Challenging Cases in Atopic Dermatitis

In this exclusive interview as part of the National Eczema Association’s Atopic Dermatitis (AD) Expert Series, Raj Chovatiya, MD, PhD, chatted with Matthew Zirwas, MD, about navigating challenging cases in AD, including considerations when a patient does not respond to therapy. Dr Zirwas has published close to 200 peer-reviewed articles, is a primary author of the latest edition of Fisher’s Contact Dermatitis, and frequently speaks at conferences. Through his work in clinical trials, Dr Zirwas is engaged in exploring solutions for patients with difficult to treat AD.

Dr Chovatiya: One of the things we have begun to realize about AD is that treating for body surface area or basing therapy selection on a single measure does not truly indicate disease severity in any meaningful way. AD is more than what we see on the skin; it is a composite of skin signs and symptoms, quality of life, and other factors. When someone is not responding adequately, we are not controlling all those things well. For a patient who is appropriate for topical therapy, but topical steroids did not work on your first shot, where might you go next? How would you handle potency and escalate within topical corticosteroids?

Dr Zirwas: I rapidly go to class 1 topical steroids. Even on the face, I will use clobetasol. I tell patients, “Do not use it on your face more than 5 days a week.” For locations on the body other than the face, I tell them, “You can put it on 3 days a week.” I use class 1 topical steroids in combination with a topical calcineurin inhibitor. If that combination does not work, then I go to a topical Janus kinase (JAK) inhibitor. If that does not work, then I have a discussion with the patient about systemic medication.

Dr Chovatiya: I think a big issue in dermatology and eczema care is this idea of when to transition from topicals. Part of the reason why there has been slow buy-in on advanced systemic therapy is that a lot of people just stay on topicals probably longer than they should. I know your threshold is lower than most, but maybe you can take me through the thought process that led you to the point in your career where this is an easy transition for you to make. How do you know when someone is not adequately responding and how do you think about adequate response for jumping up to systemic therapy?

Dr Zirwas: For me, the most practical indicator is the need for a systemic steroid. A big part of why I have such a low threshold is data from the United Kingdom, Denmark, and the United States. Large insurance claims database studies show that people with moderate to severe AD have a dramatically increased risk of serious and even life-threatening infections. Some of the data have shown a significant increase in mortality, primarily related to infections. In those studies, the way they defined the severity of AD was based on prescription history. For example, they categorized the patient as moderate instead of mild if they were on their second prescription for a topical steroid. Having ever been on a systemic therapy means you are now moderate or maybe even severe and having been referred to a dermatologist means that you are moderate or severe. I believe 100% that the quality-of-life issues with AD are through the roof. But it is not just about quality of life. We have meaningful data now that controlling AD reduces the risk of infections.

The second part of it is that I am so used to prescribing what I would call relatively toxic, relatively ineffective drugs, such as cyclosporine, methotrexate, azathioprine, and mycophenolate. Cyclosporine works great but you cannot keep a patient on it and the rest of them do not work all that well for AD. The drugs that we have now are so much safer than anything I prescribed in the past and so much more effective. I actually regularly say to patients, “If cost were not an issue, I would probably never prescribe another topical steroid.” If somebody came in with mild AD that did not immediately clear up within 2 days of using a topical steroid, I would put them on a systemic. Cost is really the only thing that is preventing me from using systemics almost universally.

Dr Chovatiya: We have a much richer tool chest when it comes to treatments for AD than we did before. For systemics, in the United States we have a choice of 2 biologic therapies, dupilumab and tralokinumab. We also have 2 oral JAK inhibitors, upadacitinib and abrocitinib, and there are more on the way. How do you connect the right patient to the right therapy in those tough cases? And then if you have an extremely tough case, how do you combine therapies?

Dr Zirwas: First, the patient always makes the decision. I am a huge believer in shared decision-making. For me, this means offering the patient 2 options at a time. Each option gets 3 bullet points, and each bullet point must be less than a sentence. For example, “Mrs Smith, I am going to give you 2 options and then you are going to tell me which one sounds better to you. The first option is a shot that you will give yourself about every 2 weeks. It is going to take about 2 weeks to 2 months to start working, does not weaken your immune system at all, and is completely safe. The second option is a pill. You will not have to give yourself any shots and it starts working in about 2 days, but it does slightly weaken your immune system.” And most patients say either, “I could not imagine giving myself a shot” or “I would never want to take something that is going to weaken my immune system if I can avoid it.”

