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Today on The Fundamentals, our guest is Dr. Michelle Kahlenberg, an Associate Professor of Internal Medicine and Dermatology, the Giles Bole and Dorothy Mulkey Research Professor of Rheumatology and the Vice Chair for Basic and Translational Research in Internal Medicine.

Her clinical work is centered on the care of patients with lupus, including those with refractory skin disease. In addition to running her lab, she's an active member of the Immunology Training Program and has received national recognition for her research.

Learn more about Dr. Kahlenberg, and you can follow the Kahlenberg Lab @Kahlenberglab and the department of internal medicine @UMIntMed on X.

Resources

• Find out more about the research stories mentioned at the top of the show at the links below:
  • Obesity leads to a complex inflammatory response inside fat tissue
    New single-cell study uncovers diverse immune cells in obese mice
  • Could ginger help treat autoimmune disease symptoms?
    After ginger root was proven to halt autoimmune disease progression in mice, researchers are now trialing the same concept in humans
• You can learn more about The Fundamentals on our website.
• Learn more about other exciting research happening at the University of Michigan, by checking out Health Lab, Michigan Medicine's daily online publication featuring news and stories about the future of healthcare.

Transcript

Kelly Malcom:

Welcome to the Fundamentals, a podcast focused on the incredible research at Michigan Medicine. I'm your host, Kelly Malcom.

Jordan Goebig:

And I'm Jordan Goebig.

And in this week's episode, we'll be talking about lupus and other research related to inflammation at U of M. But before we meet our guest, I just wanted to highlight research that fits within the theme of this episode. An extra bonus, it's summarized in an article written by the one and only Kelly Malcom. The story shares how University of Michigan researchers are attempting to uncover the basics of how fat tissue is structured, and specifically the changes in the inflammatory response inside fat tissue associated with obesity, in the hopes of unlocking the connection between the accumulation of fat and poor health outcomes.

Kelly Malcom:

And this next very spicy study is about one of my favorite foods, ginger. It found that ginger supplements can modulate the activity of white blood cells, called neutrophils, and prevent them from releasing inflammatory products called neutrophil extracellular traps, or NETs. Blocking net release may help control inflammation and disease in patients with autoimmune diseases such as lupus and antiphospholipid syndrome.

Jordan Goebig:

We'll provide links to the full articles and info about our featured guests in the show notes.

Now let's get on to our guest.

Kelly Malcom:

Today's guest is Dr. Michelle Kahlenberg, an Associate Professor of Internal Medicine and Dermatology, the Giles Bole and Dorothy Mulkey Research Professor of Rheumatology and the Vice Chair for Basic and Translational Research in Internal Medicine.

Her clinical work is centered on the care of patients with lupus, including those with refractory skin disease. In addition to running her lab, she's an active member of the Immunology Training Program and has received national recognition for her research. Welcome.

Michelle Kahlenberg:

Thank you so much.

Jordan Goebig:

Okay, so I want to start things off by just asking you: why lupus? In the decade of running your Michigan medicine research lab, has there been anything you've uncovered about autoimmune diseases, like lupus, that surprised you?

Michelle Kahlenberg:

Thank you. That's a great question. So, why lupus?

I think my passion for lupus is driven from the patients. When I met my first lupus patient, I was a resident in Cleveland, and she was twenty-something and was on dialysis from her disease, and it was very motivating to see somebody that we didn't have a lot of treatment options to help. I wanted to do something about that. And so my time as a rheumatologist, I've learned that there is so much we don't understand about lupus. And also, just as in practice, that not every patient has the same resources and opportunities afforded to them to help take care of their lupus. And that things like systemic racism and health disparities have a huge impact on patient's ability to manage their disease. And so all of these things really made me very passionate about wanting to do better for patients. And I'm trained as a molecular biologist, and so research is my tool that I have to try to make that happen. So that's why I chose to work on lupus.

And in terms of what has surprised me, I think there's so much that you learn, not just from the research, but also from the patients, in terms of surprises. I think one of the things that our work has uncovered is that even when patients look fine, like nothing's going on, we have found that there's abnormalities that are lying under the surface that are priming the pump for things to go wrong. And so thinking about preventive strategies and how we keep patients from getting sick has become a really important mission of our work, because, especially in the skin, and we're focused mostly on skin disease in our lab, even when it looks normal, it's actually not normal. So that's been I think an eye-opening aspect of what we've found with our work so far.

