Ananta Paine, PhD, on Metabolic Factors Associated with Psoriatic Arthritis

Dr Paine discusses the findings and implications of a study he and colleagues at the University of Rochester conducted into whether certain metabolic factors indicate a patient's risk of progressing from psoriasis to psoriatic arthritis.

Ananta Paine, PhD, was Principal Investigator/Research Assistant Professor in the Department of Medicine the University of Rochester Medical Center at the time of the study. He is now Team Lead/Principal Scientist for ORNA Therapeutics.

TRANSCRIPT:

Hello and welcome to this podcast from the Rheumatology and Arthritis Learning Network. I'm your moderator, Rebecca Mashaw. And I'm very pleased to welcome Dr. ‪Ananta Paine today to discuss research he and colleagues conducted at the University of Rochester in Rochester, New York, to investigate factors that may drive the transition to psoriatic arthritis among patients with psoriasis. Thank you for joining us today, Dr. Paine.

Dr Paine:

Thank you, Rebecca. It's my pleasure.

RALN:

You mentioned in the article published in Arthritis & Rheumatology about this research project that we still don't have a clear understanding of the mechanisms that work in the development of musculoskeletal diseases. This particular study was designed to investigate whether metabolic factors influence the progression from psoriasis to psoriatic arthritis. What led you to focus on the potential involvement of these metabolic factors?

Dr Paine:

Yeah, thank you for that great question. Unlike many other diseases, such as rheumatoid arthritis, where a lot is known, psoriatic arthritis has been less studied. And there is one very interesting fact, actually I even did not know before entering to this field. In psoriasis, not all patients will develop arthritis, but only a fraction of those patients eventually will develop arthritis.

So basically all psoriasis patients will have skin inflammation, not necessarily will have joint inflammation. But a subset among them eventually will progress to psoriatic arthritis. But when patients develop the arthritis in the joint, it results in permanent damage.

The thing is there are treatments for psoriatic arthritis, but if we do not know the patient developed psoriatic arthritis, we cannot treat them. And as a result, many times diagnosis is often delayed, which leads to permanent damage. If you can identify the patients who are at risk of developing psoriatic arthritis, we can either take some preventive measures or at least can treat them before they develop the symptoms of arthritis or clinical symptoms of arthritis.

With that goal we wanted to study a subset of patients. At the University of Rochester, our group has been collecting samples from many psoriasis and psoriatic patients; we have more than 500 patients. There are very few places where these kinds of samples are available with a very well characterized patient cohor. We could only do this study because of this cohort, which our group, and especially that effort, has been led by Dr. Christopher Ritchlin over many years. We analyzed a subset of 71 subjects among this 500 patient or subjects cohort. And among them we have a group of 13 patients who came as psoriasis patients but over the years developed a symptom for psoriatic arthritis.

Again, this is unique. We have collected samples before the onset of arthritis and after the onset of arthritis. Then we also got some patients who came as psoriasis patients and even until the date of study remain psoriasis patients—they did not develop psoriatic arthritis. Now with these samples you can compare and try to understand why certain patients developed psoriatic arthritis where the others did not. We actually did a transcriptomic study which led us to believe there are some underlying metabolic dysfunctions, which is an important contributing factor along with all the genetic contributions and other unknown factors.

Piloted by that observation, we actually thought if we analyze the samples from this different group of patients and compare them with healthy subjects as well as rheumatoid arthritis, we might identify some unique signature with which we can identify which patients are at risk and probably can be even used as biomarker to separate from the rheumatoid arthritis patients. Because it's very difficult to even differentiate between rheumatoid arthritis patients and psoriatic arthritis patients. And to our great surprise we found especially a group of bile acids were decreased among the patients who developed psoriatic arthritis over that time. And this level of this bile acid was lower even before the onset of arthritis. So it suggests this patient who developed psoriatic arthritis actually were probably predisposed, based on their metabolic signature. Again, this is only based on our study. We don't know if the same observation can be made among other patients from a different geographical location with a different genetic background or different food habit.

But what we consistently see among these patients, this bile acid and some of the other metabolites were distinctly lower. Another very interesting factor, which we noted were lower, especially in the patient who developed psoriatic arthritis, were butyric. It's a metabolite which is already known to be very important for gut health. And it's known a lower butyrate or butyric can induce actually tolerogenic effect by affecting certain immune cells such as T-cells.

