Misha Rosenbach, MD, director of the sarcoidosis and granulomatous clinic at the Perelman School of Medicine, reviews how to diagnose and treat cutaneous manifestations of sarcoidosis.
Dr Rosenbach is the director of the Cutaneous Sarcoidosis & Granulomatous Disease Clinic, and associate professor of Dermatology at the University of Pennsylvania, Perelman School of Medicine.
Melissa Weiss: Hello, and welcome to another podcast with the Autoimmune Learning Network. I’m Melissa, Contributing Editor to ALN and Associate Editor with The Dermatologist. Today we’re going to be speaking with Dr Misha Rosenbach about the diagnosis and treatment of sarcoidosis.
Dr Rosenbach is the director of the Cutaneous Sarcoidosis & Granulomatous Disease Clinic, and associate professor of Dermatology at the University of Pennsylvania, Perelman School of Medicine. Thank you so much for joining us today, Dr Rosenbach.
What important considerations should physicians remember when diagnosing a patient with suspected sarcoidosis?
Dr Misha Rosenbach: That’s a great question. One of the challenges with sarcoidosis is that in many cases it ends up being a bit of a diagnosis of exclusion. What physicians should remember is that there are some diagnostic criteria. There are some organizations like WASOG, stands for World Association of Sarcoidosis and Other Granulomatous diseases, which is a mouthful.
That organization has some proposed guidelines that go through, is this definitive sarcoidosis, or probable, or possible? But the short answer is that sarcoidosis is, by strict definition, a multi‑organ disease. People should have signs of an illness in more than one organ, and there should be a biopsy that shows granulomas. It’s helpful to make the diagnosis if there’s other supportive evidence like suggestive radiological findings.
From a dermatology standpoint, often you’re seeing a rash, you get a biopsy that shows granulomas, you may think that means its sarcoidosis. But one of the first things dermatologists should remember is they should try to make sure it’s a multi‑organ disease because there are other things that cause granulomas in the skin.
Because sarcoidosis patients often or almost always have lung involvement. That simple, straightforward thing for dermatologists to remember is if you have a biopsy or a lesion that comes back as showing granulomatous inflammation, should probably get at least a chest X‑ray and eye exam because 90, 95% of sarcoidosis patients are going to have some pulmonary findings, often something like hilar adenopathy, and also about 25% will have eye findings.
Just like a crude rule of thumb for dermatologists is, skin biopsy showing granulomas, that’s putting you in the vague category of sarcoidosis could be there. Then you want to look for other organ involvement and nail down that that’s what you’re dealing with while you’re excluding some other things that could mimic sarcoidosis.
Melissa: What therapeutic options are available for treating sarcoidosis?
Dr Rosenbach: I think dermatologists should be excited that we’re in 2020. While this year has not been great overall for society, there are continuous advances in medicine and they’re promising new treatments on the horizon.
But sarcoidosis tends to be a fairly neglected disease. There’s not a lot of FDA‑approved therapies, so everything we’re going to talk about is off‑label. The first thing that we say for patients with sarcoidosis is you should figure out where their sarcoidosis is, which organs are most affected, and then that most affected organ is often going to be what’s driving treatment.
From a dermatologist standpoint, you might diagnose sarcoidosis and say, “Boy, this patient’s really short of breath. I’m going to send them to a lung doctor.” Then when the pulmonologist puts them on some strong immunosuppression for their lung, their skin will get better. First thing is, figure out where the disease is and what needs to be treated.
From a dermatology standpoint, we’re often left with either patients whose skin disease has not responded to systemic treatment or patients whose skin disease is the most severe part of their sarcoidosis. What dermatologists should know is that topical treatments can do something for small, thin sarcoid lesions and are fairly low‑risk. You can use topical steroids or topical tacrolimus. Intralesional steroids do tend to help.
Topicals don’t tend to penetrate either enough or deep enough to get at the granulomas, but intralesional injections of steroids will often make lesions get better. Sometimes they will recur and need repeated injections. But every dermatologist is probably comfortable using creams and injection.
Beyond that, we generally divide treatment for skin sarcoidosis into two categories very broadly. One is anti‑inflammatory, immunemodulating drugs, and the other categories immunosuppressive medications.
Generally, it’s better to try to use lower‑risk or less immunosuppressive medicines if you can get disease control, especially in the face of COVID‑19 pandemic.
