Dr Jenny Murase: Understanding Dupilumab Treatments

Jenny Murase, MD, is associate clinical professor of dermatology at the University of California, San Francisco, and director of Medical Consultative Dermatology, Palo Alto Medical Foundation in Mountain View, CA. A founding member of the American Academy of Dermatology Women’s Health Resource Group and co-editor-in-chief of the International Journal of Women’s Dermatology, she has authored or co-authored more than 147 book chapters and peer-reviewed articles in addition to delivering more than 210 regional, national, and international presentations on topics in the field of medical dermatology. Dr Murase shares her insights and experiences working with dupilumab in various studies she has authored.

 

Oftentimes patients with acquired brachioradial pruritus will have issues with their cervical spine. They might have had whiplash or some injury to their neck. The skin does not have any primary lesions. There may be secondary lesions from someone scratching, but this is not a primary skin issue.

When we are thinking about how to treat a chronic itch in the skin, we have to consider three elements: whether there is an inflammatory target, whether there is an issue with the skin itself such as the skin barrier, and whether or not there is an issue with the nerves sensing the itch. 

Dermatologists are actually very capable of treating the inflammatory target, because one of the very first things dermatologists do is prescribe a topical cortisone in order to decrease the inflammation in the skin. They will also commonly attempt to treat the skin barrier with emolliation. When those fail, they may attempt to use neuropathic agents to address the itch.

In this particular case that we published, dupilumab was actually quite effective. Dupilumab has been shown in some studies to be effective in treating pruritus alone, with chronic pruritus defined as lasting greater than 6 weeks. There was a study in 2019 in the journal Medicines by Lisa Zhai and colleagues² in Philadelphia. They examined 20 patients on dupilumab for chronic pruritus and 12 had complete resolution of itch. That was one of the ways that we came up with the idea to use the dupilumab. Sensory neurons are influenced by IL-4, as this has been shown in both mice and humans in the dorsal root ganglion of the spine

Type 2 cytokines like IL-4, IL-13, and IL-31 are expressed, and they activate the sensory dorsal root ganglion nerve roots. If you ablate IL-4 receptors in mice or rodents, for example, you will eradicate chronic itch.

We already know that there is a mechanism to explain why the type 2 cytokines could affect each nerve specifically. It was with that data, additionally with its utilization in cases of pruritus alone without any visible skin inflammation, that we decided to try it. It did work and it was effective for this particular patient.

Referencing your October 2018 study,³ what mechanisms did you identify that explain why dupilumab was effective when used with patch testing? Is this mechanism similar or different from dupilumab’s efficacy when used on brachioradial pruritus (BRP)?
There were three patients that we published on, my first three patients, where they had residual face, neck, or eyelid dermatitis after I started them on dupilumab. I patch tested them and then they improved after they removed the allergens they had inadvertently been exposed to. So, they actually completely cleared as a result of the patch testing.

This was early on in this process of prescribing dupilumab. When I was initially using the medication in patients, I found that my success rate in getting patients clear was extremely high compared to my colleagues using the medication. The dupilumab was essentially a magic bullet for a patient with chronic atopic dermatitis (AD). If the patient had AD, and it was pure AD, it was incredibly effective.

Over time I started to realize that my colleagues were sending me cases where the patients had failed the dupilumab with AD, and I thought, "Wow, it's funny because I've never seen that." In fact, I still have not seen a case of classic AD fail dupilumab, and I have used the medication in over 220 patients. I began to realize that it might be the fact that I was doing expanded series patch testing before I would put them on dupilumab that was resulting in my high clearance rate on the medication. I had very thoroughly looked for allergens in their environment and removed the allergic contact dermatitis to whatever extent that we were able to with the current expanded series patch testing technology that we had available. With this allergen avoidance we had removed the exogenous (outside) triggers as much as possible and we were left with the endogenous (inside) inflammation. At that point I would put them on dupilumab, and they would do very well. 

When I was chair of the Business Policy Committee of the American Contact Dermatitis Society, we created a publication in 2018 for Dermatitis titled "A Review of the Medical Necessity of Comprehensive Patch Testing."⁴ When we analyzed the literature, we found that the True Test would detect about a third of allergens patients were allergic to.

