Intro: Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Melanie Cole.

Melanie Cole, MS (Host): Welcome to UAB MedCast. I'm Melanie Cole. And joining me today is Dr. Joseph Barney. He's a pulmonologist in Critical Care Medicine and a professor at UAB Medicine, and he's here to highlight sarcoidosis diagnosis and management today.

Melanie Cole, MS: Dr. Barney, thank you so much for joining us. Tell us a little bit about sarcoidosis, the prevalence of the disease, anything we know about the epidemiology as a commonly encountered disease in a variety of specialty clinics.

Dr Joseph Barney: Oh, yeah. Thanks for having me. It's an incredible pleasure to be able to tell people about sarcoidosis, a disease that I know and see every day. UAB has a multidisciplinary sarcoid clinic, and has had for almost 20 years now. And it's a very fascinating disease. It affects predominantly or intrepidly African Americans more than Caucasian patients in the United States, although it really can affect anybody. And it's really considered what we would think of as an autoimmune disease that falls into a sort of the general family of autoimmune diseases like lupus or rheumatoid arthritis, in that the immune system creates these collections of cells in the body called granulomas that release inflammatory proteins and cause disease in multiple ways. One of which would be by just causing patients to have a lot of symptoms that are unusual like joint pain, unusual skin rashes, cough, shortness of breath. And the other way that it can cause disease manifestations is when these granulomas multiply in an organ like, for example, the lungs and eventually replace a certain amount of functioning lung tissue causing the patient to have a decline in lung function. And we would see that on things like pulmonary function tests.

So, sarcoid is really what we would consider a protean disease in that it can cause different manifestations in different people. One person may come to clinic and have diffuse skin lesions or skin rashes from it. Another person comes in and they have no skin rashes and they have diffuse granulomas in the lung and they are shorter breath and requiring oxygen. So, it manifests in different ways in different people. There tends to be a bimodal distribution of age, and that the time that it's discovered or diagnosed peaks in about the 20s to 30s in people. And then later in life, in around the 50s to 60s, we see a second bump in new diagnosis or cases. And again, if you had to name people who were affected the most or had the worst disease in the United States, it would be African Americans and women. And African American women tend to have the most complicated disease, the most refractory disease, requiring treatment and often are on therapy for life, whereas some other patients will have remission of their disease and come off of treatment.

Melanie Cole, MS: Dr. Barney, is there strong evidence of a genetic predisposition or exaggerated immune response in a genetically susceptible individual to undefined antigens such as environmental factors?

Dr Joseph Barney: Well, that's a great question. People have been looking for the collection of gene clusters or mutations that cause sarcoidosis. And it really remains somewhat elusive. Unfortunately, it's not a single gene mutation disease like, for example, cystic fibrosis where we know a handful of different locations on a single gene, for example, that affect CFTR that cause cystic fibrosis. Sarcoid is actually probably caused by multiple gene mutations at different locations that cause that. We do know that it behaves like a disease that is a response to an antigen in the environment. And most likely what happens, among people who see this on a regular basis, is the model fits best with multiple antigens. So as opposed to one antigen in the environment that causes sarcoidosis, there's probably many antigens in the environment and people have an aberrant genetic response to the antigen where their immune system remains activated even though the antigen is gone at some point. And they have perpetual inflammation leading to lung disease, skin disease, joint disease, combinations of those and some other things.

Melanie Cole, MS: Interesting. So, is the differential diagnosis for sarcoidosis broad because of the non-specific symptoms and diverse clinical presentations you were discussing? As many other diseases, Dr. Barney, can present with similar clinical radiologic and pathologic findings, are there criteria for confirmation of the diagnosis? Help other providers here to identify the clinical manifestations and any diagnostic criteria that you'd like to talk about.

Dr Joseph Barney: That's absolutely right. Many things look like sarcoid and sarcoid can look like other things. And in fact, when we see patients for sarcoidosis, we really start on a journey of excluding other diseases that can look like that, because we have to take those off the table before we conclusively diagnose someone with the disease. And really the gold standard today still remains a tissue biopsy of some part of their body that shows that they have non-caseating granuloma, which are the hallmark feature of the collections of immune cells as they manifest in tissue, for example, like in a lymph node in the body or in a skin biopsy in the body. And once we know that they have that, we also have to exclude that they have other infections that can cause granulomas.