In that first category of anti‑inflammatory or immunemodulating medications, there’s two main classes that we reach for all the time, and that’s tetracycline‑class antibiotics, which is minocycline and doxycycline, and then anti‑malarial agents, which for all intents and purposes at this point is just hydroxychloroquine, Plaquenil.
Most patients with some skin sarcoidosis, first‑line treatment is to start Plaquenil. You can augment that with starting minocycline and doxycycline. Minocycline has more risks for severe adverse reactions and can cause drug‑induced pigmentation, especially within the granulomas.
So often when I see a patient with cutaneous sarcoidosis, I will say, “Here’s some topicals. I’m not sure is going to do very much. We can inject that one or two worst spots that you have with some intralesional Kenalog. We’re going to start you on hydroxychloroquine and doxycycline combination therapy.”
That’s pretty standard for a first visit for someone with fairly widespread skin sarcoidosis. About 60 to 70% of patients will respond to the hydroxychloroquine tetracycline combination. Then it’s the non‑responders who, at their follow up visit, you might start talking to about some treatments from the other category, those immunosuppressive meds.
That might mean low‑dose prednisone, that might mean starting methotrexate, that might mean a discussion of use of TNF‑alpha inhibitors, such as adalimumab or infliximab, which we often end up having to use for patients with really severe or really extensive facial sarcoidosis, who have lesions on their nose or cheeks, which is often called lupus pernio.
When you see those patients walking in the door, we generally counsel them that, “We’ll try these anti‑inflammatory immunomodulatory medicines, but there’s a good chance we’re going to need to ramp up just stronger therapy.”
Melissa: Going after that, are there any clinical features that influence your treatment and could indicate treatment response?
Dr Rosenbach: That’s a great question. Let’s go with skin exam in general. First of all, if someone walks in and might have sarcoidosis, or let’s say someone else biopsied them and said it sarcoid, or let’s say a pulmonologist gets an X‑ray and it shows hilar adenopathy and they don’t think that they can go in and do a transbronchial biopsy and they send them to a dermatologist, where should the dermatologist look first?
Generally, a lot of patients with sarcoidosis will have lesions around their eyes and mouth, but especially on and around their nose. Physical exam should include looking at the nose. Many people have involvement of the neck, sometimes in the scalp, sometimes in the ears. Sarcoidosis is a great mimicker, so there should be a pretty low threshold to do a skin biopsy to see if what you’re looking at is sarcoid.
Beyond that, sarcoidosis sometimes shows up in scars or in tattoos. So, it’s important to ask patients about that and to look at those areas. That’s generally the beginning of a physical exam for sarcoidosis.
There’s two main findings that will convey some degree of prognosis. One is if patients have erythema nodosum, which is a form of panniculitis, where you get tender reddish‑brown nodules often on the lower legs or anterior shins, common to have it symmetrical or bilateral.
When people have erythema nodosum in the setting of sarcoidosis, often it occurs in conjunction with arthritis arthralgias, fevers, and if you get a chest X‑ray, hilar adenopathy. That combination of hilar adenopathy, joint symptoms, and erythema nodosum, it’s often called Lofgren syndrome.
That usually happens in Caucasian patients or patients of Northern European ancestry. Those patients have a pretty good prognosis. They might be miserable from their acute disease, they might need treatment in the short term, but they’re not going to have a chronic course. They’re going to get better from their sarcoidosis.
Patients who have more typical sarcoidosis lesions, particularly African American patients, and particularly patients who have lesions on the nose or central face, those patients are more likely to have a chronic course of sarcoidosis.
What we know as patients who have lupus pernio, so lesions of the nose and cheeks, are more likely to have upper airway involvements, involvement of the sinuses, or pharynx, and will often need to see an ear, nose, and throat doctor. Also, those patients with lupus pernio are more likely to have severe lung disease. That form of sarcoidosis just tends to be more treatment‑resistant.
There’s a paper in 2009 by Mark Jetson that showed patients with lupus pernio will only respond to all treatments about 10 to 30% of the time, except for TNF‑alpha inhibitor therapy where they will respond up to 90% of the time.
That’s the one kind of morphology. Someone walks in the door with a lot of expansive central facial sarcoid, nose and cheeks, lupus pernio sarcoid, that’s someone who you’re probably going to want to start laying the groundwork even at your initial visit for either referral to a specialist if you’re not comfortable managing that or to laying the groundwork to get blood tests and paperwork in order to try to get them TNF‑alpha inhibitor therapy approved.
