Study highlights potential for targeting macrophages to improve rheumatoid arthritis outcomes

Trinity College DublinSep 27 2024

Currently there are no cures for rheumatoid arthritis (RA) which affects 40,000 people in Ireland. The disease costs an estimated €20,000 per patient, per year with an overall cost to the health system of ~€544 million. Only 1 in 4 patients achieve remission and a significant proportion of patients have suboptimal responses or no response at all to current available therapies. As it is impossible to predict who will develop severe, erosive disease and who will respond to treatment, a trial-and-error approach prevails leading to potential irreversible joint damage before the patient has received the correct treatment.

Now, a study published this morning [Thursday 26^th September 2024] by researchers in Trinity College Dublin and St Vincent's University Hospital proposes a better understanding of the site of inflammation in RA which will allow for the development of new treatment strategies or predictive biomarkers which could support the potential for a 'personalized medicine' approach. The study is published in the journal Science Advances.

This work was led by Professor Ursula Fearon and Dr Megan Hanlon from the Molecular Rheumatology Group in Trinity, and by Professor Douglas Veale, from St Vincent's University Hospital.

The team performed an in-depth investigation of a specific population of cells: 'the macrophages' that reside in the synovium of RA patients, 'individuals-at-risk' of RA and healthy controls. Researchers demonstrated for the first time, the presence of a dominant macrophage subtype (CD40-expressing CD206+CD163+) in the inflamed RA synovium, which importantly was associated with disease-activity and treatment response. 

The team identified that these cells are resident in the joint which, in health play a protective role, but in disease - for reasons we are unsure of - become pro-inflammatory, and release proteins called cytokines that induce inflammation, and also have the ability to activate the invasive fibroblast cell type which leads to cartilage and bone destruction. 

Researchers identified that the pro-inflammatory status of these macrophages is maintained by specific signaling and metabolic pathways within the joint, the targeting of which may induce resolution of inflammation. Importantly the team identified that these changes in the macrophage status occurred pre-disease onset.

Combined, these findings identify the presence of an early pathogenic macrophage cell/gene signature that shapes the RA joint inflammatory environment and represents a unique opportunity for early diagnosis and therapeutic intervention.

Key findings

Researchers:

• Identified a novel macrophage subtype in the joint and showed that these are the dominant macrophages in patients with active RA.
• Found this macrophage subtype is highly pro-inflammatory and releases proteins called cytokines that cause further inflammation in the joint. 
• Identified that these cells also have the ability to activate other cell types (the fibroblast) in the joint that specifically invade and breakdown adjacent cartilage and bone.
• Identified that the frequency of this cell type in the joint at baseline predicted patients' response to treatment and subsequent disease flare.

 Also:

• In parallel, the protective barrier macrophages (CX3CR1+) were depleted in established RA, showing a switch in the dominance of joint macrophages from protective macrophages to pro-inflammatory macrophages.
• Importantly, the identification of a dominant macrophage subtype (CD40-expressing CD206+CD163+) suggests targeting of CD40 signalling could represent a new strategy for patients who currently don't respond to treatment. 
• Finally, and really importantly the team identified that these cells are present and become activated in individuals at risk of developing RA, thus prior to clinical signs and symptoms. Identification of the early cellular/gene patterns and cues that transform protective macrophage population into a dysfunctional pro-inflammatory macrophage may provide opportunities to target early and reinstate joint homeostasis in RA patients.

Ursula Fearon, Professor of Molecular Rheumatology, School of Medicine, Trinity College Dublin said:

 "This is an important breakthrough in our understanding of what goes wrong at the initial stages of disease in RA, which also has an impact on patient's progression and relapse. We have identified a dominant macrophage subtype/gene signature associated with driving the pro-inflammatory responses early in disease and therefore reprogramming of macrophages towards resolution of inflammation has the potential to be therapeutically targeted."

Dr Megan Hanlon, post-doctoral fellow in Molecular Rheumatology, School of Medicine (at the time of the study, and now based in Harvard University), said:

 "The presence of these macrophages in individuals at risk of developing RA, highlights the possibility of an early cellular biomarker of disease onset, resulting in early treatment intervention."