Researchers probe how lupus develops and persists

[00:00:00] Host Amber Smith: Upstate Medical University in Syracuse, New York invites you to be "The Informed Patient" with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith. Medical scientists don't really understand why the most common and most serious type of lupus develops or persists in people, but they are beginning to learn more through a branch of biology called immuno metabolism. Here to tell about this is Dr. Andras Perl, a distinguished professor of medicine at Upstate, and also the chief of rheumatology, and Dr. Marlene Marte, who's in her second year of fellowship training in rheumatology at Upstate. Welcome to "The Informed Patient," both of you.

[00:00:44] Andras Perl, MD, PhD: Thank you.

[00:00:45] Marlene Marte, MD: Thank you, Amber.

[00:00:47] Host Amber Smith: You both published a paper in the Journal of Clinical Immunology recently that focused on systemic lupus, erythema ptosis, which I may not be saying correctly. Can you explain briefly who's affected by this disease?

[00:01:01] Marlene Marte, MD: Sure. So, lupus is just a type of what we call an autoimmune disease. And this is just what happens, that the immune system, instead of killing only the bad cells, it also starts attacking your own healthy cells. And this is what we call an autoimmune response.

And in lupus it can affect pretty much any organ, causing a wide variety of symptoms. The reported prevalence in the United States is about 20 to 150 cases per hundred thousand people in the US. And it's more seen commonly in women.

[00:01:33] Host Amber Smith: So it is more common in women. What age range do you start seeing this in people?

[00:01:38] Marlene Marte, MD: The median age, depending on the studies, is something around 16 to 55. It's more prevalent in people of Asian, African American, and Hispanics, and again, especially in women.

[00:01:53] Host Amber Smith: So how does this diagnosis impact the lives of people?

[00:01:57] Marlene Marte, MD: Patients with lupus are going to have it for the rest of their lives. And it might be severe, or it might be mild. So depending on the symptoms and how it progresses, every patient is going to have a different prognosis. But in general, we have good management, and hopefully we're able to treat them adequately.

[00:02:15] Host Amber Smith: So we do have treatments that are helpful at this point?

[00:02:20] Marlene Marte, MD: So far, we don't have any cure for lupus. However, we have a wide variety of treatments that can be used to reduce the symptoms, to limit the damage to vital organs and to reduce the risk of recurrence as well.

[00:02:35] Host Amber Smith: What have been the leading theories that researchers have for what causes someone to develop lupus? Because that's still pretty much a mystery, right?

[00:02:45] Marlene Marte, MD: Oh, it is. And that is mostly because lupus is a very heterogeneous disease. That just means that there's a lot of factors going on, so multifactorial. And this also explains why there are so many different presentations of patients. They're going to have different symptoms, manifestations, even the disease course is going to be very different from one patient to the other, and even the treatment response. So not because something didn't work for a patient, it won't work for the other one. And that is because there are lots of genetic, hormonal, and even environmental factors that play a role into the disease pathology, and of course, immune dysfunction as well.

[00:03:25] Host Amber Smith: So when you say genetic, does that mean it runs in families, and if I have a mother or an aunt or a grandmother who had this, that I'm more likely to get it?

[00:03:36] Marlene Marte, MD: Well, yes. Some of the studies that have been done on this area that show that there is an increased risk of lupus in patients that have a family member that was diagnosed with lupus. But majority of cases are sporadic. That means that it happens in patients without any family history of lupus.

[00:03:55] Host Amber Smith: So what genetic factors have been identified? Are there specific genes that a person could be tested to see if they have that would set them up to have lupus?

[00:04:05] Andras Perl, MD, PhD: So let me answer this question. There are approximately 100 genes, the range of a hundred genes that are implicated in causing lupus. The prevalence of lupus is about 25% in identical twins. That gives you an idea that genes contribute about 25% the development of the disease, which leaves a lot to the environment. So there's a 75% discordant rate in identical twins.

