animal models of disease.

In parallel, we will investigate the anti-inflammatory pathways used by damage-associated stimuli to turn off inflammation in healthy immune cells, comparing these responses to cells from people with RA.

Reinstating the precise natural immune checkpoints that are lost in people with RA is a novel approach to treatment that may be safer and more effective than current drugs which cause global immune suppression.

This strategy could offer targeted treatment for large numbers of people with RA with severe, hard-to-treat disease, and who are easily identifiable by a simple blood test to measure antibody responses.

It may also provide the possibility of very early intervention in people at risk of developing RA, with a view to disease prevention.