New Research Identifies Predictive Changes in Joint Microenviroment Prior to RA Onset

Megan Hanlon, PhD

Credit: Research Gate

New research has identified a change in the synovial tissue microenvironment that precedes rheumatoid arthritis (RA) onset that could potentially help inform early diagnosis and intervention for RA.¹

“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,” Ursula Fearon, PhD, Professor of Molecular Rheumatology, School of Medicine, Trinity College Dublin (TCD), said in a statement.²

Lead investigator Megan Hanlon, PhD, and colleagues investigated the myeloid cellular landscape in the synovium of patients with RA, people at risk for RA, and healthy controls. They analyzed the environment with flow cytometric analysis and identified a CD40-expressing CD206+CD163+ macrophage population that dominated the inflamed RA synovium which was associated with disease activity and treatment response.¹ At the time of the study, Hanlon was a post-doctoral fellow in molecular rheumatology at TCD and is now at Harvard University.²

“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,” Hanlon added to the statement.²

The investigators further investigated the macrophage population with in-depth RNA sequencing and metabolic analysis and found that it is transcriptionally distinct with unique inflammatory and tissue-resident gene signatures. It has a stable bioenergetic profile and regulates stromal cell responses. They also identified 9 nine transcriptionally distinct macrophage clusters after single-cell RNA sequencing profiling 67,908 RA and HC synovial tissue cells.¹

They specifically found that IL-1B+CCL20+ and SPP1+MT2A+ were the principal macrophage clusters in the RA synovium. These clusters had heightened CD40 gene expression and were capable of shaping stromal cell responses. The clusters were highly pro-inflammatory and promoted cytokine release and fibroblast activity.

Furthermore, the pro-inflammatory macrophage clusters dominated protective CX3CR1+ barrier macrophages. The findings support CD-40 signaling as a potential target for patients with RA not responding to treatment. Notably, the clusters were enriched prior to disease onset and the frequency of clusters in the joint at baseline predicted patients’ response to treatment and subsequent disease flare.

“In conclusion, we have presented an extensive characterization of the transcriptional and phenotypic landscape of myeloid populations residing in synovial tissue from health to disease. We describe the presence of a CD40-high myeloid signature that becomes activated early in RA disease pathogenesis, before clinical signs and symptoms, and correlates with disease activity and response to treatment,” Hanlon and colleagues wrote.¹

“Uncovering the early molecular patterns and cues that transform this immunoregulatory macrophage population into a dysfunctional inflammatory activation state may provide opportunities to reinstate joint homeostasis in patients with RA,” they concluded.¹

REFERENCES

1. Hanlon MM, Smith CM, Canavan M, et al. Loss of synovial tissue macrophage homeostasis precedes rheumatoid arthritis clinical onset. Sci Adv. 2024:10. doi: 10.1126/sciadv.adj1252

2. Research findings offer a unique opportunity for early diagnosis and therapeutic intervention for rheumatoid arthritis. News release. Trinity College Dublin. September 27, 2024. https://www.eurekalert.org/news-releases/1059591#:~:text=Combined%2C%20these%20findings%20identify%20the,early%20diagnosis%20and%20therapeutic%20intervention.