Joerg Ermann and Vikas Majithia Discuss Genetics of axSpA: Part 1

Drs Majithia and Ermann begin this podcast series to discuss genetics and pathogenesis of axial spondyloarthritis.

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. Vikas Majithia: Hi everyone. Welcome to our podcast series on axial spondyloarthritis. 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 for Spartan, and a rheumatologist at Brigham and Women's Hospital in Boston. Welcome, Dr. Ermann. I really appreciate you doing this part podcast on genetics and pathogenesis. You obviously have worked in this area for a long time. And I'm going to start by asking you specifically about genetics. So as we know that genetics plays a big role in pathogenesis of axial SpA, could you just summarize for the audience how.

Dr. Joerg Ermann: Axial spondyloarthritis, like other diseases, occurs as the result of the interplay of genetic risk factors and environmental risk factors. But we know that the genetic component in Axial spondyloarthritis is really quite high. So most of these studies have been done in ankylosing spondylitis, which is the older disease and very well defined disease. And we know from studies in ankylosing spondylitis that for instance, the concordance rate in monozygotic twins is higher than 60%, which is a lot higher than for instance in rheumatoid arthritis. So there's a very strong genetic component.

We also know that HLA-B27 is the biggest genetic risk factors. The vast majority of patients with ankylosing spondylitis are HLA-B27 positive. But we also have learned from genome-wide association studies that a lot of other genes contribute to the development of the disease. As of now, we know that more than a hundred risk loci contribute to the disease. Most of them have only a very small contribution to the overall risk. And despite of these efforts, we still don't understand all of the genetic risk factors for the disease. So there's been estimated that, all in all, only about 30% of the genetic risk in ankylosing spondylitis is explained at this point.

Dr. Vikas Majithia: I'm glad that you mentioned HLA-B27. Actually, B27 continues to be one of the most intriguing and important genetic test in axial spondyloarthritis. So what is your opinion on its contribution to development of the disease, and then overall diagnostic utility?

Dr. Joerg Ermann: So I already mentioned that there's this strong association between HLA-B27 and ankylosing spondylitis. And also between HLA-B27, axial spondyloarthritis... more broadly, and the other types of spondyloarthritis. The association with ankylosing spondylitis was described in 1973, so almost 50 years ago. And initially it was not clear whether HLA-B27 itself, is actually the risk factor or whether HLA-B27 might only be a marker for a risk gene that is in close vicinity of the B27 gene. Now, there is no question really anymore that it is B27 itself that is associated with the disease. Because we have the genome sequence, and the data from the genome-wide association studies have mapped susceptibility to... actually, amino acid polymorphisms within the gene itself... within the coding region of the gene. So there's no question that it is B27 itself that plays a role. And that makes it also a major factor in driving the disease pathogenesis.

What we don't know, 50 years after the discovery of the association, is what explains this association mechanistically. And so, there is a number of theories and of hypotheses that have been put forward, but which one of these is correct, we don't understand at this point. I can go into more detail if you want me to. There are also some data to suggest that HLA-B27 may actually have an impact not just on the development of the disease, but that it may also have an impact on the disease phenotype. So there are studies that have shown that, for instance, bone formation in osteoblast like cells, is more prominent in HLA-B27 positive individuals compared to the controls. So there's still a lot that we need to learn about what B27 does even 50 years after that initial discovery.

Dr. Vikas Majithia: What about its diagnostic utility?

Dr. Joerg Ermann: So I think it's an important marker to check. There is this strong association. The initial studies in AS, showed that more than 90% of AS patients were HLA-B27 positive. I think, in more recently clinical trials is often more 80% to 85%. The association is less stringent with other types of spondyloarthritis, more around 50%. And is also not as high for patients with non-radiographic axial spondyloarthritis. Nevertheless, it's important factor to check. But one needs to keep in mind that HLA-B27 is a variant that is prevalent in the general population.

So a study about 10 years ago showed that 6.1% of the US population is HLA-B27 positive. That number is a little higher in whites and a little lower in other ethnic groups. So checking HLA-B27 is very different when you use it as a diagnostic test, than for instance, checking an anti-nuclear antibody or an anti-CCP antibody. Because both the sensitivity and specificity are limited. But in a patient, it can be both a factor that contributes to making a diagnosis, or if negative it can also be a factor that argues against the diagnosis. So it helps us in the diagnostic process. But it is only one of multiple factors that need to be considered.

Dr. Vikas Majithia: Thank you. Wonderfully said. What additional genes may be playing a role? Any particular recent advances about them? Anything which is at the forefront of discovery?

Dr. Joerg Ermann: Yeah. The answer here is actually, no. There haven't been any recent advances. Well, depends a little bit on what you consider as the timescale. There was a decade of genome-wide association studies, from around 2007 when the first GWAS Study was published in ankylosing spondylitis until 2016. And so, there were multiple studies and they discovered more than a hundred risk loci for ankylosing spondylitis. And so, since then we haven't had any new data. We are in anticipation of a new analysis of a much larger data set, but that is not going to be published until next year at some point.

So what have we learned from those studies? So the biggest risk factor that came out of the genome-wide association study, was of course, also HLA-B27. But the other loci fall into a number of categories that play important roles in immune processes. And so from that perspective, these studies were quite insightful into disease pathogenesis. So several polymorphisms are in genes related to MHC class one androgen processing. So they are related to the pathway where HLA-B27 and MHC class one complexes act. Then several transcription factors were identified that play a role in both the generation and differentiation of lymphocytes. And then many genes involved in cytokine signaling were identified... or polymorphisms in these genes were identified to be associated with ankylosing spondylitis.

Be sure to join us for the continuation of this discussion between Drs. Vikas Majithia and Joerg Ermann, on the genetics and pathogenesis of axial spondyloarthritis.