So a granuloma is not a collection of cells that is unique just to sarcoidosis, it's an immune response. But sarcoidosis is a disease that features diffuse granulomatous inflammation. Other things can cause that. So if you were to think about something that looks very similar to sarcoidosis, tuberculosis can look like it. And if you had a patient who came from an area of the world that was very endemic or had a high rate of tuberculosis and they had nodules in the lung and we biopsied them and they had granulomas, we would want to be absolutely certain that they didn't have tuberculosis growing before we called them sarcoid, because they can look very similar.

So, the standard would be that we need a tissue biopsy from some part of the body, typically in the lungs or the chest or in the skin, although some other places can be biopsied. And we would want to show that nothing grew from cultures from that place also, in addition to having these granulomas. And once we know after, sometimes several weeks that, the cultures remain negative, sarcoid remains the diagnosis because we have excluded other things and it looks like sarcoid and behaves like sarcoid.

Melanie Cole, MS: Are there any established screening guidelines?

Dr Joseph Barney: There are some good guidelines. Most of them come from Foundation for Sarcoid Research and WASOG. The WASOG tool is part of this as well as some ATS criteria. There are some guidelines in the American Thoracic Society. And most of them focus on having a clinical manifestation that can look like sarcoid. So, there are some phenotypes or clinical presentations that can look like sarcoidosis. And once we have a patient that is suspected of having sarcoidosis, they really need to meet pretty stringent criteria, if possible, to obtain a tissue diagnosis and show that they have granulomas in a part of the body that looks like sarcoid and behaves like sarcoid. And we have excluded other diseases that can look like this. So, that's the main feature of that. And we typically would follow American Thoracic Society guideline statements related to that and tissue remains the gold standard in most patients, unless you just can't obtain that.

Melanie Cole, MS: Well then, speak about treatment modalities that you have available, clinical management. You can start with any medication intervention that might be used. But because the initial presentation can have a big range, can you tell us a little bit about some of those treatment options available?

Dr Joseph Barney: So first and foremost, I think when we see patients in clinic, what we need to decide once we understand or feel pretty confident that they have a diagnosis of sarcoidosis, we need to make a decision as to whether they need treatment or not to begin. With some patients, and in fact, as many as 30% of patients who come to sarcoidosis clinic, don't really need treatment, and they could be followed with observation.

And one example of that would be a pretty common referral to clinics or patients that get evaluated for sarcoid, who have it, who have sarcoidosis, have it mainly manifest with lymph node enlargement in the thorax or in the chest, and their lung tissue remains clear and their lung functions are clear, and they have undergone a biopsy of these lymph nodes because they were enlarged out of concern that there might be something else in there. It's very common for patients who have sarcoidosis to initially be found incidentally on a chest x-ray where they have really large lymph nodes in the chest, and the concern is in a younger patient that this might be lymphoma. And so, the right thing to do would be to biopsy those lymph nodes to make sure that there is no lymphoma. And in some of those patients, they don't have lymphoma, they actually had sarcoidosis all along. And when we encounter them in clinic, we do a formal evaluation with a history, we try to confirm their diagnosis, we do pulmonary function testing and some lab work to make sure that no other manifestations of organ disease from the sarcoidosis are present besides the lungs. And if they have normal labs and they have pulmonary function testing that is pretty normal, we don't actually treat that patient. We will typically watch them if they don't have a lot of symptoms, because they will often have remission of their inflammation on their own. And they will just be followed by us perhaps every six to 12 months for a while and many of them never require treatment.

Now if you take a different patient who, for example, might have diffuse skin lesions and lung function testing that is abnormal, those two things are pretty good criteria to begin treatment. And so, we would need to start that person on therapy and we would need to decide a therapy that fits them the best. There isn't one treatment medication for sarcoidosis anymore. In the past, it used to be corticosteroids or prednisone only. There are many different agents that are used now that modulate or change the immune system's response that can effectively treat sarcoidosis. And what we like to do is pick one that is as bespoke as possible for the individual patient.

