Skin & Joints: Experts Discuss Advances in PsA

SAN DIEGO—The understanding of the microenvironment in which immune cells interact with stromal cells in the synovium of psoriatic arthritis (PsA) and rheumatoid arthritis (RA) is deepening, potentially giving clues for treatments. As this understanding improves, so does the appreciation for its astounding complexity, an expert said here in a session at ACR Convergence, which also included discussions on the microbiome in PsA and a new mouse model for PsA.

Mechanisms 

Ursula Fearon, PhD

Ursula Fearon, PhD, professor of molecular rheumatology at Trinity College Dublin, said that while common mechanisms of disease are at play in both RA and PsA, they differ in many aspects due to the complex microenvironment of the joint, including the presence or absence of autoantibodies, distinct vascular morphology and different cellular infiltrates, such as macrophages, T cells and B cells.

Even she finds the complexity staggering. When her lab did a single-cell analysis on the whole synovium two years ago, the researchers found 33 subclusters of cell types in the RA and PsA joint, and since then that number has increased to about 50.

“I’m just showing you this to [illustrate] how complex the microenvironment of the joint is,” she said. “And I’m amazed sometimes that we even have one therapy that works in any of these diseases.”

In images of healthy joints, RA joints and PsA joints, stark differences can be seen: the translucent synovium of the healthy joint, with just a few blood vessels nourishing it; the increased synovitis in the RA and PsA joint, with distinct vascular morphology demonstrated with straight, regular, branching blood vessel observed in RA in comparison to the dilated, elongated, tortuous blood vessels seen in PsA.

What accounts for these differences?

Through an extensive series of analyses of single cells and flow cytometry, her lab has found distinct differences in the characteristics of fibroblasts in RA joints and PsA joints. The fibroblasts dominant in PsA are associated with invasion and extracellular matrix regulation, while in RA, the dominant fibroblasts are associated with immune-cell regulation and cytoskeletal rearrangement.

When they looked at macrophages in RA and PsA, the researchers didn’t find distinct M1-like macrophages, associated with an inflammatory environment, or M2-like macrophages, associated with an anti-inflammatory environment. Instead, they found that an anti-inflammatory, an M2-like macrophage was dominant, but highly expressed a pro-inflammatory marker, CD40, which was expressed at higher levels in RA than in PsA and minimally expressed in HC, according to Dr. Fearon.¹