In recent years huge strides have been taken in understanding the pathogenesis of psoriatic arthritis. One of the key discoveries has been a link between enthesitis –  inflammation of the entheses, the sites where tendons or ligaments insert into the bone – and the production of key pro-inflammatory cytokines such as interleukin-23 (IL-23).

We caught up with Professor Dennis McGonagle of the Leeds Institute of Rheumatic and Musculoskeletal Medicine, UK, after his talk at ARA 18 to learn more about how the enthesis is not just an attachment structure but an organ involved in immune activation of the key interleukins responsible for psoriatic arthritis and spondyloarthrosis.

The limbic: What have been the factors driving the new understanding of the pathogenesis of psoriatic arthritis?

Prof McGonagle: The understanding of the pathogenesis has been driven by a number of things. One is the better understanding of the tissue basis for disease localisation in rheumatoid and psoriatic arthritis. Secondly, the genetics of rheumatoid and psoriatic arthritis are different. There’s lots of genetics around IL-23 and IL-17 and psoriatic but not rheumatoid arthritis. Thirdly, the animal models link two of those together showing that in mice disease psoriatic-like problems start at the mouse enthesis – that’s where the ligaments and tendons are anchored to bone.

The way therapies are working in psoriatic arthritis, but not rheumatoid arthritis in humans, is also what we term reverse translation – it’s allowing us to describe the human immune system based on the fact the IL-23 and IL-17 pathways work in psoriatic but not at all or minimally in rheumatoid arthritis.

So, it’s all coming together from a synthesis of a better understanding of tissue microanatomy, human genetics and support from animal experimental models. And then finally the impact of different therapies and their different outcomes in rheumatoid and psoriatic arthritis.

The limbic: At the conference you described the enthesis as an organ that points the way to a unified anatomical explanation for spondyloarthrosis – can you elaborate on that?

Prof McGonagle: The enthesis is an anchorage point of the muscles to the bone. And the place where they are anchored is a spot of high physical stress. There are many of these around the body. The ones most people will be familiar with are the Achilles tendon or patellar tendon and tennis elbow, golfer’s elbow, these are all types of enthesitis.

With inflammation at attachment sites, the two biggest causes are mechanical injury and degeneration or it may be due to inappropriate immune activation. In animals and humans we think the inflammation spreads from the attachment site into the bone and into the joint cavity and hence it may look like rheumatoid even though it is fundamentally different.

The limbic: How did the focus come to be on tissue studies of enthesis?

Prof McGonagle: The timeline for progress was basically MRI and ultrasound studies in humans, which are superior to x-ray studies in that they can see abnormalities at the early stages of disease or even before clinical disease. Those studies have been going on for two decades and the evidence is building all the time on the imaging side. The tissue studies of the human enthesis have only appeared in the literature in 2017.

The limbic: Why has it taken so long to look at enthesis?

Prof McGonagle: These anchorage points of tendons and ligaments to the bone are very inaccessible and people tend to stay away from them. So it’s technically very difficult to get at it and very little is known about the immune system at this structure. The biggest challenge to our research is the procurement of samples. Our samples are collected by our orthopaedic collaborators at the time of spinal surgery, including disc surgery and correction of spinal deformities / kyphoscoliosis

The limbic: What does the enthesis have to do with the immune system?

Prof McGonagle: What we’re doing is explaining why drugs work in psoriatic arthritis and not in rheumatoid arthritis on the basis of the indwelling immune system that the normal enthesis have. The enthesis is a relatively avascular structure and it is completely shielded from the external environment unlike the skin and gut. There’s no reason why you need a fully armed aggressive immune system at your enthesis attachment sites. We suspect the discovery of this immune system in human enthesis is related to the fact that the immune system is probably involved in tissue repair where there is injury at these sites of high physical stress.

The limbic: And what is its part in disease?

Prof McGonagle: We think because of the genetic dysregulation in disease, the immune system [in enthesis] is overactivated so what should be a normal immune repair response is then converted into a hyperactive state of innate immune inflammation. And when the innate immune system is activated that primes the adaptive immune system – CD8 and CD4 – cells. So you have a scenario where the local abnormal reaction to the microdamage at these attachment sites triggers local immunity, which then triggers systemic immunity, then the T cells carry the disease far and wide around the body. So there is an over-exuberant repair response and as a result you may get excessive new bone formation. That would manifest as joints knitting together, which is different to rheumatoid arthritis, where it is destruction.

The limbic: How long have we known about the involvement of the enthesis in IL-23 pathways and arthritis?

Prof McGonagle: I’ve been making the argument from two decades of research that the enthesis is the primary target of disease in man just like it is in mice, and recognising the genetics around IL-23. With animal models showing IL-23 receptor cells at the mouse enthesis, we then went after the human enthesis – not in disease but in health. And we pulled out two different populations of IL-23 receptor positive cells. When we stimulate these human cells in vitro: we take them out, digest the enthesis, sort the viable cells, put them in culture, stimulate them with IL-23; it signals with its receptor, then the readout from that is IL-17. And both of these cytokines are targeted by modern therapies.

The limbic: What’s the current state of understanding on IL-23 and arthritic inflammation?

Prof McGonagle: IL-23 is a cardinal cytokine linked to inflammation across spondyloarthropathy diseases including skin psoriasis, IBD and psoriatic arthritis. The role of IL-23 in cutaneous disease is possibly one of the most compelling arguments from human immunology. There are already IL-23 blockers licensed for the skin and they give spectacular skin improvements. The role of this pathway in the skin is unquestionably one of the strongest of any immune pathway in the whole of human immunology.

So the IL-23 pathway is pivotal. It drives the IL-17 cytokines and also IL-22. Both are vital cytokines for barrier function and they affect stem cells in the gut and in the skin. IL-22 also effects stem cells in the bone marrow – mesenchymal stem cells. So the IL-23 pathway is not just for immunity it is also pivotal to tissue homeostasis and repair. And because these cytokines can modulate the gut barrier and immune system one of the areas of interest going forward will be how blocking this pathway might impact on the risk of intestinal tumorigenesis

The limbic: Where to from here?

Prof McGonagle: The Holy Grail down the track is we want to have a very deep immunological understanding of the human enthesis so that when people present with new enthesitis our knowledge base will be so great that we will be able to pick it up immediately and effectively suppress inflammation. And ultimately aiming towards cures. The existing treatments are very good but they don’t work in everyone and we need to understand why. The study of these cells that we are taking out – that might inform therapeutic choices and also end up re-purposing existing drugs to treat entheseal biology.

The limbic: Is there a take home message about your research?

Prof McGonagle: Dysregulation of pivotal pro-inflammatory cytokines including TNF, IL17 and IL-23 pathways at the enthesis is the key to understanding the pathogenesis of psoriasis and psoriatic arthritis, IBD and AS.

This article was sponsored by Janssen-Cilag Pty Ltd. The content is developed independently and is based on published studies and experts’ opinions. The views expressed are not necessarily those of Janssen.