Jordan Goebig:

That actually transitions really well into my next question, which is what happens biologically when a disease like lupus is triggered, and how is your research addressing this?

Michelle Kahlenberg:

So, it's a little bit of a complicated question to answer because so many different things can happen in lupus. I will say that in a fifty-thousand-foot view, what happens is that patients have some sort of predisposing factors. Sometimes it's genetic, so it runs in people's family, sometimes it's patients have been exposed to various chemicals and other things that can prime the pump for lupus, and then there's a trigger, usually. One of the most common triggers in lupus is sunlight, and that's one of the things that we're really focused on trying to figure out why. Other things that can trigger lupus, very stressful life events, exposures like smoking, viral infections, actually, probably are an important trigger, but something happens to sort of flip the immune system into overdrive. And that increased activation of the immune system activates what we call the adaptive part of the immune system, which is our T and B cells, that make more specific responses.

And in lupus what happens is they start to make responses that recognize self. So you start to get antibodies against self proteins, you get T cells that recognize proteins that are part of our own body, and so the immune system starts to attack its own organs instead of viruses and bacteria like it's supposed to. Then, from a treatment standpoint, most of our therapies come in and smack the immune system down, and that comes with its own set of complicating side effects. And that's been the status quo for up until the last five years or so, we started to get some more targeted therapies for lupus.

Kelly Malcom:

When I was researching a little bit about you before this interview, I noticed that the notion of precision medicine came up time and time again, and I was curious as to why that's so important in the context of lupus.

It sounds like it can manifest in a lot of different ways depending on the person, so can you talk a little bit more about why precision medicine is important?

Michelle Kahlenberg:

Absolutely. It's a great question.

Lupus, especially, is what we call a "heterogeneous disease," meaning that it has many different ways it can show itself. Patients can have skin disease, they can have kidney disease, they can have inflammation in their lungs, they can have inflammation in their brain and patients, patients can have a mix and match of all of those things. Sometimes patients have all of it. Sometimes patients have one or two aspects of it.

So, first of all, understanding how to treat each manifestation of lupus, we still don't understand what is the best drug for arthritis in lupus versus the best drug for skin. And so part of precision medicine is trying to understand what therapies we should be using for what manifestations.

The other part of personalized medicine is that each patient gets lupus with a different combination of risk factors, and sometimes those risk factors change how patients respond to therapy. And so, one patient with skin disease might respond to therapy X, but another patient with skin disease won't, and we don't have good predictors for who is going to respond to what. And so what ends up happening in the treatment is that we say, "Well, let's try this and see if it works." And we give it three months to six months. It takes a long time for some of these drugs to work. And some do fine and some patients don't. And the patients that don't end back up on steroids, because they're flaring again, and then we try a different drug, and then we wait and see another three to six months.

So it becomes a very frustrating process for both the patient and the physician, because we keep having to try new things to try to get things as good as we can get them. And so what precision medicine hopes to do is to be able to find predictors ahead of time so that when a patient comes in with X and we can profile their background risk factors, whether it's genetic or epigenetic, meaning inheritable changes in the chromatin that aren't related to the genes, if we can find those predictors when a patient comes in, the ultimate goal is to have a test and say, "You're going to respond best to this therapy and this is what we should put you on." Because right now it's still a guessing game.

Kelly Malcom:

That sounds incredibly frustrating. A lot of trial and error.

Michelle Kahlenberg:

And it's very frustrating for patients.

Sometimes they think we don't know what we're doing, but that's not the case. It's just, unfortunately, we don't have enough understanding of the disease process to be able to make better judgments. And that's why research is so important, because we have to figure that out.

Jordan Goebig:

You're doing a wonderful job of just transitioning into the next things that I have questions about, because you touched on there are lots of different risk factors. There are lots of different things that can trigger an autoimmune disease, and so it takes a long time, a longer time, to diagnose and start to figure things out.

And so I'm just curious how a patient can advocate for themselves as they're going through this process.