Melissa: What are some of the common pitfalls physicians can encounter when treating sarcoidosis?
Dr Rosenbach: Sarcoidosis can be both underdiagnosed and overdiagnosed. You don’t want to assume someone has sarcoidosis based on…they have one papule on their skin and a biopsy showed granuloma, but they have nothing else.
Someone could get, let’s say, a splinter or foreign body reaction, or have a tattoo where they have a granulomatous reaction to the tattoo pigment, but it’s just localized in their skin and it’s not really representative of sarcoid. It’s just a granulomatous tattoo reaction.
Or people can have, let’s say, a biopsy of their lip that shows granulomas and someone might assume that’s sarcoidosis, but that might be their initial presenting sign of something like inflammatory bowel disease or Crohn disease.
But the big thing we worry about is infections can show up with granulomatous inflammation. What you don’t want to get in a situation of is you assume someone has sarcoidosis and start treating them with more and more drugs and more and more immunosuppression and they get worse and worse, so you think they need more and more treatment.
If you treat someone with the right treatment, they should get better. If you start someone on treatment and they’re getting worse, you should pause and rethink things.
I have had patients referred to me for sarcoidosis management that was quote, you know, “recalcitrant,” and it turns out that they had cutaneous tuberculosis or a cutaneous mycobacterial infection. Had patients who have granulomatous inflammation in their central facial area, and they were sent for treatment and it turns out that that was a form of lymphoma. So, at the edges of some lymphoma, you can get some granulomatous inflammation.
I would just say that people should be cautious, especially if you’re treating someone and they’re not getting better in general. Looking and talking to your pathologists and doing clinical pathologic correlation is important.
Most sarcoid biopsies are non‑caseating granulomas. If you had a biopsy that shows a lot of caseous necrosis but there’s a lot of neutrophils there, it’s worth pausing and maybe considering doing a tissue culture or asking for deeper cuts from your pathologist or some special stains.
Assuming you have sarcoidosis, one of the other things that is a fairly common error is that in patients of sarcoidosis, the granulomas are metabolically active, so the granulomas are trying to do something. They’re doing it wrong, they’re doing it too much, the disease is that they forgot to turn off.
But still, patients who have sarcoid have granulomas that are working. One of the ways that granulomas do stuff is they convert vitamin D from the vitamin D inactive 25 storage form to active 1,25‑dihydroxyvitamin D. This is a very hard concept over a podcast. I usually draw a picture. But still, in patients, granulomas in sarcoidosis, they’re doing something. They drain out your vitamin D 25 storage form, turn it into vitamin D 1,25, and then they’re trying to do something with that.
Then for physicians, if you get blood tests for sarcoidosis patients and you’re looking at their vitamin D levels, most people will just check your vitamin D level, say, “I’m ordering vitamin D.” That means that they’re checking their vitamin D 25 level.
In sarcoidosis patients, their vitamin D 25 level is actually artificially low because it’s been drained out and converted to vitamin D 1,25‑dihydroxyvitamin D. For a physician seeing sarcoid patient, it looks like they have low vitamin D, you give them vitamin D supplementation.
But secretly the vitamin D levels are actually much higher or more active or doing more stuff, and then you can get iatrogenic hypervitaminosis, and hypercalcemia, and problems and complications as a result of that. Basically, if you’re looking at vitamin D in sarcoid patients just pause and think twice.
The last warning I want to emphasize is that when I started a sarcoid clinic about 10 years ago or so, at the time, we thought the rates of cardiac sarcoid were something like 5 to 10% of patients had heart involvement.
Now, with more advanced diagnostic tests and use of PET imaging and cardiac MRI, the feeling in the field is that the rates of cardiac sarcoid is more like 15 to 20%. But the most common symptom of cardiac sarcoid is sudden death. If you’re reading this, or listening to this, or hearing this podcast, you’re like, “Whoa, whoa, hold up. Did you just say sudden death?” “Yeah. That’s it.”
That’s the worst symptom to present with, right? What patient wants to present with sudden death and what doctor wants to hear a phone message that, “Hey, your patient presented with sudden death.” That’s all terrible.
