Dr Jenny Murase: Insights into Utilizing Dupilumab

Your April 2020 study⁶ highlights how allergic contact dermatitis (ACD) could be missed or delayed by several months to years due to a lack of clinical suspicion. Meanwhile, individuals diagnosed with atopic dermatitis (AD) during childhood may have a heightened risk for delayed ACD diagnosis owing to the overlapping clinical manifestations of ACD and AD. How can this discovery help dermatologists identify whether a patient is suffering from AD or ACD?
In April 2020 we published a case report in the International Journal of Women's Dermatology where we discussed a case of an adult who was 50 years old and was told her whole life that she had terrible atopic dermatitis. She would go into the emergency room because she thought that she was going to die since her face was so swollen. She was getting panic attacks. She couldn't use her hands or go out in public. Her life was severely compromised by her eczema. Then we did the patch testing and identified her allergens, and she started to avoid them. She came back to my office three years later and said, "I haven't had a speck of eczema in three years. For me, all of this was allergic contact dermatitis all along and I had no idea.  I want as many people as possible to hear about my story because I don't want this to happen to anyone else ever again."

In that same year, I also published a case in the journal Dermatitis on tocopherol-induced allergic contact dermatitis in a 13-year-old child.⁷ When he came in, he was told that he had lifelong atopic dermatitis and his mother was smearing topical cortisones on his skin on a daily basis.

We identified a couple allergens—tocopherol being the main allergen—that was in this Blue Lizard sunscreen that she would put on every day as well as other skin care products. Also, he was eating cereal bars that contained tocopherol. The mother and son came back a year-and-a-half later and they said that he hadn’t had any eczema for over a year.  I honestly feel like there are a lot of patients out there that don't realize how much of their eczema is actually from an outside source and is driven by allergens or other exogenous factors.  In cases of purely endogenous inflammation, like genetic eczema, patients often experience the rash in the antecubital fossa, behind the knees and on the neck. They will say, "I feel like I'm allergic to my own sweat." They are reacting to their sweat in these very classic areas for atopic dermatitis. But when it is accentuated on the hands, face, and genitals, you need to consider allergic contact dermatitis.

This is particularly true in cases when the eczematous dermatitis was mild over the years, but in the past few months to year, has become extremely severe.  If the dermatitis is suddenly severe and involves atypical areas on the face, hands, genital area, and perianal area, you have to consider patch testing them to make sure your diagnosis is correct. Recently we presented a study on 80 patients on dupilumab to clarify the role of patch testing in patients with facial dermatitis; our research won the Oral Fischer Research Award at the American Contact Dermatitis Society meeting.⁸ At 50 percent of the time, the allergens that were identified in patients who were patch tested with residual facial dermatitis on dupilumab were not in the North American series. I feel like this is extremely common and expanded series patch testing is available only in a few specialty centers throughout the country.

I feel strongly that there is a lot of undiagnosed allergic contact that is either being suppressed by potent immunosuppressants, where the patient’s immune system is being suppressed unnecessarily, or patients are just suffering through the pain and discomfort each day without getting the necessary diagnostic testing. 

In a November 2019 study⁹ it concluded, “All patients with eye involvement while on dupilumab had a history of eye involvement prior to dupilumab, suggesting that dupilumab may encourage rather than cause ocular surface inflammation.” What further research is needed to determine how dupilumab encourages ocular surface inflammation?
There are a few different mechanisms that have been proposed in terms of why dupilumab causes dry eye.

The first is that there are oil glands on the eyelid margins that are called the Meibomian glands. They have cells in them called sebocytes that secrete oil to lubricate the eye. IL4 facilitates the lipid production in these sebocytes in the Meibomian glands. The Meibomian glands secrete this meibum on the ocular surface that coats the aqueous layer of the eye, and it prevents evaporation of the tears. It smoothes the ocular surface and stabilizes the tear film. If oil is not secreted in sufficient quantities, then you develop ocular surface disease.

Also, IL4 and IL13 have been shown to enhance goblet cell proliferation and mucin secretion which is another potential mechanism. This results in tear film instability and dry eye. In my experience, from the study I mentioned earlier for the ACDS when we examined my first 80 patients on dupilumab, we measured the number of people that had dry eye on dupilumab, it was about 19 percent of patients.

For the November 2019 study on the ocular complications on dupilumab that we published in the International Journal of Women’s Dermatology, I had every single patient seen by an ophthalmologist. We defined eye involvement as either blepharitis, which is inflammation of the eyelid margin itself; conjunctivitis, which is inflammation of the conjunctiva; and eyelid dermatitis.