If they choose a pill, we talk about JAKs. Because I think that upadacitinib and abrocitinib might as well be the same drug, it is more a matter of which one is going to be easier for me to get this patient on. If they pick a shot, I give them 2 more options. I tell them, “I have 2 options for you. Again, I am going to tell you about them and then I want you to tell me which sounds better. The first option is called dupilumab. It has been around for about 5 years, so we know just about everything there is to know about it. It starts working quickly but you are going to have to keep giving yourself a shot every 2 weeks indefinitely. The other option is called tralokinumab and it is almost identical to dupilumab. It works a little bit slower but once you get better, you can space out your shots and only give yourself a shot once a month. One has been around longer and works a little bit faster, but it means a shot every 2 weeks indefinitely. The other one is a little bit newer, and works a little bit slower, but you are going to be able to go down to a shot once a month after you get better.” Some patients say, “I want the one that has been around the longest and we know the most about” or “I want the one that works the fastest.” Others say,“I would hate giving myself a shot every 2 weeks. It would be better to get to once a month.”

Regarding combining therapies, I probably have a half dozen patients who I have on both a JAK inhibitor and a biologic. In my opinion, there is zero safety concern with doing that because the data show the only risk with JAK inhibitors is immunosuppression. We know the biologics we have are not immunosuppressive at all, so the only adverse event of putting together a JAK and a biologic is cost. We are now looking at $100,000 a year for eczema treatment. I will say that I have been underwhelmed. I have several patients who failed a biologic, then failed a JAK inhibitor, and then I tried putting them on both together and I have not seen it be a real additive effect. I think there is some incremental benefit, but for the people who have resistant disease, I often find that combining therapies is not that much better than what I was able to get with the individual systemic therapies. These are the patients for whom I start to go outside the box.

There are 3 main things that I do which I think are relatively unusual and I will give a patient scenario to illustrate. If the patient’s AD has a significant head and neck, upper chest, and upper back component, then I suspect it is being driven by a hypersensitivity to Malassezia yeast. I will put them on itraconazole, 100 mg twice a day for 2 months. If they get better over those 2 months, then I decrease the itraconazole to weekend-only dosing. If they do not get better over the 2 months, either yeast is not the issue or it is the issue, but we do not have a way to address it.

If the patient’s AD is more widespread and especially if it is very inflammatory, then I suspect that they are colonized with a superantigen-producing strain of staphylococcus. For this patient, I will often try a 10-day course of a relatively aggressive antibiotic regimen, such as doxycycline combined with rifampin or I will use linezolid. If it is staph, in the 10 days we will see a huge difference. Then it becomes a question of what do you do long term? I would use antibacterial washes. I might try bleach baths. And I might have to prescribe a course of antibiotics several times a year as the patient gets recolonized with the strains that are driving the AD.

If the patient does not fall under either of these categories or if those treatments do not work, I will sheepishly admit that I have many patients on chronic oral steroids. I have not seen any adverse events with the regimen I use, which is dexamethasone, 0.75 mg for 10 days on and 4 days off. Certainly, if the patient has diabetes, it will affect their blood glucose. But in a situation in which I have tried a biologic, I have tried a JAK, I have addressed microbiome issues as much as I can, and I have tried all the topicals, at that point the dexamethasone regimen works well.

I am thinking specifically about a 13-year-old patient of mine who has had severe eczema since birth. I had him in a clinical trial for a JAK inhibitor, which was not strong enough and he only got a little bit of benefit. He was on dupilumab before being in the study, which had not been effective for him. I tried combination therapy with upadacitinib and dupilumab, still nothing. Then I tried 4 mg/ kg/day of modified cyclosporine and still really nothing. At some point you must ask yourself, “Are you sure this is AD?” Because you have pretty much thrown the kitchen sink at it, and nothing has worked. But this patient has been patch tested and worked up for immunodeficiencies. He has a strong family history of AD, atopic comorbidities, and a sky high IgE level. So, it is truly resistant AD.

He is doing well on the dexamethasone regimen that I mentioned. Certainly, I talked to the family about oral steroids and the adverse reactions that could happen. But at the low dose we are using, the chances of any of those horrible things happening is incredibly small. You are more likely to die in a car accident driving to my office than you are to have a negative side effect from the steroid. I will often use that analogy whenever I talk about adverse reactions with patients. I say, “I must warn about this, and I know it sounds scary. But let me tell you, if the FDA oversaw automobiles, every day before you left your house, you would have to sign something that says, ‘I might die in a fiery crash. I might be paralyzed for the rest of my life because I got rear ended. I might get run off the road by somebody with road rage.’ And all those things could happen every time you get in your car. Those are all possibilities. It is the same with this medication. Are these things possibilities? Yes. Are they likely to happen to you? Absolutely not.”

For more from this in-depth conversation, including how AD’s effect on pathophysiology correlates with the way we treat the disease, monotherapy vs combination topical therapy, the use of probiotics, and suggestions for what to do if you are suspicious that a patient does not have AD, visit the-dermatologist.com to listen to the full interview.