The environmental factors that have mainly been implicated over the years are UV light, UV exposure, infections, viral bacterial infections. And now as we realize from this paper, we studied metabolism, and apparently metabolism also has a significant role in triggering disease. So these are the main factors that contribute to development.

In terms of genetics, lupus is about four- to five-fold more common in African Americans than Caucasians, and the disease tends to be more severe. So the genetics, ethnicity and genetics, also has an important role in lupus besides hormonal factors. The prevalence rate is about tenfold greater in females as opposed to males. It's attributed to estrogen to a large degree. Not only estrogen. The X chromosome also plays a role.

[00:05:35] Host Amber Smith: Well, let me ask you real quick before we -- because I know we're going to get into the immuno metabolism more -- but you mentioned the exposure to UV light. That's the light we get from the sun, right? So how would, I mean, everyone's exposed to that.

[00:05:48] Andras Perl, MD, PhD: Everyone is exposed to that. So one of the diagnostic criteria is actually sensitivity to UV light. People who get easy sunburn, that is one factor that contributes, not only to the disease development, but also to our ability to diagnose the disease.

As part of the causation. we remind patients to protect themselves from UV light, either wear UV resistant clothing, or both -- UV resistant clothing as well as sunscreen. Put it on every day, even in the winter.

[00:06:26] Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith. We're getting an update on research into lupus with Upstate rheumatology chief Dr. Andras Perl, and Dr. Marlene Marte who's in her second year of fellowship in rheumatology at Upstate. So Dr. Perl, can you describe the field of immuno metabolism? I think that's a kind of a new word for people.

[00:06:50] Andras Perl, MD, PhD: Yes, the immuno metabolism is actually a new field. We at Upstate actually started to develop this field over 20 years ago. Our laboratory discovered something called mitochondrial dysfunction. Mitochondria are little organelles within the cell that create energy, chemical form of energy, using oxygen and glucose and other metabolites like fat to create ATP, (adenosine triphosphate) which is a chemical fuel that most cells use.

Lupus patients have dysfunctional mitochondria, and they don't produce enough ATP. ATP is like gasoline within the cell. The cells don't make enough ATP. As a result, they are deficient in certain functions that depend on mitochondrial production of ATP. Others have looked at other metabolic pathways over the years. And immuno metabolism actually has become a very hot field, not only in lupus research, but also in cancer research. Our laboratory also conducts some overlapping studies in models of cancer. So metabolism is actually a very important factor in disease development, including lupus and autoimmune diseases. But it's not only confined to this disease. This new discipline called immuno metabolism actually has relevance to many other diseases, including cardiovascular disease and cancer.

[00:08:26] Host Amber Smith: So let me ask you, if a person's immune system was functioning properly, how would it, or how should it react to lupus? Is there something that it should do to prevent lupus from causing any damage?

[00:08:41] Andras Perl, MD, PhD: That's an excellent question. So the immune system has checks and balances. They were not developed rationally, but evolution plays an important role in this. One arm of the immune system is called regulatory cells, regulatory cells within different cellular compartments. The two main players, teams, are the T-cell team and the B-cell team. Most of these types of cells have subsets that downregulate immune responses.

So one of the defects in lupus is known to be a deficiency of regulatory T cells that down regulate immune responses. And these cells are actually highly dependent on mitochondrial metabolism. What I just mentioned, that deficient mitochondrial metabolism is a cause of lupus, but in particular it's a cause of the dysfunction of so-called regulatory T cells that normally downregulated in responses.

As you imagine, you get an infection, your immune system is revved up, makes a lot of antibodies, and cells proliferate in response to an infectious organism. Your lymph nodes swell up. You have fever. The whole inflammatory response team is upregulated. And once the infection is gone, this team has to be downregulated. The lymph nodes are no longer swollen. Something reverses the mechanism. And these are the regulatory T cells. These types of cells are deficient in lupus, and these cells depend on mitochondrial metabolism. That's an important link, between inflammation and metabolism in a particular role in lupus.