Eye involvement meant they had one or all three of those diagnoses. In the first 48 patients that we did this analysis on, there were 14 patients that had had some history of eye involvement before we started the dupilumab. I didn’t have—and still don't have—any patients that developed new onset eye involvement on dupilumab where they hadn't had any history of eye involvement before dupilumab.

If a patient tells me, "I don't know if I'm going to get issues with my eyes on the dupilumab," and they don't have any eyelid dermatitis or a history of eye involvement, I relay to them that it is extremely unlikely that they are going to have issues. They may develop just a little bit of dry eye and will need to use Refresh Tears or something over-the-counter for the dry eye.

For those 14 patients that already had eye issues before starting dupilumab, when we did the patch testing on those patients, 9 out of the 14 improved, and 4 out of the 9 completely cleared after patch testing. So, when there is a patient that has eyelid dermatitis and eye involvement, it is important to consider the possibility of allergic contact in that situation as well.

The most common issues in this study were the emulsifiers and surfactants, which create the bubbles in shampoo. This makes sense because the shampoos could affect the eye. For example, we would see cases of decyl glucoside or lauryl glucoside in the Free and Clear Shampoo products or other low-allergy-risk shampoos. At 37 percent of the time the offending allergen was fragrance, and 12 percent of the time it was a preservative. Also, it was useful to test the skincare products that the patient was actually using, like the facial washes, soaps, or shampoos, because positives can be very helpful in indicating to the patient what products should be discontinued.

Is there anything else about dupilumab’s efficacy and impact on treating various disease states that you’d like to share with your colleagues?
I mentioned our study of 80 patients on dupilumab recently presented at the American Contact Dermatitis Annual Meeting,⁸ of which 61 percent had facial involvement before starting the medication. The average improvement at three months was about 80 percent. Out of those patients that we tested; 71 percent had some kind of a facial dermatitis—even on dupilumab.

Yet that means that 30 percent of the time on dupilumab the facial dermatitis resolves. It can still be effective for patients that have facial dermatitis. Meanwhile, for the 71 percent of patients who had facial dermatitis, 85 percent of the time this represented, at least in part, allergic contact dermatitis. Also, half of the time the allergens were not on the North American series. So that means that, in cases of residual facial dermatitis on dupilumab, allergic contact dermatitis is not the exception, but the rule.

So, if there's any point that I'd like to make clear to dermatologists, it is to emphasize that we are diagnosticians and therefore we are therapeuticians.

I think that there is a tendency to go straight to treatment, for example to immediately prescribe a topical corticosteroid in cases of rash. Indeed, in the past, it was thought that we really didn't have that many diagnostic tests to offer patients who come to us with chronic eczematous dermatitis.  But, with the advent of expanded series testing, we really do have diagnostic options, and they are very helpful in clarifying the diagnosis.

Basically, my mantra is to use the diagnostic tests that we have available because I believe that this allows us to not only “treat” patients by slamming their immune system with an anti-inflammatory sledgehammer, but it helps us to cure and permanently clear the patients once the diagnosis is clarified and when any potential outside source of the rash is removed.

References
6. Semaan S, Raffi J, Murase JE. Allergic contact dermatitis masquerading as atopic dermatitis. Int J Womens Dermatol. Published online April 18, 2020;6(4):329-330. doi:10.1016/j.ijwd.2020.04.005

7. Chen R, Raffi J, Murase JE. Tocopherol Allergic Dermatitis Masquerading as Lifelong Atopic Dermatitis. Dermatitis. 2020;31(1):e3-e4. doi:10.1097/DER.0000000000000543

8. Ashbaugh AG, Murase E, Raffi J, et al. Characterization of residual facial dermatitis on dupilumab (DFD): a retrospective chart review to delineate the potential role of expanded series patch testing.  Presented at: American Contact Dermatitis Society 32nd Virtual Annual Meeting; March 17-18, 2021; Virtual. Accessed 06, 2021. https://www.contactderm.org/UserFiles/AM21FinalAbstractBooklet.pdf

9. Raffi J, Suresh R, Fishman H, Botto N, Murase JE. Investigating the role of allergic contact dermatitis in residual ocular surface disease on dupilumab (ROSDD)^,. Int J Womens Dermatol. Published online November 7, 2019;5(5):308-313. doi:10.1016/j.ijwd.2019.10.001