Photo Credit: Dr. Microbe
Advances in the immunology and genetics of psoriatic disease have led to the recent therapeutic targets that we are using in clinical practice. Carl Goodyear, PhD, University of Glasgow, Scotland, discussed how immune processes impact disease development and how we can use genetic analyses to predict treatment responses to various therapies.
Autoimmune and inflammatory diseases are characterized by an imbalance between immune activation and control. “Disease, for the most part, is just dysregulated health,” said Prof. Goodyear1. “It’s not that the immune system is doing something that it wasn’t meant to do, it does everything it was programmed to do, just at the wrong time and place, probably with the wrong drivers.” The problem with immunological diseases is that they are chronic and self-perpetuating, even if the original trigger is gone.
Prominent pathogenic mechanisms are present across tissues in psoriatic disease2. “We have the inflamed skin, the synovium, and the enthesial site and you will see very similar cytokines and very similar cells, although there are subtle differences. And it’s those differences we need to understand”1. However, the commonality of pathways leads to common therapeutic options including agents targeting TNF, IL-23/IL-12, IL-17A IL-17A, and PDE4 inhibitors. Yet, it should be noted that therapeutic responses tend to diminish over time, regardless of their target, leading to psoriatic disease being harder to treat with subsequent therapies3.
This poses the question of whether “we actually help the disease evolve when we give people the wrong drugs,” said Prof. Goodyear1. “Drugs are all active and will change the immune system, which will adapt and respond. There are no data to confirm this, but we need to understand what we are doing to people, which is why personalized medicine is important.”
Biomarker signatures have been used to predict methotrexate response in patients with rheumatoid arthritis. Using data from the SERA registry in Scotland, Prof. Goodyear’s group identified a five marker chromosome confirmation signature that can predict early response to methotrexate with a positive predictive value of 89% and a negative predictive value of 87%4. But can this be expanded to psoriatic arthritis? Prof. Goodyear reported unpublished data identifying 30 potential markers for methotrexate response in psoriatic arthritis. However, the model needs refining to an 8–12 model marker and further validation. “Additionally, we are also looking at adalimumab where we’ve gone down to a 12-marker model, where we can classify people who do or do not have a response. Now we need another cohort to do a blinded validation to see if this test can work in the clinic.” Other similar analyses are ongoing for response to tofacitinib and anti-IL-17 medications.
Finally, Prof. Goodyear discussed the possibility of finding new targets through genomic, epigenomic, environmental, microbiome, and tissue function analyses. “We have these responders and non-responders and we have to use this differential to find new mechanistic understanding that could be in circulation or tissue,” said Prof. Goodyear. “There’s lots of hope there and we are moving in the right direction.”
Copyright ©2024 Medicom Medical Publishers