I could talk about this being also important in cancer. They are important in cancer. For example, these regulatory cells when they are very, very active in downregulating immune responses, and promote cancer. In fact, there is a new field, called checkpoint inhibitors, that revolutionized the treatment of cancers by blocking these regulatory T cells and unleashing effector T cells. In fact, these treatments trigger autoimmune diseases in the setting of cancer treatment. So these autoimmune diseases, in fact, can include lupus.

So immuno metabolism is very important, not only for autoimmune disease and lupus, but also for cancer and cardiovascular diseases, which is not the topic of discussion today. But one needs to realize that this is a really important new field, which covers not only auto immunity, but other important diseases.

[00:11:23] Host Amber Smith: Now you use the term downregulating. What does that mean?

[00:11:28] Andras Perl, MD, PhD: Downregulating means inhibiting, reversing the process, blocking inflammation, regulating in the negative direction, inhibiting.

[00:11:38] Host Amber Smith: So if the immune system is malfunctioning or deficient in lupus, and the metabolism isn't working in lupus, is the immune system and the metabolism, are they working together? Are they opposing each other? Are they against each other?

[00:11:57] Andras Perl, MD, PhD: So metabolism is supporting the immune system and certain types of cells develop. Some of them, like regulatory T-cells, depend on mitochondrial metabolism. So when mitochondrial metabolism is inhibited due to genetic factors or environmental factors, these cells do not develop. That disposes to inflammation.

On the other hand, the inflammatory cells, particularly CD4 T cells -- this is a type of cell that orchestrates the inflammatory process involving other types of cells such as so-called B cells that make antibodies and the innate immune system that produces inflammatory proteins. So these CD4 T cells depend on glucose, for example, and glycolysis, sugar. So sugar, especially processed sugar, is highly inflammatory, in many ways. But one mechanism involves the expansion of these effector inflammatory T cells, which are highly dependent on sugar.

[00:13:04] Host Amber Smith: So it sounds like this immuno metabolism, the work that you're doing, you are learning a lot more about lupus this way?

[00:13:13] Andras Perl, MD, PhD: Yes. We are learning a lot more about biology, as well as lupus. And these metabolic pathways are also very important in trying to control the disease, so we are finding ways of controlling inflammation through metabolism. What we put in our body is actually quite relevant on the functioning of the immune system and potentially treating or preventing inflammatory diseases.

[00:13:39] Host Amber Smith: Let me ask Dr. Marte,can you give me a rundown of some of the studies that are underway, that are showing the most promise?

[00:13:48] Marlene Marte, MD: Absolutely. Currently there is one that is actually very promising. They're studying a medication called deucravacitinib. It's basically a TYK2 (selective tyrosine kinase) inhibitor, which is one of the pathways that has been implicated in lupus. And again, this medication that has been shown to be effective in psoriasis, for example, has been showing very good promise in lupus patients, as well, in the clinical trial.

And more of the future, I think it is very promising. I think that now that we understand a little bit better the pathophysiology of lupus, we have been able to do a more targeted approach in terms of treating. So for example, now, we're getting more genetic testing, at least in Upstate, for our patients to understand a little bit better their patient profile, which is completely personalized. And then we also obtain, usually, a cytokine panel, which helps to understand which cytokines, which is just basically the markers of inflammation of each of the pathways involved in the pathophysiology of lupus are either increased or decreased in these patients.

So again, we're trying to get a more personalized approach to each of these patients because as we mentioned before, lupus is not just one gene that is mutated and then you get the disease. There's a lot of things that go into play when developing the disease. So we're trying to approach it in a more targeted way. And there's even this new -- that Dr. Perl made comment on as well -- this new effort that we're trying to put together, in getting Car T-cell therapy, which is one of the latest advances that we have in rheumatology. In fact, I think the whole field is very enthusiastic about this treatment, where basically patients give their own cells, and they're pretty much engineered, I would say, in a lab. They get engineered in the lab, they get back in the patient bloodstream. And then the idea is that it kind of cures the autoimmune disease by decreasing the autoantibodies that are produced and potentially improving and even getting off medications, the lupus patients.