Michelle Kahlenberg:

I think it's really important, and there's many ways. One, I think patients need to educate themselves on their disease, and there's ways that they can do that. Support groups are great. There's different foundations. Michigan Lupus Foundation, Detroit Lupus, around here, have support groups for patients. We've developed a website called Conquer Lupus that has a lot of self-help work in there, and also has good tips on how to advocate for yourself. And a lot of this was actually informed by patient groups that Rachel Bergmans ran for us, and the patients really gave great advice on the types of things lupus patients needed to know. So having a lupus patient understand their disease is super important.

Obviously, developing a good relationship with your rheumatologist, your primary care doctor and making sure that everyone's in communication with each other I think is really important. My patients do a really great job of telling me and updating me on when they've gotten a new med from a different doctor. And so you have to have a really good communication network. You have to find a rheumatologist that you trust and that clicks with you so that you feel comfortable sharing what you're experiencing and going with going through.

And I think the other important thing that patients can do to advocate for themselves is if things aren't right, to speak up. And you shouldn't be shy about telling your doctor that whatever is happening isn't working, or the side effects are too terrible, or you have to be... Don't just accept the status quo. If you feel like it's not right, you need to speak up. And I think physicians want to hear that from their patients. We don't want to just assume everything is fine. We want to help and make sure that you're doing as good as we can possibly do.

The other thing that's important, I think, is to also recognize that treatment of autoimmune diseases isn't all just about drugs. So it's not just medications, there's lifestyle factors like quitting smoking, trying to exercise, getting enough sleep, working on stress reduction. All of these other things are important pieces of the puzzle of feeling better when you have a disease like lupus. And so being open to thinking about all the things that you can do to help your disease is also, I think, important.

Jordan Goebig:

And I feel like those support groups and those foundations can help provide that support, because not easy to always make a big lifestyle change, but it can really impact their lives.

So, looking to the future, what are some of the most promising or exciting avenues of research for lupus and other autoimmune diseases? And please feel free to shout out some of the stuff you're doing in that area as well.

Michelle Kahlenberg:

Well, I think one of the really exciting things that's happening is that we have gotten technology in the past five years that has allowed us to dig down to a single-cell level in terms of understanding what's happening in disease. And so some of the work we're doing, we published the first study looking at the skin of patients at a single-cell level, and we look not only at the immune cells which cause inflammation and other things, but we actually also look at the structural cells of the skin itself.

And what we've found is that the structural cells of the skin are also contributing to disease. So I think these single-cell technologies are really opening our eyes in terms of what is contributing to disease development. And so I think there's going to be a huge amount of information that comes across in the next five years or so because these technologies just really allow it. They're getting cheaper, they're very expensive, but they're getting cheaper, so we're going to be able to look at a lot more samples and get a much bigger understanding towards a personalized medicine approach to understand that.

So I think just the change in technology, and how we can ask questions, and the types of things we can learn, I think is one huge exciting piece. I think the other exciting piece is that lupus finally caught the attention of the pharmaceutical industry. And what we have now are so many clinical trials in lupus. We have so many drugs in the pipeline, and that, I think, is a huge piece of the puzzle in terms of improving care for patients.

One of the challenges with that, is because now there's so many drug companies that are interested in developing therapies for lupus, we don't have enough patients involved in the research process to actually do the studies that we want to do. So at University of Michigan, we're very selective on which studies we choose to do because we want to make sure that they're safe, that they have a good chance of being successful for patients. But even so, we usually only do one study at a time, even though we could be doing 10 or 15 based on what's out there, because we just don't have enough patients that want to participate in the research process.

And I understand why some people are hesitant, but I just want to put a very strong plug out there that if people are interested in participating in research, that they should talk with their doctor and make sure it's a right decision for them, but to not be afraid of the process, because we try very hard to keep it safe and you actually get monitored so heavily when you're doing something like a clinical trial, you get more care than you probably ever had in your life.

Kelly Malcom:

I bet. Wonderful.

So I wanted to circle back to basically how we opened the discussion that the population that is most impacted by lupus has been historically overlooked.

Michelle Kahlenberg:

Yes.

Kelly Malcom:

And it's a disease that disproportionately affects women and Black women in particular. Do we have any understanding of why that is? And if you could go into how the health disparities around lupus have impacted your research, that'd be great.

Michelle Kahlenberg:

So there's many aspects to that question.