But that is because the granulomas in the heart can interfere with the conduction system and then lead to arrhythmias. What physicians should know is, one, not to shut down and say, “Boy, sarcoid’s terrible. I’m scared of this. I’m never going to deal with it.” It’s to say like, “Well, our job is if we’re diagnosing someone with sarcoid, we should know how to screen for that,” and it’s pretty easy.
Screening is you ask if someone has palpitations. You say, “Can you feel your heart beating in your chest? Are you aware of your heart? Does it sometimes feel like it skips a beat or is pounding your chest?” If someone says that they have palpitations, they have to see a cardiologist. Then you should order an EKG. If their EKG’s stone‑cold normal, you’re fine. If the EKG is anything but normal, you send them to a cardiologist.
That’s pretty low‑hanging fruit to just say, “Do you have palpitations? Here’s an EKG.” You want to diagnose it when it’s intervenable and that’s a chance for dermatologists to save someone’s life.
Melissa: Going off of that, why is it important for physicians to use a multidisciplinary approach and work with other physicians outside their field when treating patients with this disease?
Dr Rosenbach: I feel like sarcoidosis is like the granddaddy of all multi‑organ diseases. Sarcoidosis is one of the few diseases that can affect almost any organ in the body. It can do it in either obvious or subtle ways.
Most dermatologists’ role with sarcoidosis is going to be someone thinks the patient has sarcoid and they’re referring them because it’s easier to biopsy the skin than something internally, or that patients who are on therapy have some leftover skin disease that needs to be addressed.
But if you’re a dermatologist, you’re making the initial diagnosis of sarcoidosis, you’re left with saying, “Gosh, this is a disease that 5 to 10% of the time could affect the brain, 15 to 20% of time could affect the heart, maybe 50% or more can affect the liver but we don’t often know or have trouble finding it, 90% in the lungs, 25% eyes.” You can rattle off almost every organ and say, “Gosh, as a dermatologist, do I really need to know how to evaluate for all these things? I don’t want to miss anything.”
The good news is that sarcoidosis is something that all these other specialties know affects their organ and know how to look for it. It’s not like there’s some weird, rare derm disease that no one’s ever heard of, or that it’s not clear what you’re asking people when you’re referring patients with sarcoidosis.
This is something that people know and expect is going to require multidisciplinary care. It’s a disease that people recognize each field has its own fund of knowledge and approach to managing it. It can be challenging in this era of everyone overworked, and overwhelmed, and too many messages, and too many prior auths, and too much administration to have a patient who sees six other doctors and to be able to coordinate.
What does the pulmonologist want to do? What does the ophthalmologist want to do? What does the neurologist want to do? Most patients don’t actually have sarcoid in six organs.
Most patients, after the initial screening, it’ll be very obvious like, “This is their main manifestation.” If this is a patient with primary lung disease, their pulmonologist going to call the shots and they’re going to coordinate everything with everyone else.
But it’s a good chance to work with and learn from colleagues and collaborate to make sure that you don’t have dermatology giving some creams and ophthalmology giving some drops and pulmonary medicine giving some inhalers when maybe it could all be addressed with one low‑dose methotrexate prescription or something like that.
Melissa: What areas of future research are needed to improve treatment of sarcoidosis patients?
Dr Rosenbach: Treatment approach, just to sum up since I touched on it earlier, basically, is figure out which organ is most effective, and that organ or physician is going to probably dictate treatment. But from a skin sarcoid standpoint, you can always use creams and injections. Usually, first‑line is going to be antimalarials and tetracycline‑class antibiotics.
Then, if it’s resistant to that or recalcitrant, you’re going to move to probably some low‑dose methotrexate. If that doesn’t work, probably to a TNF‑alpha inhibitor, again, taking into consideration global pandemic, and patient comorbidities, and preferences.
Again, as a reminder, these are all off‑label and not FDA‑approved treatments. But there’s papers and evidence and public algorithms. We have a number of publications summing these things up.
But in terms of what’s on the horizon, you know, there was a paper out of Yale by Brett King and Bill Damsky that was in the New England Journal, which is good for our field to be pushing the envelope and making advances that other specialties read and learn from, but which was the use of JAK inhibitors.
JAK inhibitors are an exciting new drug in the field, where they’re being looked at for atopic dermatitis, and psoriasis, psoriatic arthritis, and other diseases in dermatology. JAK inhibitors work on a pathway that’s very important in granulomatous formation and offer a lot of promise for potential targeted therapy that is highly effective.