It's used in (the) oncology field right now. But this procedure of Car T-cells, it comes with risks. So, for example, these patients have to be monitored close in the ICU because they might complicate with something that is called cytokine release syndrome, where basically there's a lot of inflammation at once happening, and they require medications like tocilizumab to decrease the symptomatology of this complication. The thing is that it's a treatment that has been very promising. Again, the patients that have been on CAR T-Cells have been able to decrease their auto immunity. So basically autoantibodies have been decreased, and disease activity is close to zero. So it's very promising.

[00:16:35] Host Amber Smith: Well, you being new in the field of lupus research, I wonder what your outlook is and whether you think science is getting close to having an understanding of the cause or what makes lupus last?

[00:16:48] Marlene Marte, MD: Definitely, I do think so. I still have some of my attendings telling me that rheumatology, back in the days, used to be just gold injections and methotrexate, very, what we call conventional synthetic DMARDs, (disease-modifying anti-rheumatic drugs.) But now we have all these biologics that again, are trying to have a more targeted approach into treatments.

And now looking in the future, I think that, again, when we talk about lupus and autoimmune disease, we're talking about diseases that are not curable, but with this CAR T-cell, it's very new to the field, but this promise that it could potentially lead to complete remission, it's very, very, I would say, impressive. So yes, I am excited.

[00:17:29] Host Amber Smith: Well, Dr. Perl, do you think we're close to having some new treatment options to give patients hope?

[00:17:35] Andras Perl, MD, PhD: Yes. Going back to immuno metabolism, and going back to the mitochondria which are dysfunctional in lupus. So these mitochondria create, actually, oxidative stress in the cell. That's one of the reasons why they cause inflammation. Rather than making ATP providing energy, the oxygen is used to make reactive oxygen, which is very destructive.

This particularly happens in T cells. These are the memory cells within the immune system, and these maintain the longevity of the disease. That's why the disease is chronic, because these memory cells are dysfunctional and maintain the memory of disease. To counter that, we started a clinical trial at Upstate, which is organized from this institution, where we treat patients with an antioxidant amino acid called acetylcysteine, which is a derivative of a natural amino acid called cysteine.

It is actually deficient in lupus, so we are replacing this amino acid now in patients. This trial is now ongoing. We previously showed that this treatment is effective, which has been reproduced by other centers across the world. We are trying to determine whether this treatment has a durable effect on lupus and how long it lasts. Previously, we found it to be effective over three months. And this trial is a 12-month intervention, which is important, considering the chronicity of the disease. And Dr. Marte's involved in this study in evaluating patients. We will all learn how this medication works. This is a very unique study that's ongoing at Upstate.

[00:19:25] Host Amber Smith: Well, that's very good to know. I want to thank both of you for making time to tell us about your work.

[00:19:32] Andras Perl, MD, PhD: Thank you so much for having us, both of us. It's been a pleasure.

[00:19:35] Marlene Marte, MD: Thank you very much for having us. I appreciate the opportunity.

[00:19:40] Host Amber Smith: My guests have been Dr. Andras Perl, a distinguished professor of medicine at Upstate and division chief of rheumatology, along with Dr. Marlene Marte, a second year rheumatology fellow at Upstate. "The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York and produced by Jim Howe. Find our archive of previous episodes at upstate.edu/informed. If you enjoyed this episode, please tell a friend to listen too. And you can rate and review "The Informed Patient" podcast on Spotify, Apple Podcasts, YouTube, or wherever you tune in. This is your host, Amber Smith, thanking you for listening.