A snapshot of ongoing psoriatic arthritis research

| Steve Bieler
As our research portfolio, with your help, continues to grow, it’s a good idea to stop and take a snapshot of a few of our ongoing projects. Who are these NPF-funded researchers, and what do they hope to accomplish? In this story we present a trio of currently-funded researchers and a look at their work.
 
Jose U. Scher, M.D., is an associate professor and director of NYU Langone’s Psoriatic Arthritis Center and the Microbiome Center for Rheumatology and Autoimmunity. He was the recipient of a 2019 Psoriatic Arthritis Diagnostic Test Grant. 
 
In the grant’s layman’s statement, Scher wrote:
Genetic susceptibility partially accounts for disease development and progression. Genes are known to play a significant role in psoriatic disease susceptibility. In fact, individuals with psoriasis who have first-degree relatives with PsA have 40 times the risk of progressing to PsA compared to the general population. Research on twins demonstrated that genetic contribution is insufficient for predicting disease, particularly in regard to the transition to PsA.
Scher is known in our field for his work with the microbiome, but, as he explains, working with genetics and the population of twins is building on his past work, not a different approach.
 
“We’re really trying to understand what are the downstream inflammatory responses that occur before and after psoriatic arthritis develops. Essentially, we’re using a new methodology that can pinpoint specific cell phenotypes or molecular features of a particular immune cell population, how they circulate from the skin, through the blood, and get attracted to the joint space,” he says. 
 
“The question is, Why is it that twins are discordant for psoriatic arthritis? One aspect is the microbiome, which is a potential triggering factor. But another related aspect is what happens to the host immune system once the insult [the trigger] has occurred.”
 
If one twin has psoriasis and PsA, is his or her identical sibling more likely to have PsA?
 
“No,” Scher says. “If you ask the question about psoriasis: How many monozygotic [identical] twins of those with PsA also have psoriasis? The answer is about 55 to 60 percent. So the concordance for skin inflammation is significant. But if you ask the same question about arthritis, only one in 10 monozygotic twins are concordant for PsA. No one knows why. It’s fascinating.”
 
Scher laughs at the suggestion that he study triplets as well. “There are not that many triplets out there,” he says. “It would be hard to ascertain. But the other way to ask that question is with siblings of the pair. We don’t know the answer to that, either.”
 
Sara Rahmati, Ph.D., is a postdoctoral fellow at University Health Network, Toronto, Canada. Her 2019 Early Career Research Grant is called “A multi-omics approach to characterize heritable and de novo genomic dispositions and pathways involved in severe psoriatic arthritis.” 
 
This is an excerpt from her layman’s statement:
We aim to characterize novel and heritable genetic markers predictive of developing severe PsA. We will use DNA sequences of patients with severe PsA and their parents to identify genetic variations in patients. Since genes work cooperatively to accomplish cellular tasks, we will use a bioinformatics pipeline to discover the circuits among these variants and other biomolecules in severe PsA. 
 
… [We] will determine pathways predictive of patients at high risk of developing severe PsA. Thus, clinicians may be able to recommend an appropriate course of action based on genetic composition of patients to stop disease progression.
If we can identify the specific genetic pathways or circuits that lead to severe PsA, then someday will we be able to use gene-testing to predict the vulnerability of a psoriasis patient?
 
“Correct,” Rahmati says. “To be more precise, it is known that genetic factors significantly contribute to PsA and its progression. We believe that different combinations of genetic variations may help us subdivide patients with psoriasis/PsA into groups with similar characteristics (for example, similar severity of joint damage). Given these similarities, we believe that pathways and functions affected by the varied sets of genetic variations might partly overlap.”
 
Rahmati believes that finding these overlaps might benefit us in at least two ways:
  1. It will help us estimate the likelihood that an individual patient with psoriasis/PsA will develop severe PsA early in the disease.
  2. It might shed light on a larger group of what Rahmati calls “role-player” genes in PsA. This, in turn, could help us find novel treatments.
Rahmati makes an interesting point about our current state of knowledge about PsA and these “novel treatments.” 
 
“It’s quite possible that we have effective drugs in the market, but they are not available to PsA patients, due to our lack of knowledge about their potential effectiveness on PsA-relevant pathways,” she says. “By understanding genetic variations and their disrupted pathways and functions in PsA patients, we may be able to repurpose drugs indicated for other diseases for PsA.”
 
We hear a lot about omics today. When asked about omics and her own experience with these tools, Rahmati divided omics users into two (potentially overlapping) groups:
  1. Laboratory scientists who have expertise in advanced technologies to collect omics data. 
  2. Computational scientists (biostatisticians, computer scientists, data analysists, for example) who are experts in processing and analyzing large volumes of omics data. 
“I belong to the second group,” she says. “My expertise is in developing methods for analysis and interpretation of different omics data. I consider myself to be a scientist who can contribute to designing experiments and developing omics (analysis) tools.” 
 
Iannis Adamopoulos, D.Phil, is an associate professor of rheumatology at the University of California-Davis. His 2019 Bridge Grant is for his project already in progress, 
“The IL-23/IL-17 Axis in Inflammatory Arthritis.” 
 
Here is an excerpt from his layman’s statement:
Activation of our immune system cells regulate the development as well as the resolution of inflammation and hence can evoke and/or subside the pathological features that are observed in PsA patients. For more than 10 years we have developed multiple animal models that resemble the pathological features observed in human PsA that we interrogate with traditional genetic and biochemical techniques to reveal the pathogenic mechanisms of PsA. 
 
In this study we plan to translate our murine findings back to the human disease to determine which identified cellular and molecular mechanisms are applicable to PsA patients.….Our study will determine the pathogenic mechanisms relevant to human PsA and open new avenues of treatment for PsA patients.
“This is what people call molecular medicine,” Adamopoulos says. “What we are really trying to do is to define cellular and molecular pathways that govern disease pathogenesis and development. We use an interdisciplinary approach involving a plethora of techniques ranging from bone biology, immunology, genetics, structural biology, bioinformatics and beyond to identify cells, molecules and pathways that can be exploited for molecular therapeutic intervention. We are focused on the IL-23/IL-17 pathway as it is extremely promising therapeutically.”
 
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Driving discovery, creating community

For more than 50 years, we’ve been driving efforts to cure psoriatic disease and improve the lives of those affected. But there’s still plenty to do! Learn how you can help our advocacy team shape the laws and policies that affect people with psoriasis and psoriatic arthritis – in your state and across the country. Help us raise funds to support research by joining Team NPF, where you can walk, run, cycle, play bingo or create your own fundraising event. If you or someone you love needs free, personalized support for living a healthier life with psoriatic disease, contact our Patient Navigation Center. And keep the National Psoriasis Foundation going strong by making a donation today. Together, we will find a cure.

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Three NPF-funded researchers talk about their work.