That New England Journal paper was very nice. It showed a recalcitrant patient getting better. Since then, there have been a couple of papers in the JAAD about use of JAK inhibitors for sarcoidosis and some other granulomatous diseases. JAMA Derm has a couple of papers about use of JAK inhibitors for other granulomatous skin diseases.
It’s like a new category of drug that should work on pathways that are very involved in granuloma formation, and has to be studied to see, is the efficacy on par with TNF-inhibitors? Is the efficacy’s better than systemic immunosuppression that we currently use, and what is the safety profile in these patients?
But that touches on, I said, JAK inhibitors work on a pathway that’s involved in granuloma formation, but right now is a fantastic time for dermatology patients with granulomatous diseases.
We went from one or two physicians who were focused on this as an area of interest to, there’s a granuloma group that, was going to meet in person but it’s now met virtually due to the pandemic, but there’s like 10 or 12 dermatologists who are focused on either clinical research, or basic science research, or translational research, or epidemiologic research, trying to get at, what is the real burden of disease? What are the unmet needs? What pathways are involved in granuloma formation? How can we adapt drugs that we have for other skin diseases for treatment of these patients? Or, how can we work with pharma companies to develop new treatments to give therapeutic benefit with favorable side effect profile and costs?
Now that we’re developing a little bit better understanding for what’s happening biologically in the skin, that attracts more interest from drug companies to say, “You know what? You found that pathways up in this disease, we have a drug that targets that pathway.”
Then if you end up translating that conversation to a clinical trial, during that trial, you learn much more about the pathophysiology of the disease if you’re taking biopsies or blood samples, and you’re saying, “This drug on this pathway is leading to this patient’s getting better. Look, the biomarker went down. That’s great.”
Then these things snowball where then you have a network of people that work with patients’ interest in pharmaceutical companies understanding of the biophysiology of what’s happening in granulomas and that lets you translate that knowledge into better treatments for patients.
Melissa: What key takeaways would you like to leave with our audience?
Dr Rosenbach: One, sarcoidosis is a disease that skin is usually the second most commonly affected organ, so dermatologists definitely have a role.
Dermatologists can define their role however they’re comfortable in their practice pattern, whether that means they’re going to help with the diagnosis and then refer them out, or serve as a consultant for maybe a pulmonologist who’s running the show, or end up being the primary person prescribing medicines to treat it. But we’re good at treating skin disease and sarcoid patients have pretty bad skin disease and we should be doing stuff to help them.
Dermatologists should be aware that there are non‑immunosuppressive treatments that all dermatologists are probably comfortable prescribing. Antimalarials and anti‑inflammatory, like tetracycline‑class antibiotics. Don’t be scared to start treating your patients appropriately.
The other thing is that this is a really exciting time. There’s a lot of new work coming on the horizon. Dermatologists, listen to this. If you want more stuff on this, just make your voices heard. Melissa Weiss is contacting me to do this. I don’t know what drove that. I don’t know how much interest there is.
But at the Academy, we have once a year at the annual scientific meeting, there’s a granuloma session that’s run by Dr Joe English at University of Pittsburgh Medical Center and myself. It’s routinely standing room only and it’s always a two‑hour session. We’ve submitted to the scientific planning committee that it should be a three‑hour session and there’s more speakers and whatever, but that doesn’t happen.
But if you’re sitting there saying like, “Gosh, this is an exciting time. I wish we learned more about sarcoid and granulomatous diseases,” and heard maybe a little bit disproportionately less about psoriasis, or eczema, which are super important diseases, I don’t want listeners to think I’m belittling that, but our field has made huge advances in psoriasis. Like 80% of our publications are psoriasis associated.
If you say, “Hey, AAD Scientific Assembly Planning Committee, can we get more granuloma content proportionately?” then you guys will have more chance to hear about stuff.
In general, my take‑home point would be, these patients need and deserve our help and we are the right doctors to help them and we have a lot of tools in our toolbox that you can put to use and trying to improve the skin disease in patients with sarcoidosis.
Melissa: Thank you for listening. Stay tuned for part two, where we will discuss the impact of the COVID‑19 pandemic on patients with sarcoidosis. If you have any questions regarding the treatment of sarcoidosis or you’d like to hear more, please submit your feedback in the comments box below. We really appreciate any feedback you send us.