The slightly larger North American tray would detect up to two-thirds of allergen, but you really needed the expanded series patch testing to get to as close to 100% allergen detection as possible. The expanded series included trays from Allergeaze and Dormer such as the Emulsifier/External agents, Fragrance, Corticosteroid, and Cosmetics trays. In fact, patients with AD are more likely to test positive to “hypoallergenic” allergens and topical medications since that is what they have been exposed to over the years in the low allergy risk products they use and the medications that they are prescribed. So, these expanded series trays become that much more important. When partial patch testing was being performed by my colleagues, I noticed a trend that the patient would be reported as a “dupilumab failure” when it was the fact that the allergens had not yet been properly identified. If the patient had received the True Test or North American Series, allergens would be missed. When I examined my first 80 patients and looked at the people who benefited from patch testing, we found that, 50% of the time, the allergens they tested positive to were not on the North American tray, which is considered the gold standard.

Patients with AD are more likely to become allergic to things that are considered hypoallergenic. This is something that was demonstrated in a paper developed by Dr Jennifer Chen and colleagues from Dermatitis in 2016 titled "A Pragmatic Approach to Patch Testing in Atopic Dermatitis Patients."⁵ It talks about how the emulsifiers, the surfactants, the preservatives, and the topical medication allergies are much higher in patients with AD just because that is what they have been exposed to over the years.

Patients with AD also have a predisposition to develop the allergic contact dermatitis because their skin barrier is compromised. It is easier for the chemicals to penetrate and then, therefore, easier for the patient to become sensitized to these allergens. Also, the chronic colonization with Staphylococcus aureus bacteria makes it easier for the patients to be sensitized to these allergens.     

In the past, before we had dupilumab, patients were labeled as having eczematous dermatitis or adult AD, and physicians would use prednisone, cyclosporine, azathioprine, or mycophenolate mofetil. All of these completely suppress both the cell-mediated immunity and the allergic arm of the immune system; whereas dupilumab was the first medication that only suppressed the T_H2 arm—the allergic arm.

So, when we would use these “sledgehammers” in the past that just shut down both aspects of the immune system like prednisone and cyclosporine, the patient would get better simply because all inflammation had been suppressed. But when we started to suppress only the T_H2 arm of the immune system, the AD would clear but the allergic contact or systemic contact dermatitis would still be present. The dermatitis would remain in areas that are common for allergic contact dermatitis, the top three of which are the face, hands, and genitals.

There would be residual dermatitis in these three key areas, and that would be the hint that there actually is allergic contact superimposed in the patient with genetic AD. When we looked at the first 80 patients, 85% had concomitant allergic contact dermatitis when they had residual facial dermatitis on dupilumab.

Additionally, this study stated that comprehensive patch testing before inducing dupilumab “is recommended because it further delineates potential allergens, decreasing the chance of falsely identifying treatment as having failed.” What can you tell us about how dermatologists misuse dupilumab and what can they do to better utilize it?
Again, I've never seen a patient with pure classic genetic AD not respond, but I've also used the medication in other conditions as well. There are a lot of different diagnostic tests that you have to consider if a patient is failing dupilumab. If they are failing dupilumab, you probably don't have the right diagnosis of genetic AD. What else could it be?

Number one would be infection, like scabies or Staphylococcus aureus superinfection, for example. I have been referred patients with “AD” who have failed dupilumab and they ultimately had scabies. Scabies can look exactly like a chronic eczema dermatitis that's not responding. The highest yield areas include examining between the fingers, the sides of the ankles, on the penis in men, and on the areola in women. Those are all high sites of likelihood, in terms of getting a potassium hydroxide (KOH) skin scraping. You have to look in those areas in particular to make sure that you haven't missed that diagnosis.

Also, it is important to perform a swab for bacterial infection to make sure that staphylococcus is not driving the dermatitis. Usually, I think dermatologists are pretty good at identifying eczema herpeticum because of the classic punched-out ulcerations that form. Then, of course, tinea as well, but that tends to be more of an annular lesion. This can absolutely occur in patients using topical chronic corticosteroids on their skin, so when annular lesions are present, dermatologists often know to do a KOH scraping to look for hyphae.

The next kind of “dupilumab failure” that I see would be more of an eczematous psoriasis or parapsoriasis. Parapsoriasis is when you get these digitate lesions on the trunk. Then you can get circular ovoid lesions as well. With a diagnosis of parapsoriasis there is a slightly increased risk of developing mycosis fungoides, which is a kind of lymphoma of the skin. That is why we examine patients with clinical lesions of parapsoriasis on the sides of their trunk, the so-called “digitate plaques,” carefully. We perform lymph node examinations and, occasionally, complete blood counts to monitor patients. I've certainly seen cases of mycosis fungoides or other forms of lymphoma that were misdiagnosed as chronic inflammatory eczematous dermatitis, so we have to keep the possibility of malignancy in mind.