So if you had a patient who had pulmonary or lung disease and skin lesions and they met some threshold criteria for needing treatment, we would consider whether they have other comorbidities that might affect some of the medications being better or worse. For example, if they have pretty hard-to-control diabetes, we would try to avoid corticosteroids if at all possible. And we might use a medication like methotrexate or a medication called azathioprine, which are both oral medications that can be effectively taken at home by the patient and followed by us every few months with lab work to make sure that they're responding to that. And each of those medications has different side effect potential panels and different ways that they're metabolized. So, we try to pick and choose a medication based on the least amount of side effects possible with the most likelihood of controlling the disease in the patient. And that's the general approach.

Melanie Cole, MS: Well then, tell us please, who is an integral part of this multidisciplinary approach taking care of these patients?

Dr Joseph Barney: I would love to tell you about all the people I work with. In general, what we have tried to amass are all the specialists who get involved with taking care of our patients that we can collectively think together and also design treatment options and regimens for these patients that will work the best.

So at UAB and many other centers of excellence for sarcoidosis, this involves a pretty cohesive team of thoracic radiologists, pulmonary specialists, cardiologists who have experience managing cardiac sarcoidosis, dermatologists who have a lot of experience working with advanced immunosuppressive treatments. We work fairly closely with some neuroimmunology clinicians at UAB who manage neurosarcoidosis with us. We work closely with the pulmonary rehabilitation program and the respiratory therapy staff that specialize that, because many of our patients are in pulmonary rehab related to the chronic lung disease. We collaborate closely with the heart and lung transplant clinic staff because some of our patients would be referred to them ultimately for lung transplant consideration. Many, many other people on campus contribute and participate in clinic with us, but that's just the tip of the iceberg of some of the specialists that work together in the multidisciplinary clinic at uab.

Melanie Cole, MS: Thank you for all this great information. As we wrap up, Dr. Barney, do you feel that working to improve diagnostic tools and that clinical studies in the foundation for sarcoidosis research will soon play an integral part in this whole process? And what are you working on at UAB that you would like other providers to know about?

Dr Joseph Barney: Well, first of all, I'd have to tell you that the Foundation for Sarcoid Research is invaluable. I couldn't even begin to tell you how important they are for advancing research and patient advocation in this disease. Without them as a cornerstone, we would be decades behind on collaborative work and pushing the envelope further on understanding the disease process.

In general at UAB, we have been focusing on designing and advocating for better access to care, more work with clinical trials with industry on some newer agents that work directly to inhibit specific molecules in the immune system, several of which have really shown promise and are currently in phase III clinical trials, not only UAB, but sites around the world, to try to bring new therapy that controls the disease with much less side effects for the patient and controls the disease in patients that have refractory disease. Many patients fail current treatment and continue on multiple agents with progression of disease and we are really desperately in need of treatments for that.

One thing that we have been really working at lately at UAB specifically Is a project that understands management of hypercalcemia in patients with sarcoidosis. This is a really unique feature in patients with sarcoid, in that some of them will have derangement in calcium metabolism and they will present with hypercalcemia and altered mental status, and it requires immunosuppressive treatment to control their calcium. And we are currently trying to understand, by looking retrospectively, as an initial part of the project which immunosuppressive agents seem to have worked historically the best to control calcium levels in patients and which ones have worked less effectively and try to understand phenotypically what patients look like who get hypercalcemia and build a way to have a risk stratification and to describe risk factors for developing hypercalcemia related to sarcoidosis.

So, one of our newer faculty is spearheading this project. We're very excited about it. We have so far identified about 850 patients that have had hypercalcemia in the last 20 years at UAB and will be digging in and trying to understand which medications that worked best for this. That's an astronomical number of people to be able to do research on.

Melanie Cole, MS: So interesting. Thank you for such an informative episode, Dr. Barney. And for more information, please visit our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole. Thanks so much for joining us.