Now we also contributed some of this observation potentially due to gut microbiome dysfunction. I will just tell you the rationale behind that. We are just hypothesizing. Some of those bile acids were primary bile acid, which is basically synthesized in liver. But there were also multiple secondary bile acids. Only gut microbiome can convert primary bile acid to secondary bile acids. So a decreased level of secondary bile acids also potentially suggests that there are changes in liver dysfunction and second, gut microbiome dysbiosis, or most likely the third scenario, contributed by both the factors.

Liver has a very important metabolic function. It's constantly detoxifying lots of toxic substance. But the bile acid also has a lot of important effect in the gut. Dysbiosis in the gut microbiome or the changes in the bile acid can affect each other. Based on all this observation, there is a good possibility both of these things are correct. One is metabolic dysfunction and the second is gut microbial dysbiosis.

RALN:

You mentioned specifically that decreased bile acid and butyrate levels and elevated guanine levels were found in patients with psoriasis who were at risk for PsA and that these were particularly striking and that that might be a reflection of gut microbiome dysfunction and dysregulation of the hepatic metabolism. So that's what you're talking about here that led you to conclude that this is actually a 2-way path there? That one affects the other in terms of gut and liver dysfunction in these patients?

Dr Paine:

Yeah. And actually with the guanine we have noted a significant difference. While for the bile acid we can make a biological connection, like what might lead to that change, guanine was a strong observation but we still don't know what led to that change and what might be impact of that change in the guanine. But it's a nucleotide. So for that we don't have a clear explanation why this is changed. But we have noted very significant change in the guanine as well.

RALN:

Well, often with research like this you answer some questions but you uncover new questions that need further research to answer. So that was one of my questions for you is, are you planning additional research along these lines to see if you can dig a little deeper and see how these interconnections work?

Dr Paine:

This study actually gave us some answers, but many questions. So definitely our group will be interested to follow up and some studies in Scandinavia are already ongoing like changing the diet, if it is going to have big impact in the onset of the disease or progression of the disease. So those studies, what I have seen so far are already indicating that changing the lifestyle or changing the metabolism by food habit or potentially with microbial changes might lead to alternative treatment

Definitely will be very interesting. So there are multiple avenues and we only reported a part of our observation. There are multiple other things which came across in our study which need further study and will be dependent on the further funding in the area.

RALN:

What do you see in terms of how these findings might apply to the actual care and monitoring of patients with psoriasis?

Dr Paine:

One simple thing will be just to see if patients with psoriatic arthritis have increased liver dysbiosis or liver dysfunction, or any changes in the liver health.

Multiple pharmaceutical companies are already working on certain metabolites which can be used for treating autoimmune disease such as IBD and most likely that kind of drug also will be relevant for psoriatic arthritis because there have been overlaps between IBD symptoms and many of the patients of psoriatic arthritis also suffer from chronic inflammation in the gut. So if we just draw the hypothetical conclusion, definitely those kinds of approach will be much more feasible over time with this kind of research.

But having a hypothesis and resulting or converting to a clinical treatment takes multiple years. One of the biggest challenges in this line of work is, suppose that you are thinking bile acid as a potential treatment or a supplement as a potential treatment, it will require systematic, well-funded study. But the question will be, who will be funding those kinds of research? It has to be coming from government bodies or some academic setup. The hypothetical answer is, it's feasible but the practicality always comes with the funding and the support in this kind of research. Which is not always easy in academic setting.

RALN:

So it's going to be a while before we know if this is directly applicable to the treatment of patients in the clinic—but at least it's an interesting course to follow in terms of doing additional research and seeing what you can find.

Dr Paine:

So I also would like to add one thing. I think the patient community or any organization involved in this kind of effort, they can take initiative of conducting observational studies. At least there will be some trends emerging from those studies which might lead to this kind of solution. Maybe there might be some observational data kind of suggest if we are correct in our hypothesis or maybe we are wrong. So we just cannot advise anybody to take any random step and take something without having the full knowledge, what or how it's potential effect there.

But I personally believe that those kinds of observational studies when combined with systematic scientific study can bring a treatment regimen, which might not be very expensive but rather feasible. But that will also require some effort.

RALN:

Well, this is a very interesting idea and I will look forward to following what happens next and what's discovered in subsequent research. And we thank you very much for taking the time to talk with us today. Thank you.

Dr Paine:

Thank you very much, Rebecca. And I'm glad to discuss about our work. We strongly believe this research will have long-term implications.