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Irish RA research could bring major benefits

By Priscilla Lynch - 27th Jan 2025

RA research

New Irish research findings offer a unique opportunity for early diagnosis and therapeutic intervention for rheumatoid arthritis

Rheumatoid arthritis (RA) affects an estimated 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 one-in-four RA patients achieve remission and a significant proportion of patients have suboptimal responses or no response 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. This can lead to potential irreversible joint damage before the patient has received the correct treatment.

 However, a recent study published by researchers in Trinity College Dublin and St Vincent’s University Hospital, Dublin, 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 ‘personalised medicine’ approach.

This work was led by Prof Ursula Fearon and Dr Megan Hanlon from the Molecular Rheumatology Group in Trinity, and by Prof Douglas Veale (RIP) from St Vincent’s University Hospital.

Study details

The team performed an in-depth investigation of 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 unknown reasons – become pro-inflammatory, and release 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 signalling 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

▶ Identification of a novel macrophage subtype in the joint and showed that these are the dominant macrophages in patients with active RA.

▶ This macrophage subtype is highly pro-inflammatory and releases proteins called cytokines that cause further inflammation in the joint.

▶ These cells also have the ability to activate other cell types (fibroblast) in the joint that specifically invade and break down adjacent cartilage and bone.

▶ The frequency of this cell type in the joint at baseline predicted patients’ response to treatment and subsequent disease flare.

▶ 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.

▶ Crucially, 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 do not respond to treatment.

▶ Most 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.


This is an important breakthrough in our understanding of what goes wrong at the initial stagesof disease in RA, which also has an impact on patients’ progression and relapse

Prof 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 patients’ 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 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.”

Source:

Hanlon MM, Smith CM, Canavan M, Neto NGB, Song Q, Lewis MJ, et al. Loss of synovial tissue macrophage homeostasis precedes rheumatoid arthritis clinical onset. Sci Adv. 2024 Sep 27;10(39):eadj1252

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Medical Independent 28th January 2025

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