There have also been cases of dermatitis herpetiformis which failed dupilumab and is a kind of gluten-related hypersensitivity that presents as a rash in the skin. This is diagnosed through a biopsy for direct immunofluorescence instead of our normal skin hematoxylin-eosin (H&E) biopsies. Also, it is diagnosed by performing a celiac panel on the blood. Dermatitis herpetiformis classically presents as more of an extensor surface eruption of itchy red papules.

Once that diagnosis is made, either through the direct immunofluorescence or the celiac disease blood panel, completely different therapy is necessary for the patient. We prescribe oral dapsone and have the patient avoid oral gluten in their diet. It's really important to be able to know how to catch that diagnosis because it's just treated so differently than the other conditions.

There is another diagnosis I have seen in “dupliumab failure” patients called urticarial bullous pemphigoid, which is a disease that tends to occur more in the 70s and 80s; although, I have seen it in 50s, 40s, and even 30s. However, it tends to be a disease of the elderly. This is an autoimmune disease where antibodies attack antigens between the dermis and epidermis such as bullous pemphigoid 180 or 230.  This can be diagnosed through the direct immunofluorescence test as well, just like the dermatitis herpetiformis. It can also be detected through doing enzyme-linked immunosorbent assays (ELISA) when you look for BP180 or BP230 in the blood.

Another common dupilumab failure I see is cutaneous lupus, dermatomyositis, or other undifferentiated connective tissue disease. I perform an antineuclear antibody (ANA) blood test, or a lupus panel depending on the situation, and also perform a biopsy for both H&E and direct immunofluorescence. Interestingly, the cases I have seen so far that ultimately had dermatomyositis or cutaneous lupus had joint pain on dupilumab, as well as a worsening of their dermatitis, but, to my knowledge, this has not yet been reported in the literature. Also, it is not uncommon for patients with AD to also have residual polymorphous light eruption. So, even though their AD is controlled with the dupilumab, they can still have eruptions of polymorphous light eruption. Therefore, I screen for this as well. They will tend to complain of rashes in intermittently exposed areas of the skin such as the face, dorsal hands, and forearms. 

Of course, to rule out lymphoma of leukemia, I will order a leukemia/lymphoma flow cytometry blood panel and a complete blood count. I’ll also do a careful lymph node exam and have a low threshold to repeat biopsies if I see cigarette paper wrinkling on the skin or follicular accentuation of the dermatitis in doubly-covered areas such as the buttocks and trunk.

But the highest yield diagnostic test for patients who have residual dermatitis on dupilumab is definitely the expanded series patch testing. It is important for dermatologists to not just offer a North American or a True test, but to refer them to a provider who can offer the expanded series tray to make sure that the patient receives very comprehensive patch testing if there is residual dermatitis on their face, their hands, or their genitals on dupilumab.

Just to review, if a patient is not getting a marked improvement on dupilumab with AD at the 2- to 3-month mark, it is important to consider diagnostic testing. This includes, depending on the clinical context, patch testing, a biopsy for H&E, biopsy for direct immunofluorescence, ELISA blood test, celiac panel, ANA or lupus panel, bacterial or viral cultures, scrapings for both scabies and/or fungus depending on what lesions look like clinically, and leukemia/lymphoma blood panels.

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References
1. Abel MK, Ashbaugh AG, Stone HF, Murase JE. The use of dupilumab for the treatment of recalcitrant brachioradial pruritus. JAAD Case Rep. Published online February 17, 2021;10:69-71. doi:10.1016/j.jdcr.2021.02.005

2. Zhai LL, Savage KT, Qiu CC, Jin A, Valdes-Rodriguez R, Mollanazar NK. Chronic Pruritus Responding to Dupilumab-A Case Series. Medicines (Basel). Published online June 29, 2019;6(3):72. doi:10.3390/medicines6030072

3. Suresh R, Murase JE. The role of expanded series patch testing in identifying causality of residual facial dermatitis following initiation of dupilumab therapy. JAAD Case Rep. Published online October 3, 2018;4(9):899-904. doi:10.1016/j.jdcr.2018.08.027

4. Zhu TH, Suresh R, Warshaw E, et al. The Medical Necessity of Comprehensive Patch Testing. Dermatitis. 2018;29(3):107-111. doi:10.1097/DER.0000000000000362

5. Chen JK, Jacob SE, Nedorost ST, et al. A Pragmatic Approach to Patch Testing Atopic Dermatitis Patients: Clinical Recommendations Based on Expert Consensus Opinion. Dermatitis. 2016;27(4):186-192. doi:10.1097/DER.0000000000000208