I think, first of all, systemic racism plays a huge role in the disparities. So just unhealthy environments contribute to disease, living in poverty contributes to disease, and so some aspects of those populations that does affect. The fact that research tends to focus on what the researchers were comfortable focusing on. And so we know that Black women get diagnosed later, they come to our attention later, and that contributes to more severe disease and more damage from that disease. We know that having poor access to resources and social support also contributes to disease. So if you're a single mom and you don't have anybody to watch your kids, you might not go to your doctor's appointment you should having. If you can't afford certain medications, like some of the medications we use to treat lupus come only available as a compounded drug. It's $300 out of pocket. Hardly any of my patients can afford that.

So there's all sorts of things that contribute to health disparities. I think also the mistrust of healthcare system, things like the Tuskegee study and other things have made Black patients more reluctant to participate in research. And so we actually have this outreach that we're doing at University of Michigan to try to talk with underrepresented patients to understand where the hesitancies are coming from and how we can bring advocates into the community to try to encourage patients to at least consider research and understand the process of research and why we want to do it and why it's so important to have patients from all demographics in these studies.

Because, going back to this personalized medicine approach, one of the things that has come out is some of the genes that are more like the variants of certain genes that are more common in patients from African descent, for example, they tend to turn on a certain inflammatory gene more readily. And so there might be drugs that would be better for patients of African descent to have a drug that's targeting that particular pathway versus another. And so we really have to understand how genetics, and social disparities, and racism, and all of these things have affected how patients experience their lupus and how it affects them. And I'm sorry, I can't remember the other part of your question.

Kelly Malcom:

Oh, it was about how it's impacted your approach to your research, and I know that part of it is just getting enough people involved.

Michelle Kahlenberg:

So I think I trained as a basic scientist, so I trained on test tubes and tissue culture dishes, and then I learned as I became a clinician how to also study samples from patients. And one of the things that I had to learn was how to engage patients on a different level. And so the way that it's impacted by research is that we've had to build a network of expertise that also can help engage the patient populations, get opinions from patients, because I can't do everything myself.

So now what I've learned is that I have to grow my research team to include people who are advocates for health disparities, who understand how to do survey work with patients, and get their opinions into how we design our research studies. So it's a much bigger team approach than I was trained, which was like, "Pipette this thing and run this special test." And so that's been I think a huge growth opportunity for me as a researcher is just to realize that you have to bring all of these aspects together in order to have an effective research program and to really engage the patients in a way that they're also feeling benefit from the research, too.

Jordan Goebig:

So my question is a little bit of a wrap up one, but we can spend as much time on it as we need to, because it's all about you, which is great.

In your lab and the work that you've been doing, I feel like we lead up to this, but are there any specific projects that you're working on right now, any collaborations that you'd like to talk about or give a shout-out to or any upcoming publications that you'd like to tell us about?

Michelle Kahlenberg:

So, our work right now is focused on a few aspects.

One, we're still very interested in trying to understand why sunlight is such a toxic exposure for patients, and in other autoimmune diseases like psoriasis, we actually treat patients with ultraviolet light, or sunlight, to make their skin rashes better. And in lupus, it's the complete opposite, that the rashes come out when they get exposed to the sun, even tiny amounts of sun. And so that's been a big focus of our lab trying to understand that.

We do have a paper that we're in the process of finishing up where we actually use some of this newer single-cell technology, and we had seven amazing patients come in and do a study where we exposed their skin to a tiny little amount of UV and then let us biopsy that 24 hours later so we could understand what's happening in the skin of healthy controls versus lupus patients. And we've actually found some very interesting things. It's not that the cells that are getting recruited to the skin are different, but how those cells get educated in the skin is very different in lupus. And this, again, goes back to the fact that this underlying skin is not normal, and it's causing too much inflammation from the get-go. So, that aspect we're still very interested in.

I think another aspect of lupus that we're trying to understand is what makes the switch from being predisposed to lupus to actually getting disease? And you may know there's this thing called the ANA antibody that many people in the world have. So, depending on your age, anywhere up to 10% of people can have a positive ANA antibody, but it is one of the tests that we look for to screen for lupus. And so we're also very interested in trying to understand if you have some evidence of autoimmunity, like the development of this ANA antibody, what differentiates the people that just continue to have the antibody and never get sick, versus those that go on to have disease? And so we've been building collaborations with a group in the Netherlands that have done some skin biopsies on these "incomplete lupus patients" as we term them.

