Joerg Ermann and Vikas Majithia Discuss the Pathogenesis of axSpA: Part 2

In part 2 of this podcast series, Drs Majithia and Ermann continue their discussion on axial spondyloarthritis with a focus on the pathogenesis of the disease.

Vikas Majithia, MD, is a senior associate consultant and division chair of rheumatology at Mayo Clinic-Florida in Jacksonville. Joerg Ermann, MD, is an assistant professor at Harvard Medical School, a rheumatologist at Brigham and Women's Hospital in Boston, Massachusetts, and the chair of SPARTAN.

TRANSCRIPT:

Dr Majithia: Hi, everyone. Welcome to our podcast series back on axial spondyloarthritis, and this is part two for genetics and pathogenesis. I'm excited to have Dr. Ermann with me today. Dr. Ermann is an assistant professor at Harvard Medical School. He is the current chair of SPARTAN and a rheumatologist at Brigham and Women's Hospital in Boston. Welcome, Dr. Ermann.

Dr. Ermann: Hello.

Dr Majithia: So what are the typical steps in pathogenesis of the disease?

Dr. Ermann: I don't know.

Dr Majithia: That's a great answer. That's a great answer because I think the audience needs to know this is an upcoming and continually evolving field, that we just don't have good answers on some of them.

Dr. Ermann: Yeah. But I have a longer answer. So it starts that we don't really understand what HLA-B27 does, and that's one of the critical aspects here. But there are 2 major hypotheses at this time. The first hypothesis is about mechanical stress. So this is based on the insight or the observation that enthesitis is very common in axial spondyloarthritis and ankylosing spondylitis. As opposed to, for instance, synovitis, that is the basis of inflammation in rheumatoid arthritis.

So it seems that in spondyloarthritis in particular, and axial spondyloarthritis, it is enthesitis. And so the idea here is that mechanical stress at entheses results in acute inflammation and that this is something that's quite normal, but in most individuals this inflammation simply resolves. But in patients with risk factors for excess bone arthritis there is an exaggerated inflammatory response, or a failure to resolve inflammation, so that the inflammation becomes chronic and then ultimately leads to destruction and pathogenic new bone formation.

So the proponents of this concept, for instance, consider the edges of vertebral coronas as entheses. And so syndesmophyte formation here is really the result of initially mechanical stress that then results through this exaggerated response into a new bone formation and syndesmophyte formation. And the second major hypothesis actually starts with the gut. And so this is based on observations that patients with ankylosing spondylitis have dysbiosis, so they have an altered intestinal microbiome. And also that up to two-thirds of patients with ankylosing spondylitis have subclinical inflammation in the intestines. And so the idea here is that in the intestine there is inflammation, which results either into a leaky gut and then the trafficking of bacterial products, or the cellular mediators, through the bloodstream to the spine where they can initiate inflammation.

Or alternatively that inflammatory cells get primed in the intestine, then traffic through the bloodstream to locations in the spine where then these cells that are derived from the intestine become resident and drive inflammation. It's also feasible that a combination of these two, the mechanical stress hypothesis and the GI hypothesis really are involved, but we need to learn more to figure out what is actually true. The biggest problem here might actually be that we have no access to, or it's very difficult to, get inflamed tissue from patients with axial inflammation. And that has been a major problem for progress in this field.

Dr Majithia: Thank you. So what do you think the future holds in store for the science of axial spondyloarthritis?

Dr. Ermann:  Well, ultimately, we want to understand the process which will result in, should result in, more effective therapies and a cure, or possibly also the prevention of the disease in high risk individuals.

There's a couple of things where I see major progress happening right now. One of them is the progress in the analysis of single cells. So there has been a lot of technology developments. So just to name a few techniques, single cell RNA-seq, mass cytometry, or CyTOF, spatial cytometry. So these are all high-dimensional strategies to analyze single cells and understand their phenotype. And this for instance, could result in the identification of small subsets of lymphocytes that are the drivers of the disease process in axial spondyloarthritis and AS. So for instance, it is now possible to sequence the T-cell receptor sequences of individual cells. And this type of study has actually shown that there seems to be an expansion of certain clonotypes of CD8 positive T-cells in patients with ankylosing spondylitis and axial spondyloarthritis.

So this could provide proof for the so-called peptide hypothesis, which is that at the heart of the inflammation is actually a CD8 positive T-cell response against arthritogenic peptides presented by HLA-B27. So the attempt to identify those peptides have been unsuccessful over the last decades, I can say. But it might be possible to actually approach this from the other perspective—to first identify expanded T-cell receptors, expanded T-cells, and then with the help of these T-cell receptors then identify the peptides that they recognize. So that's one of the exciting things I think that is happening right now.

Dr Majithia: Well, that is fabulous. That is kind of mind blowing. Thank you. Are there any parting words? I really, really do appreciate you coming on this podcast today.

Dr. Ermann: I want to mention just a second field that I find very interesting and that's advances, in imaging. Both for diagnostic purposes, but also for understanding pathogenesis. So there are now strategies, for instance, to turn MRI scans into images that look like CT scans. So this is called synthetic CT or bone MRI. And so these images really provide much better information on morphology of SI joints or of the spine. And they're also techniques to do functional imaging—for instance, with PET, with labeled antibodies that allow us to interrogate pathogenesis, without actually sticking a needle into the spine of subjects. And so I hope that these strategies will actually help us to better understand what's happening in the spine even though it's going to continue to be very difficult to get biopsy specimens.

Dr Majithia: Thank you. Again, wonderful.