The RheuMuseum Lecture Series: The Pathogenesis of Psoriatic Arthritis

The RheuMuseum Lecture Series continues with Professor Iain McInnes taking a deeper dive into the pathogenesis of psoriatic arthritis.

Iain McInnes is vice principal and head of the college of medical, veterinary, and life sciences at the University of Glasgow, Scotland.

TRANSCRIPT:

I'd like you to imagine the last psoriatic arthritis patient you saw. They may have had cutaneous psoriasis, entheseal disease, synovial disease. They may have had dactylitis. They may have had nail changes, or they may have had only some of those clinical features.

Now, think back to the last 5 patients you've seen with psoriatic arthritis, and the one thing I'm pretty sure of is that they will all have been phenotypically distinct. The clinical heterogeneity of psoriatic arthritis is part of its clinical conundrum. What we do know now is that the cytokine profile in people with psoriatic arthritis is almost entirely responsible for that clinical heterogeneity. The last decade has seen an explosion of understanding of how the cytokines that are present in the different target lesions are operating, leading to end tissue damage.

Let me start paradoxically in the skin. Here, the IL-23-IL-17A-17F axis is absolutely dominant. [2-9] IL-17 superfamily, remember, is a synergen. It works together with other proinflammatory molecules, for example, TNF. [2-9] And the consequence of that is keratinocyte activation and proliferation, recruitment of leukocytes on an ever-increasing vicious cycle.[2-9] And when it is targeted in the psoriatic plaque particularly, we see profound diminution of cutaneous inflammation. It also, fascinatingly, leads to structural changes in skin, and even though lesions disappear, actually at the molecular level, lesions are not normal, even after effective therapeutics. And in all of this, IL-17A and F are acting as the dominant effector regulators. [2-9]

Now let's move into the musculoskeletal system and think first of all about synovium. Here, the classic lesion, leukocyte infiltration, stromal activation, in this case, fibroblast-like synoviocytes that in turn are activated to release metalloproteinases that will cause cartilage damage. And also other proinflammatory cytokines from the leukocyte infiltrate—particularly macrophages, and possibly also neutrophils and usually indistinct from rheumatoid-releasing TNF, IL-1, and other inflammatory cytokines that activate osteoclasts, leading to bone damage, bone loss.[2-9] And so IL-17, as a superfamily, sits at the center of this vicious cycle of inflammation.[2-9]