And we also are trying to get funding to build a cohort of ANA positive people here that we can follow to see those that go on to get disease versus those that don't, what are the differences that underlie them? So that, I think, is a really important piece to understand in order to have a better preventative strategy to keep people from getting lupus in the first place, that would be the ultimate goal. If they never have to go on medications, we just keep them from getting sick in the first place.

So I think that's another important aspect that we're trying to build that area of research. I think the next five years or so, that's going to... Keep writing grants, trying to get funding. You got to have funding. Unfortunately, it costs a lot of money to do these types of things, but that's one of the things that I'm really passionate about building.

And then we have a lot of other really cool more intracellular, mechanistic studies that we've been doing that have identified some really important reasons why the skin is abnormal and how that might be contributing to systemic inflammation in patients, and why sometimes when a patient gets a sunburn, they get kidney disease. So we're very interested in that skin-systemic connection. And we've got a couple really cool leads on things that might be contributing, so we're also going down that path. So those are the hot topics in our lab right now.

Jordan Goebig:

Very fascinating. I'm going to follow up with a very ignorant question, I feel like. Dumb question.

I was listening to you talk about the sun being a trigger for lupus patients, and I had this chicken and egg scenario in my head. Did scientists figure this out while doing research in the lab that sun was a contributing factor or do you know? Or if patients kept saying, "I'm in the sun a lot and then I notice I have flare-ups" and that's where the research started? Do you know?

Michelle Kahlenberg:

I think it's the second part. The patients really drove that question. It's been a known factor of lupus for a very long time, but sometimes sun exposure would just make people very sick. And patients will tell you, the ones who are really sun sensitive, like five minutes in the sun, they try to go to their kid's soccer game and they're like nauseated. They get a rash, they feel completely fatigued, it wipes them out. And we all have patients who've, despite our best advice, go on break, forget to wear their sunscreen, and six weeks later come back and have really bad kidney disease flare.

So people roll their eyes at me when they come to see me in clinic, because I'm always talking about sunscreen, but I think the patients definitely drove that observation for sure.

Jordan Goebig:

Really interesting. Thank you for answering that question.

Michelle Kahlenberg:

No, it's a really important one.

Jordan Goebig:

Because you were talking about the advocacy for yourself, and I'm like... So then I started thinking, is that something? This is why it's so important to tell people, tell your position even if you think something's weird or off, not that that's weird, because the sun is very powerful, so it makes sense, but you might not think to notice something's a symptom and just brush it off. But that's a good example of patients not brushing it off. And now you've developed a whole lab devoted to this and it's really cool.

Michelle Kahlenberg:

Thank you.

And I just want to emphasize that, always talk to your doctors if there's things that you observe because you know your body better than anyone. And I always tell my patients, they'll say things that they're like, "Oh, I think this is what's going on." And I fully admit we do not have medical evidence for everything that goes on in a disease, and so it's very possible that patients experience things that aren't in our textbooks. And if you have a doctor that likes to do research, that's food for thought for thinking about what to do next.

Kelly Malcom:

Okay, I think we're wrapping up. Is there anything that we didn't touch on that you wanted to talk about or plug now's your chance?

Michelle Kahlenberg:

Oh, thank you.

No, I'll just put a plug out there, again, for the importance of research in transforming care of patients. If everyone's happy with the status quo, we don't need to do research, but I think there's so many areas that we still need to make in roads in health disparities, differences in outcomes amongst patients, understanding disease heterogeneity, meaning how patients present and respond to treatments differently, and also just understanding what starts the disease in the first place.

So there's so many areas that we still need to work on, and we need patients to be our partners to study this. So if people are interested, they can reach out to us. I've got a website, my research coordinator's on there, so we're happy to discuss options of what types of research are ongoing if people are interested.

Kelly Malcom:

All right. Thank you so much. It's been great talking with you and learning about lupus.

Jordan Goebig:

This was amazing. I feel like I learned so much. I don't think we've had a podcast episode like this yet. Very informative, and I just really appreciated all the patient advocacy information and the science. You did a great job of explaining the science for me. So I appreciate that, and I appreciate you coming and spending your morning with us.

Michelle Kahlenberg:

Absolutely. Thank you for the invitation.

Kelly Malcom:

The Fundamentals is produced by the Michigan Medicine Department of Communication in partnership with the University of Michigan Medical School. Find us and subscribe wherever you listen to podcasts.